The 19th St. Gallen international breast cancer conference ‘primary therapy of patients with early breast cancer. Evidence, controversies, consensus’: key moments and breakthroughs

Consuelo Morigi

Division of Breast Surgery, IRCCS European Institute of Oncology, 20141 Milan, Italy

Abstract

The 19th St. Gallen International Breast Cancer Conference took place at the Austria Centre in Vienna from March 12th to 15th, 2025. The event achieved remarkable success, drawing over 3,100 participants from all over the world. This accomplishment is attributable to the high calibre of scientific lectures presented by leading global experts in breast cancer (BC) treatment, the opportunity for the audience to interact with panellists through questions, the interesting and varied scope of submitted posters, the debates that punctuated the many sessions, and notably, the renowned St. Gallen Consensus Session. This year's Opening Ceremony held particular significance. In commemoration of the Swiss physician and oncologist Hansjoerg Senn, who passed away in 2023, the Hansjoerg Senn Memorial Lecture was instituted to honour his profound contributions to the treatment and care of patients, particularly those affected by BC. The Memorial Lecture serves as a platform to recognise and celebrate individuals who have significantly advanced BC research. The recipient is presented with the St. Gallen Breast Cancer Award and invited to deliver an address at the opening ceremony of the St. Gallen International Breast Cancer Conference. This year, this prestigious award was presented to Prof. Armando E. Giuliano, who delivered an insightful lecture entitled ‘My Personal Experience: Changing Surgery for BC.’ In it, drawing from his impressive surgical career during which he changed the standard of care—exemplified by the sentinel lymph node procedure and the Z0011 study—he spoke about how change, though difficult, is both necessary and inevitable, emphasising that no one is too young or too old to change.

Keywords: 19th St Gallen consensus conference 2025, SGBCC 2025, early breast cancer, neoadjuvant chemotherapy, adjuvant therapies, surgery, trials, artificial intelligence, consensus

Correspondence to: Consuelo Morigi
Email: consuelo.morigi@ieo.it

Published: 13/02/2026
Received: 04/04/2025

Publication costs for this article were supported by ecancer (UK Charity number 1176307).

Copyright: © the authors; licensee ecancermedicalscience. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Ouverture: glancing into the future—moving up innovative agents from metastatic breast cancer (BC) to early BC

G. Curigliano began his presentation by emphasising that the primary goal in the early-stage BC setting is to improve overall survival (OS). Can we improve OS? Looking at the data, the answer is yes. This is due to improved diagnosis and enhanced local and systemic treatment [1]. Regarding systemic treatment, it is interesting to note that for some drugs, such as pembrolizumab, the timeframe between approval in the metastatic setting and the early setting was very short (3 years), indicating that data from the metastatic setting can inform trial design in the early setting, potentially translating into improved OS. Validated surrogate endpoints are essential to accelerate drug development and regulatory approval. A surrogate endpoint should be associated with the true endpoint at both the patient level (regardless of the treatment arm) and the trial level (considering the real treatment effect). The association between these two is measured by the coefficient of determination R². To establish a good correlation between the surrogate endpoint and OS, R² must be ≥0.7 [2, 3]. While awaiting OS data, the mechanism of action of novel agents and the selection of appropriate intermediate endpoints can help inform patient outcomes and guide treatment decisions in clinical practice.

F. Andre spoke about novel endocrine agents. There are numerous ongoing trials on the use of adjuvant oral selective estrogen receptor degraders (SERDs) in early BC that will help clarify various aspects (e.g., CAMBRIA-1, EMBER-4 and lidERA). To ensure the proper use of SERDs, within the framework of personalised patient therapy, it will be crucial to define the risk of relapse, utilising new tools such as artificial intelligence (AI) and circulating tumour DNA (ctDNA). Moreover, it will be important to also consider patient preferences and their quality of life (QoL). It is well known that endocrine therapy (ET) is associated with a clinically relevant decrease in QoL [4]. We need to determine if SERDs improve QoL compared to aromatase inhibitors (AIs). In BC, it should be noted that non-adherence to adjuvant ET constitutes a major obstacle to optimal outcomes; the primary cause of this non-adherence is toxicity [5]. Regarding ESR1 mutations (ESR1m), they are rarely acquired during adjuvant therapy with AIs, but frequently during AIs therapy in the metastatic setting [6]. In the latter case, SERDs are effective in patients with ESR1m [7] and have similar efficacy compared to fulvestrant in patients with ESR1 wild type after the onset of resistance to ET in the metastatic setting [8]. It will be necessary to understand if SERDs are capable of preventing resistance mechanisms not related to ESR1m. SERDs also appear to be effective in ET-naive patients with early BC, with a statistically significant reduction in KI-67 when compared to that caused by AIs [9]. It will be interesting to analyse whether SERDs, like AIs, have a ‘prognostic’ value based on the response to preoperative ET [10].

J Cortes focused on new anti-HER2 approaches. The largest improvements in HER2+ BC have been achieved in the metastatic setting, thanks not only to the introduction of Trastuzumab [11] but also to several studies demonstrating progression-free survival (PFS) benefits: CLEOPATRA with the addition of pertuzumab [12], EMILIA with trastuzumab emtansine (T-DM1) compared to lapatinib plus capecitabine [13], HER2CLIMB with the addition of tucatinib to trastuzumab and capecitabine [14] and Destiny-Breast 03 with trastuzumab deruxtecan (T-DXd) compared to T-DM1 [15]. An important aspect to consider when moving from trials in the metastatic setting to early BC is patient selection based on clinical risk. Furthermore, patient selection based on response to therapy, such as pathological complete response (pCR), is crucial for tailoring therapies (e.g., COMPASS trial and Destiny-Breast 05). Randomised clinical trials have contributed enormously to advances in patient care. Nevertheless, they have several shortcomings, including the need for a large sample size and long study duration, the lack of power to evaluate efficacy overall or in important subgroups and cost. To address these limitations, adaptive trial designs appear to be the best way to move forward towards de-escalation treatment-based strategies.

S. Tolaney discussed antibody-drug conjugates (ADCs): an innovative family of agents assembled through linking cytotoxic drugs (payloads) covalently to monoclonal antibodies to be delivered to tumour tissue that expresses their particular antigen, with the theoretical advantage of an augmented therapeutic index. To date, ADCs approved in HER2+ metastatic BC are: Sacituzumab govitecan, Datopotamab deruxtecan, T-DXd and Sacituzumab tirumotecan. None of these drugs is currently approved for early BC, but with the intention of expanding their indications, several ongoing trials are underway, such as the NeoSTAR trial, TROPION-Breast04 and I-SPY 2 for use in the neoadjuvant setting, TROPION-Breast03 and SASCIA (NCT04595565) trials for patients who do not achieve pCR after neoadjuvant chemotherapy (NACT) and ASPRIA (NCT04434040) and SURVIVE HERoes (NCT06643585) trials, which rely on the presence of ctDNA post-adjuvant therapy to select patients for ADC use. In the future, it will be necessary to better understand several aspects, including whether ADCs can be sufficient to replace chemotherapy (CT), whether it is better to administer them in sequential or combination regimens, and to analyse their toxicity.

Session I: Liquid biopsy

N. Turner presented the technology for detecting ctDNA and its important role in trials and clinical practice, emphasising the necessity of using appropriate assays. Assay types for early-stage cancer ctDNA are essentially of two kinds: tumour-informed assays, which require tumour tissue to track patient-specific mutations, and tumour-agnostic assays, which target predefined signatures allowing broader applicability but with relatively lower sensitivity. Regarding tumour-informed assays, they can offer high precision in minimal residual disease (MRD) detection. Studies suggest that detection of ctDNA during follow-up is associated with a high risk of future relapse of early-stage BC, with a good temporal window over clinical relapse [16]. Regarding agnostic assays, the test panel is the same for all patients; thus, even using an advanced BC genotyping assay, if ctDNA is detected, it certainly has prognostic value but with lower discriminatory potential than tumour-informed assays. As a result, sensitivity will be lower than with tumour-informed tests [17]. Conversely, ctDNA detection with genotyping assays or circulating tumour cell (CTC) analysis shows a lack of specificity. Regarding CTCs, finding high levels of CTCs is prognostic, but high levels of CTCs are rare; low levels are more common and have limited prognostic significance [18]. Genotyping assays are not specific for the presence of clonal haematopoiesis of indeterminate potential (CHIP), which is the acquisition of somatic mutations leading to clonal expansion of hematopoietic stem cells and is a common incidental finding in ctDNA, especially in older individuals. This has the potential to seriously undermine tumour-agnostic ctDNA detection; in fact, in large sequencing panels, >50% of mutations are from CHIP instead of cancer [19]. The clinical significance of CHIP warrants further study.

F.C. Bidard analysed the role of ctDNA in screening/diagnosis of early BC. In this setting, the difficulties include: robust performance of imaging, ease of diagnostic biopsies and the fact that non-invasive and small lesions shed very few circulating biomarkers. PATHFINDER is a pilot study investigating the feasibility of Multicancer Early Detection (MCED) blood tests, which can identify a cancer signal from circulating cell-free DNA. His experience lays the foundation for larger-scale studies to evaluate the clinical effectiveness of MCED testing as a cancer screening strategy [20]. ctDNA-based detection of MRD presents a strategy to identify patients at high risk of relapse. First-generation tests were only marginally prognostic; conversely, the whole-genome sequencing-based assay resulted in improved ctDNA detection at diagnosis and long lead times (median lead time 15 months) between MRD detection and relapse. These findings merit additional investigation through further prospective studies that can establish the clinical impact of this method throughout the diagnostic and therapeutic pathway [21]. There are several ongoing trials to explore the clinical utility of ctDNA (e.g., CUPCAKE, PERSEVERE, KAN-HER2, TREAT-ctDNA, DARE, TRAK-ER and SURVIVE-HERoes trial).

W. Janni continued to describe the topic of including ctDNA in clinical trials. In advanced BC, for example, the use of ctDNA can represent a predictive biomarker to guide treatment. The Serena 6 trial aims to detect ESR1m in ctDNA. ESR1m is a frequent cause of acquired resistance to AIs plus cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i). The purpose of this trial is to evaluate the efficacy and safety of switching from an AIs to camizestrant (SERD), while maintaining the same CDK4/6i, upon detection of ESR1m in ctDNA before clinical disease progression. The primary endpoint in this case is PFS. In early BC, surrogate markers of OS are represented by invasive disease-free survival (iDFS) and, after NACT, pCR. However, even if the achievement of a pCR after NACT identifies patients with a low risk of recurrence, some of them still relapse. Conversely, not all patients with residual tumour after NACT have a recurrence of disease. This highlights the need for additional biomarkers for a more accurate stratification of the risk of recurrence, and the role of ctDNA appears promising [22].

Session II: HER2+ early BC—mission accomplished?

M. Piccart reflected on the role of trastuzumab on the 20th anniversary of its clinical use, noting that after all these years, it still remains the ‘queen’ in terms of long-term efficacy, safety and global accessibility. Many important studies have been conducted on this monoclonal antibody, which have shown that 1 year of adjuvant trastuzumab for HER2+ BC significantly improves long-term disease-free survival (DFS) (HERA trial) [11, 23], that concomitant CT + trastuzumab is better than a sequential regimen (N9831 trial) [24-25] and that adjuvant trastuzumab with a non-anthracycline-based regimen is very effective and also less cardiotoxic (BCIRG006 trial) [26]. Several studies have been conducted to evaluate different durations of trastuzumab. For example, the HERA trial clarified that 2 years had no additional benefit, the PERSEPHONE trial demonstrated that 6 months of trastuzumab treatment is non-inferior to 12 months of treatment in patients with HER2+ early BC, with less cardiotoxicity and fewer severe adverse events [27]. Conversely, the PHARE trial did not show the non-inferiority of 6 months versus 12 months of adjuvant trastuzumab [28], nor the HELLENIC trial, which showed a higher DFS in favour of the 12-month standard treatment [29]: at present, the standard of care is still 12 months of treatment. In the near future, we will likely benefit from the use of the HER2DX test to personalise the treatment of patients with HER2-positive BC.

C. Denkert focused her presentation on HER2 testing after 20 years. American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) established consistent guidelines for HER2 testing, which are essentially conservative. In the 2023 update, HER2-low and HER2-ultralow were not included as interpretive categories. Over the years, the concordance of HER2 testing among pathologists has increased, thanks to, for example, the use of two independent methods, ASCO/CAP guidelines and standardised EQA programs. This concordance has now reached more than 90%, but there is room for further improvement in the HER2-low category. Furthermore, the discordance rate is higher in ER+ BC than in the ER-subgroup. This could be explained by the RNA results, which show a bimodal distribution of HER2 mRNA in ER- BC and a continuous distribution in ER+ BC. Within the continuous distribution, it is much more difficult to determine a cutpoint [30]. This is consistent with the fact that within the HER2-low category, 60% of patients are ER+. What is the minimum level of HER2 that is necessary for Trastuzumab response? IHC 3+ or FISH amplified [31]. Regarding T-DXd response, in the metastatic setting, it has shown consistent clinical benefit not only in IHC 3+ but also in HER2-low [32] and HER2-ultralow [33]. PIK3CA mutations can be found in about 20%–30% of HER2+ BC and indicate a lower response to CT and anti-HER2 therapy, especially in ER+/HER2+ BC. The GeparPiPPa trial investigates, in the neoadjuvant setting, the clinical utility of inavolisib, an oral PI3Kα inhibitor, in addition to ET and trastuzumab/pertuzumab in early ER+/HER2+ and PIK3CA mutant BC. Recently, data on molecular subtypes of HER2 with prognostic value have been published [34]. All this information will help to better tailor therapies for HER2+ BC in the near future. N. Harbeck's presentation discussed risk-adapted neoadjuvant and adjuvant therapy for HER2+ BC. Specifically, for T1, N0 tumours, upfront surgery is reliable. After surgery, 12 weeks of paclitaxel + trastuzumab followed by 40 weeks to complete a full 1 year of trastuzumab is a reasonable treatment (APT trial) [35]. For tumours > pT1, pN0, adjuvant polychemotherapy plus 1 year of trastuzumab in N0 or dual HER2-blockade (trastuzumab + pertuzumab) in N+ is indicated. In fact, with an 8-year follow-up, the N+ subgroup maintained a significant iDFS benefit favouring dual blockade, without significantly improving OS; no benefit was seen in the N0 subgroup (APHINITY trial) [36, 37]. For tumours > 2 cm or N+, NACT with trastuzumab and pertuzumab is recommended. In the case of pCR, which has prognostic value [38], omission of further CT did not affect iDFS; these patients should continue anti-HER2 therapy for a total duration of 1 year [39]. There are de-escalation trials based on early response, such as PHERGAIN, which is a PET-based, pCR-adapted strategy capable of identifying patients with HER2+ BC who could safely omit CT [40] or TRAIN-3, in which a radiological complete response evaluated via magnetic resonance imaging (MRI) can limit the duration of NACT [41].

K. Jhaveri discussed how to manage residual disease after NACT in HER2+ BC. The current standard of care for patients with HER2+ BC and no-pCR after NACT is replacing trastuzumab with T-DM1 for 14 cycles (KATHERINE trial), which, after a median follow-up of 8.4 years, demonstrated a significant benefit in iDFS and OS [42, 43]. Data from the DESTINY-Breast05 trial in early HER2+ BC are awaited to understand if it is possible to replace T-DM1 with T-DXd, which has shown benefits in the metastatic setting. Another option that might offer a potential opportunity in patients with HER2+ BC who did not achieve pCR after NACT is to add to trastuzumab another agent, such as tyrosine kinase inhibitors like Neratinib for 1 year (ExteNET trial), which showed a significant increase in iDFS and OS in ER+/HER2+ patients [44]. However, we do not have data in patients who have previously received pertuzumab and/or T-DM1, and it is necessary to evaluate the benefit-to-toxicity ratio, as Neratinib is associated with high rates of moderate/severe diarrhoea [46]. In the COMPASSHER2 trial, the addition of Tucatinib to T-DM1 is being tested, and in the ASTEFANIA trial, the addition of Atezolizumab to T-DM1. The binary division between pCR and non-pCR is insufficient; in fact, it is more significant to consider the residual cancer burden (RCB), which has been shown to correlate better with prognosis [45].

Session III: Minimising the burden of cancer treatments: more tailoring for early BC

C. Coles spoke about the potential safety of omitting radiotherapy (RT) or ET. For patients with low-risk, early-stage BC, offering standard adjuvant treatment with RT + ET ensures excellent oncological outcomes, but it may constitute overtreatment. Scientific data indicate that ER or ET are likely viable single-modality treatments and that RT has a more favourable tolerability profile, but definitive conclusions will depend on long-term disease control outcomes [47, 48, 49]. Regarding surgical treatment, studies are also investigating the feasibility of avoiding surgery, using instead minimally invasive treatments, such as vacuum-assisted excision [50], radiofrequency ablation [51] or cryoablation [52]. Validated biomarkers can help identify patients at very low risk of recurrence and better plan a potential de-escalation of treatments.

H. Wildiers clarified the use of CT in older patients. It is certain that elderly patients do not require the same treatments as the younger population for various reasons, such as lower life expectancy, greater potential for toxicity and more pre-existing comorbidities. However, it is also true that there is huge heterogeneity in health status among these patients. There are tools to predict severe toxicity events that can aid in the decision process with older patients, such as ARG-BC, AGE-GAP and PORTRET. The data in the literature tell us that CT should not be denied to older BC patients solely because of their advanced age, but in general, only very fit older patients can be treated with sequential regimens used in younger patients. Instead, docetaxel + cyclophosphamide (TC) is a feasible regimen for the majority of older patients [53, 54]. For HER2+ early BC, Trastuzumab can be combined with the TC regimen, but Granulocyte colony-stimulating factor (G-CSF) is recommended to avoid febrile neutropenia. In frail patients, weekly paclitaxel can be considered as a regimen to combine with trastuzumab. For unfit selected patients, as highlighted by the RESPECT trial, BC adjuvant trastuzumab monotherapy can be considered [55]. In case of toxicity, it is better to evaluate a shorter duration of trastuzumab [56]. Data did not find a statistically significant increase in OS with the addition of CT to ET after surgery for high-risk ER+/HER2-BC [57]. The results of the APPALACHES trial will clarify whether these patients can benefit from the addition of CDK4/6i (Palbociclib) to ET as an alternative to CT. In the search for a balance between overtreatment versus undertreatment, in a way, every oncologist should become a geriatric oncologist, evaluating a personalised treatment for each individual patient, also considering the patient's preferences.

M. Oliveira underlined the need to understand the right balance between the pros and cons of the many new approaches we have available for BC care. For example, starting from the consideration that clinical trials often involve a selected patient population in a controlled environment, which may clash with the real-world environment, sometimes characterised by limited resources and patient populations not included in clinical trials. Moreover, beyond the efficacy endpoints of a treatment, it is necessary to consider the patients' QoL, potential toxicity, drug costs and, in general, the global burden on the healthcare system. An aid in these evaluations can come from the use of, for example, the European Society for Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale. An important aspect in the era of precision medicine is certainly the introduction of biomarkers, which can allow better patient stratification in clinical trials, identification of response and toxicity to new drugs and definition of predictive recurrence risks on which to tailor therapeutic strategies.

Session IV: Optimising locoregional treatments of the breasts

Why should we prevent mastectomies? J. De Boniface, in his presentation, provided a compelling answer to this question. Mastectomy should be avoided when breast-conserving surgery (BCS) is a viable option. This is due to several critical factors. First, mastectomy does not consistently guarantee oncologic safety. In fact, 94% of mastectomy specimens, particularly in so-called conservative mastectomies, may contain residual glandular tissue within the skin flaps. Consequently, this procedure should be undertaken by surgeons with a higher level of expertise. Second, there is a lack of survival benefit; there are indeed no randomised controlled trial data that demonstrate a significantly improved survival advantage with mastectomy compared to BCS. We should additionally consider that mastectomy is associated with a potentially more elevated risk of complications, and some studies suggest that these complications may correlate with poorer survival outcomes [58]. Mastectomy does not always result in improved patient-reported outcomes regarding satisfaction with breasts, even when combined with reconstruction [59, 60]. We must also consider that mastectomy is often related to reconstructive challenges and furthermore, it often necessitates additional symmetrisation procedures, resulting in further scarring. Therefore, the answer to the initial question appears clear: we must strive to prevent unnecessary mastectomies and offer oncoplastic BCS as an alternative to mastectomy in all women in whom it is technically feasible, while also actively involving the patient in the decision-making process.

D. Kauer-Dorner discussed tailoring RT. Historically, whole-breast irradiation with traditional fractionation, consisted of 50 Gy in 25 fractions over 5 weeks, it was the standard of care for several years. Partial breast irradiation (PBI), as compared with WBI, is associated with less acute toxicity but with no significant difference in late toxicity [61]. PBI is an evidence-based treatment option to reduce the burden of RT in selected low-risk patients aged 50 and above, with unifocal, unicentric tumours <3 cm, pN0 and resection margins of at least 2 mm [62].

Moderate hypofractionation (15 × 2.67 Gy) in 3 weeks should be the standard treatment for all indications of modern postoperative RT in BC. In fact, results from many trials (e.g., START-B, FABREC, DBCG HYPO, IMPORT-HIGH and HypoG-01) have shown no differential effect of fractionation schedule for tumour control by age, type of primary surgery, eventual reconstruction, axillary node status, use of adjuvant CT or association of boost RT. Ultra-hypofractionation (5 × 5.2 Gy) in 1 week is becoming a new opportunity, especially for elderly patients (FAST-FORWARD). An extension of indications will likely come from the results of ongoing trials (e.g., FAST-FORWARD nodal and Hyport-Adjuvant). RT is important for local control even in ductal carcinoma in situ (DCIS), but, in this case, probably the current challenge is to identify the risk of recurrence in individual patients to potentially omit RT. In this context, prospective validation of novel biomarker assays in DCIS is needed (Oncotype DX DCIS Score and DCISionRT Decision Score). The personalisation of local therapy is obviously important also in invasive BC, and there are many trials that, using gene signatures (e.g., Oncotype DX and Prosigna PAM50), are evaluating the omission or addition of RT (e.g., IDEA and PRECISION). Therefore, omitting RT in low-risk patients should be part of a shared decision-making process with our patients.

V. Galimberti presented on breast surgery after NACT. The goals of NACT for surgery are: de-escalation of breast surgery, by increasing BCS and reducing the rate of axillary lymph node dissection (ALND). Regarding margins, the optimum is to remove all known residual rather than the original tumour lesion with a ‘no ink on tumour’ resection, regardless of the presence of unifocal or multifocal disease [63, 64, 65]. Residual microcalcifications, however, may present a clinical and surgical challenge. Complete excision of tumour bed calcifications remains standard practice and a potential limitation to NACT use for downstaging patients to be suitable for BCS. In fact, although calcifications seen on post-NACT mammography might not be associated with persistent disease, the loss of MRI enhancement and changes in calcifications do not predict the absence of residual tumour with sufficient accuracy [66, 67]. In the near future, it is desirable to be able to avoid surgery in patients with pCR after NACT. What are the safest criteria for selecting patients in clinical trials to avoid breast surgery after NACT? The rate of pCR is higher in triple-negative breast cancer (TNBC) and HER2+ disease, and pCR after NACT is associated with significantly better DFS and OS [68]. Conventional imaging lacks sufficient sensitivity/specificity to predict pCR, while MRI-radiomics has emerged as a potential method for predicting the response to NACT in BC patients, showing promising outcomes [69]. The use of image-guided vacuum-assisted biopsy to obtain at least six representative samples of residual breast imaging allows reliable prediction of residual disease [70]. There are many ongoing trials on the omission of surgery after NACT (e.g., BETTY-CRASY, OPTIMISTC, JCOG1806:AMATERAS-BC and ELPIS), but in the meantime, the first results obtained in the EXCEPTIONAL RESPONDERS trial highlight that, in highly selected patients, omission of surgery after NACT was associated with an ipsilateral breast tumour recurrence-free survival of 100% [71].

C. Solbach discussed breast reconstruction, which should be an individualised decision for each patient, seeking to understand the expectations for breast reconstruction and in agreement with the healthcare team, also considering the treatments that the patient will have to undergo, in particular RT. Comprehensive information and support throughout the decision-making process is essential to ensure that patients make informed decisions that reflect their personal values and expectations. AI can further aid in this collaborative decision between physician and patient (CINDERELLA trial).

Session V: Nuances in adjuvant therapy for ER+ BC

D. Cameron gave an overview of the standard and new drugs we have available for the treatment of ER+ BC BC. Today, we have many drugs available, such as Tamoxifen (TAM), AIs, luteinizing hormone-releasing hormone analogues and CDK4/6 inhibitors. Regarding these latter drugs, which were introduced more recently, when offering this treatment to patients, it is necessary to inform them that, at the moment, this treatment offers a minimal residual risk of relapse (16%), in exchange for frequent side effects such as fatigue, diarrhoea and worse alopecia. Sadly, endocrine studies take time to mature OS data. However, we need to make sure we are delivering better long-term outcomes.

Some ER+ BC still require CT, as discussed by K. Kalinski. First, it is necessary to consider it if the benefit provided by CT is at least 5% The TAILORx trial showed similar efficacy of adjuvant ET versus CT plus ET in patients with early-stage BC and a 21-gene recurrence score (RS) of 11 to 25. However, there is a subgroup of patients younger than 51 years, with RS 16–25, and high clinical risk, who derived some CT benefits [72]. Conversely, in patients with a high RS of 26 to 100, the addition of CT improves the rate of freedom from recurrence [73]. Clinical studies have shown that patients with RS ≥ 31 had better outcomes when treated with adjuvant anthracycline plus taxane-based CT regimens compared with those receiving adjuvant taxane-based CT regimens alone. A subgroup analysis showed benefit even for tumours larger than 2 cm, regardless of menopausal status [74]. Among premenopausal women with one to three positive lymph nodes and an RS of 25 or lower, those who received chemoendocrine therapy had longer iDFS and DRFS than those who received ET only, whereas postmenopausal women with similar characteristics did not benefit from adjuvant CT [75]. An analysis of the RxPONDER trial found that premenopausal women with BC who had low levels of anti-Müllerian hormone (AMH) benefited less from CT adjunctive to ET than women with medium or high levels of AMH. AMH appears to be a stronger predictor of CT response than self-reported menopause status and age [76]. The MINDACT trial showed that in BC patients with high clinical and low genomic risk, the benefit of adding CT compared to And et alone is low, except in women younger than 50 years, defining a CT benefit that differs by age [77]. Most premenopausal patients in the TAILORx and RxPONDER trials did not receive ovarian function suppression (OFS) as part of their ET regimen. Given the observed benefit from OFS in high-risk premenopausal patients with homologous recombination (HR)+/HER2-BC in the SOFT/TEXT trials, many questioned whether all or part of the observed CT benefit in the TAILORx/RxPONDER trials may have been the result of CT-induced OFS. The ongoing trial BR009 will attempt to answer this. There are other tools, such as RSClinN+, which seem more prognostic than RS or clinicals alone, to individualise recurrence risk and CT benefit predictions [78].

P. Francis considered individualised ET in premenopausal women. In these patients, there are several factors to consider, such as age (especially very young patients), tumour stage and biology, multigene assay results, other planned systemic treatments and even interruption of treatments for desire of pregnancy (POSITIVE). For example, if in low-risk patients we can consider offering TAM for 5 years (EBTCG), as the risk of recurrence increases, we will need to modulate the treatment, for example, by increasing the duration of TAM (ATLAS), switching to aromatase inhibitors AIs (MA.17) or adding OFS (ASTRRA, SOFT and TEXT) [79]. Furthermore, there are several other drugs concurrent with ET to reduce the risk of recurrence, such as the addition of Abemaciclib for 2 years to any ET (monarchE) [80], Letrozole (or Anastrozole) + OFS + Ribociclib for 3 years (NATALEE), Any ET + Olaparib for 1 year (OLYMPIA) and OFS + Zolendronate (ABCSG 12).

T. Mamounas went into more detail regarding the duration of ET. We know that clinical and pathological factors of BC are prognostic [81], and therefore, the duration of ET should take these aspects into consideration. In the literature, there is a lot of data in favour of extending TAM or AIs (e.g., ATLAS, MA.17, MA17R, B-42 and DATA). However, ET can often have toxic effects and impact the patients' QoL. The ideal scenario would therefore be to predict the benefit of extended endocrine therapy (EET). In this, the use of clinic-pathological algorithms such as CTS5 [82], the monitoring of ctDNA after surgery, which has emerged as an accurate predictor of BC recurrence [83], and genomic assays such as breast cancer index [84, 85] or Mammaprint [86] can help. These factors will become increasingly important in helping to decide on potential EET, especially in this era of axillary surgical de-escalation.

And what about invasive lobular carcinoma (ILC)? M.J. Vrancken-Peeters discussed this topic. Routine use of MRI seems to improve the detection of multifocality and bilateral BC, even though it can lead to higher rates of false-positive findings and overestimation of tumour size [87]. However, in upfront surgery, it has shown a significant six-fold reduction in reoperations [88]. Residual lobular tumour size after NACT is often underestimated by MRI [89, 90]. Regarding staging, ILC demonstrates lower visibility on FluoroDeoxyGlucose-positron emission tomography than the more common invasive ductal carcinoma (IDC), but promising data seem to exist for the alternative use of Fluoroestradiol F18-Positron emission tomography; larger trials are needed for better evaluation [91]. Regarding de-escalation of axillary surgery, it is probably feasible, but further data are needed, as we know that ultrasound (US) has limitations in detecting lymph node metastases in this subgroup of patients, and in the major trials (SOUND, INSEMA), the percentage of patients with ILC BC is reduced. Patients with ILC who have a high RS are treated less often with CT compared with similar patients who have IDC, but the role of RS is relevant in these patients [92].

S. Zhiming considered the importance of targeted therapy in ER+ BC. Luminal BC presents a wide heterogeneity, and in this case, the basis for precision treatment, such as EET and evaluation of traditional or emerging treatments could be represented by the integration of clinical, transcriptomic, metabolomic, radiomic and pathological features. This allows for efficient stratification of patients into groups with different recurrence risks and different subtype-specific therapeutic strategies [93, 94]. It is also possible to use AI to identify these different subtypes. This is certainly a very promising topic, but real-world studies and multicentre collaborative clinical research are needed for efficacy validation of subtyping-based precision treatments.

A. De Michele discussed the use of CDK4/6i. Targeted therapy with CDK4/6i in addition to ET has been widely studied in BC. Current guidelines approve indications for adding CDK4/6i to ET in these cases: Ribociclib in N0 BC if T≥3 or T2/G3 or G2 and RS>25 or KI67≥20%, and in N+ BC [95]. In these patients, adding Ribociclib 400 mg/day (days 1–21 of every 28-day cycle) for 3 years to adjuvant ET improves iDFS. Abemaciclib shows benefit in iDFS and DRFS in patients with ≥4 positive LN or 1–3 positive LN only if T≥3 or Grade 3 [96]. The benefit of adding Abemaciclib to ET appears to exist regardless of menopausal status and first ET, with a numerically greater benefit in the premenopausal compared to the postmenopausal population [80]. The ultimate goal is to optimise and personalise therapy. Ongoing trials will help in this, for example, the ADAPTcycle trial to evaluate ET plus ribociclib versus CT in intermediate-risk ER+/HER2- early BC.

M. Kok focussed his presentation on immunotherapy. Current ASCO/CAP recommendations define ER+ tumours as having ≥1% ER expression and tumours with ER expression between 1% and 10% as ER low-positive tumours. Early-stage BC with low-positive and intermediate-positive (10%–50%) ER expression have more similarities in immune biology to TNBC than to their highly ER+ counterparts, based on tumour-infiltrating lymphocytes (TILs) and PD-L1 expression. From a therapeutic poit of view, there are studies that seem to demonstrate that, also from a therapeutic perspective, ER low-positive BC could benefit from treatments similar to TNBC, for example, with the addition of pembrolizumab to NACT followed by adjuvant pembrolizumab [97] or the addition of nivolumab to NACT [98]. The gene expression profile could also play an important role in this type of patient, as seen, for example, in the case of patients with MammaPrint ‘ultra-high’ (MP2) who showed improved rates of pCR with durvalumab/olaparib added to standard NACT [99].

Session VI: Bringing artificial intelligence to the BC clinic

We are only at the beginning, but in the near future, AI will likely become increasingly important in clinical practice, as discussed by J. Kather. The progression of individualised cancer care necessitates the development of a larger number of more accurate biomarkers for predicting treatment response, the identification of new targets in cancer cells and an accelerated drug development platform to facilitate matching targets with drugs and predict the risk of recurrences. Here, AI could be extremely useful. To fully realise the potential of AI in furthering precision oncology, several key challenges need to be addressed, such as the integration of diverse data types (e.g., imaging, genomics and clinical data), the development of interpretable and transparent AI models and the establishment of standardised protocols for data sharing and model validation. Moreover, closer collaboration between AI researchers and clinicians will be essential to guarantee that AI-based tools are clinically applicable and tailored to the needs of patients and healthcare systems [100, 101].

G. Fastner also expressed his views on the utility of AI. AI in fact can also assist in radiation oncology during all the various steps: the initial treatment-decision making (patient evaluation and dose prescription), the treatment planning (treatment simulation, image segmentation and dosimetric treatment planning), the treatment set-up and delivery (scheduling, image guidance, and motion management and adaptive treatment) and the completion of treatment (response assessment and follow-up care, toxicity prediction and management) [102]. But what is the clinical relevance of all this? For example, to compensate for the scarcity of infrastructure, to facilitate a time-consuming and technically complex cancer treatment, to decrease the lack of cancer care with RT, especially in low- and middle-income countries and to positively affect survival endpoints. These aspects are very promising, but at the moment, there are limitations that require implementations for use in clinical routine, such as the fact that software must be evaluated by medical authorities, technical development requires costs, and there is limited access to high-quality datasets.

Session VII: Is it time to update our imaging and diagnostic approach in early BC

I. Rubio clarified the use of PET-CT in staging. Although there are differences depending on the various guidelines (e.g., NCCN, ESMO, ABC and EANM/SNMMI), in stage I, where the risk of distant metastases is very low, PET imaging, in addition to having limited utility, may lead to false positive findings [103]. In stage IIA, PET-CT may be useful, but there is not enough strong data to recommend routine use in this group of patients. Specifically, PET-CT can be recommended for baseline staging in IIB, preferably before surgery, and stage III, including inflammatory BC [104]. In the neoadjuvant setting, the role of PET is primarily valuable for axillary evaluation, but it is not very sensitive at the end of treatment to reveal residual primary tumour tissue [105]. The potential effectiveness of PET-CT to predict early pCR and patient outcomes, especially for TNBC and HER2+ BC, is interesting [41]. Furthermore, it is worth considering, in addition to the clinical stage, the tumour subtype. For example, FDG uptake differs significantly, with higher FDG uptake in TNBC than in ER+ BC [106], and the histological type, as the impact of PET-CT on systemic staging may be lower in ILC. In these cases, potentially FES-PET and Gallium-68 Fibroblast Activation Protein Inhibitor Positron emission tomography may be a better option.

And what about breast MRI? B. Gulluoglu focused his presentation on the role of MRI in the upfront surgery setting. Despite many potential benefits in using MRI, such as increased diagnostic accuracy of local staging, planning of more accurate surgery and decreased re-operations, there are potential disadvantages, such as a higher number of unnecessary mastectomies and increased unnecessary visits for further imaging and biopsies, which can lead to false positives and thus delay the timing of surgery. In current guidelines, MRI in upfront surgery is recommended, particularly in invasive ILC and to identify potential additional lesions in patients with dense breasts. In reality, critically reviewing the literature, it appears that many studies often have an inadequate representation of young patients with dense breasts and ILC cases (e.g., COMICE, MONET, Finnish, POMB and BREAST-MRI). All these studies found similar reoperation rates in both arms (MRI and no-MRI), except for the POMB study. The final mastectomy rates were similar in all studies except in the BREAST-MRI study. MRI indicated contralateral breast surgery in 2%–3% of patients. Furthermore, there are similar local recurrence (LR), local-regional recurrence, local recurrence-free survival and contralateral recurrence rates in the MRI and no-MRI arms. There is also no convincing scientific evidence either supporting or opposing the use of MRI in patients with ILC [107] and not even in younger patients with or without dense breasts [108, 109]. Based on these considerations, the use of preoperative MRI should probably be reconsidered, and it appears prudent to perform it only in well-selected patients.

J. Huober began her presentation with the question, ‘Is it time to re-think our approach in BC follow-up?’. Current goals of surveillance in BC are represented by the early detection of potentially curable events like LRs, contralateral cancer and screening for secondary tumours. In clinical practice, probably not yet. In fact, just as we do not treat our patients with drugs until efficacy has been proven in clinical trials, the same principles should be applied to survivorship and radiographic surveillance. However, we should probably focus on this question to update the surveillance guidelines, which, at present, are still based on randomised trials conducted 30 years ago [110, 111], considering, for example, that in these years, the treatment of early BC has improved significantly, diagnostic imaging has notably improved, local and systemic therapies have improved and new techniques related to molecular medicine have emerged. We could therefore integrate imaging with new techniques that allow ultra-early detection of relapse in asymptomatic patients, such as ctDNA screening [16].

Session VIII: Hereditary BC

S. Paluch-Shimon discussed genetic tests. Approximately 5%–10% of BC are associated with a germline pathogenic variant (PV). The risk of developing BC in these patients depends on both the gene involved, the type of genetic mutation and age. The most common PVs are represented by BRCA1/2 mutation carriers, but there are PVs in other genes, particularly PALB2, ATM and CHEK2, that are associated with an increased risk of BC sufficient to justify altered medical management according to guidelines, such as increasing breast screening. Regarding the PV-positive rate, data suggest that it is higher among women who were diagnosed before 40 years, it does not change appreciably between the ages of 40 and 59 years, and it decreases among women who were diagnosed after 60 years, decreasing with increasing age [112]. The majority of international guidelines still focus on a risk-adapted approach based, for example, on age, family history, BC biology and ancestry. However, there is evidence to support multigene testing for BC susceptibility genes BRCA1/BRCA2/PALB2 in all BC patients, as this strategy can substantially reduce future malignancies [113]. The clinical utility of performing the genetic test is represented by the possibility of optimising treatment, such as the addition of adjuvant Olaparib in BRCA mutation carriers [114], and also the risk management of future malignancies, like contralateral BC, tubo-ovarian cancers and pancreatic cancer [115]. In the near future, concerns about genetic services, interpretation of variants of uncertain significance and appropriate risk assessment will likely be resolved by AI.

K. Metcalfe focused on risk-reducing mastectomy (RRM). BC risk surgery, including contralateral BC, needs to be considered when making surgical prevention decisions. In the case of BRCA1/2 mutation carriers, performing bilateral RRM reduces BC incidence and BC mortality, but further follow-up is needed to estimate the mortality reduction with greater precision [116]. On the other hand, risk-reducing contralateral mastectomy in patients affected by BC reduces contralateral BC incidence, but its effect on BC mortality is unclear [117, 118]. Important and more definitive future evaluations will derive from longer follow-up, with consideration of other genes such as ATM and CHEK2 [119].

J. Boughey discussed risk-reducing surgery through the so-called ‘conservative mastectomies’: skin-sparing mastectomy and nipple-sparing mastectomy (NSM), which are oncologically safe in appropriately selected patients. However, rates of BC development after NSM for risk reduction (bilateral prophylactic mastectomy or contralateral prophylactic mastectomy) in both BRCA-mutation and non-BRCA mutation carriers are limited, and longer follow-up is needed [120]. It is important that the surgery is performed by experienced surgeons with adequate thin flaps. After mastectomy, breast and nipple sensation are significantly diminished, with a significant negative impact on patients' QoL [121]. The implementation of new techniques such as Nerve-sparing or Nerve Grafting Mastectomy [122] or robotic mastectomy could lead to a reduction in this complication, but further data is needed.

Are there alternatives to RRM? C. Singer discussed this topic. Current guidelines suggest increasing breast screening [123]. In this context, in patients with BRCA1 mutations, for example, intensified screening with MRI reduces BC mortality. Further studies of patients with BRCA2 mutation carriers are needed to ascertain if these women obtain the same benefits [124]. The use of TAM or raloxifene may be an effective risk-reduction option for BRCA mutation carriers, but further studies with longer follow-up are necessary [125]. There is an international ongoing trial investigating the preventative effect of denosumab in healthy BRCA1 germline mutation carriers (BRCA-P trial). Risk-reducing salpingo-oophorectomy (as well as RRM) in young BC patients is associated with improved DFS, BCFI and OS, but it is necessary for healthcare providers to weigh the benefits and risks of these procedures, as they can lead to infertility and early menopause [126]. Lifestyle factors, such as physical activity and non-smoking, are important in reducing the risk of BC in BRCA mutation carriers [127, 128].

Session IX: Optimising locoregional management: the axilla

Can we avoid upfront axillary surgery? Urban C. attempted to clarify this. At present, sentinel lymph node biopsy (SLNB) is still widely used, but it is probably time to incorporate into clinical practice what important studies have shown. Thus, in the case of N0 on preoperative US, which has a negative predictive value of 95.1% to infer low tumour burden [129], we can apply the SOUND and INSEMA studies. In cases of suspected or limited axillary involvement during preoperative US, as well as in cases of significant axillary involvement but negative fine-needle aspiration or core biopsy, we can perform SLNB and, in case of positivity, apply various studies, e.g., ACOSOG Z0011, SENOMAC, AMAROS and SINODAR. The omission of axillary surgery should not, however, mean an increase in other therapeutic modalities, such as RT; therefore, this de-escalation requires an effort in multidisciplinary shared decision-making [130]. More data are needed for SLNB omission in: ILC, G3, T2, premenopausal patients, mastectomies, and in patients with TNBC and HER2+ BC candidates for upfront surgery. For the near future, we expect more decisions based on genomics and AI.

And what about SLNB in particular situations? M.J. Cardoso discussed this. Specifically, in inflammatory BC, where the lymphatic drainage differs from other BC types, there is currently no prospective evidence to support de-escalating axillary treatment in either N0 at presentation or radiological N0 after NACT cases. Therefore, ALND (plus mastectomy without immediate reconstruction) remains the standard approach [131]. In the case of LR, it is necessary to consider that staging with PET-CT can be helpful, but there is not enough evidence to replace surgical staging. Data seem to highlight that, in patients with ipsilateral BC recurrence, receiving surgical axillary staging was associated with better survival [132]. If SLNB is feasible, previous mastectomy and ALND are not a contraindication, but the identification rate is lower [133]. If the SLNB fails, in case of negative staging, the standard of care for now is ALND. In de novo stage IV BC, the role of axillary surgery has not been prospectively evaluated independently of primary tumour surgery, but it appears unlikely to provide a survival benefit [134]. In the context of oligometastatic disease, where a curative approach is considered, the management of the axilla should follow the same principles as in early-stage BC.

W. Weber, in his presentation, emphasised axillary surgery after NACT. In cN-, perform SLNB with a single tracer [135] and omit ALND when ≥1 Sentinel lymph node (SLN) is negative [136]. In cN+ with a good response to NACT, imaging cannot replace the SLNB procedure [137], but when nodal-pCR is determined by SLNB or targeted axillary dissection (TAD), ALND can be safely omitted [138, 139]. In this setting, both TAD and SLNB are safe [140]. In cN+ and residual disease after NACT, there are important ongoing trials (A011202 ALLIANCE, TAXIS), but results are still 4–5 years away. In the meantime, while prospective trial results are awaited, some data [141] suggest that ALND may not be necessary for all patients with residual nodal disease after NACT. Some studies show that, in selected patients with a low volume of nodal disease after NACT, SLNB + image-tailored axillary surgery and adjuvant RT may be sufficient for local control of the axilla [142, 143]. Results from the retrospective ICARO study, after 5 years of follow-up, do not support routine ALND in all patients with ypN0(i+); in this study, the mean number of SLN with ITCs was 1.2 [144]. The microNAC trial seems to support further de-escalation of surgery in residual micrometastases in selected patients; results will be available soon. Another retrospective study, MACRONAC, is planned to evaluate the association between the omission of ALND and recurrence by volume of nodal disease and biological subtype in patients with residual nodal macrometastases.

A. Munshi spoke on nodal irradiation after NACT. Currently, regional nodal irradiation is decided based on clinical stage, tumour response and the extent of axillary surgery. Results from randomised trials will guide future decisions, such as NSABP-051 for patients converted to N0 post primary systemic treatment; ADARNAT, TAXIS, for patients who remain N+ after primary systemic treatment; and OPBC-10/NOAX for patients N+ undergoing upfront surgery. A balance between axillary surgery and axillary irradiation is necessary; a multidisciplinary approach is fundamental [145]. An important aspect to consider for personalised treatments is fractionation. While 15 fractions have become the current standard, based on scientific data such as those derived from START and other related trials [146], the next step will be to understand if it is possible to extend the indication to further hypofractionation, as evidenced by FAST-FORWARD [147].

Session X: Designing clinical trials that are patients-centered, purposeful and pragmatic

M. Regan discussed the strengths and limitations of clinical trial design.

Good clinical trials are critical to the practice of evidence-based medicine, and the first step is asking well-built clinical questions [148]. The clinical trial design process is challenging, but there are tools such as SPIRIT, which provides evidence-based recommendations for the minimum content of a clinical trial protocol and outlines recommendations in a 33-item checklist and figure; and PRECIS-2, which helps trialists designing clinical trials consider where they would like their trial to be on the on the pragmatic (estimates intervention effect in usual clinical practice)/ explanatory (shows intervention works under ideal conditions) continuum.

D. Cameron reiterated the importance of the fact that clinical trials must answer a question, test a hypothesis, and therefore, patient enrolment must try to reflect this hypothesis. Furthermore, enrolment should also be as aligned as possible with the ‘real clinic population’ and not only with an ‘ideal population.’ Rarely, however, is it possible to ‘personalise’ the results by taking into consideration, for example, comorbidities or the onset of toxicities that determine an alteration of the patient's lifestyle and that would require a reduction or delay of treatment. Certainly, a shared-decision patient/physician approach is important, with emphasis, for example, on the relationship between efficacy and toxicity of what we are testing, as each patient is different from another.

F. Pignatti discussed the usefulness of stated preference studies in drug regulation, which, along with other methods such as focus groups and expert opinions, have the potential to become an important tool for gathering patient views in a systematic way to inform regulatory and treatment decisions. Indeed, for example, there is data showing that attitudes towards PFS are spread out and associated with individual differences in the willingness to trade between toxicity and PFS, hence, the importance, once again, of patient communication [149]. Furthermore, research focusing on optimising the use of health technologies in clinical practice, known as 'treatment optimisation research,' should be implemented. This is because when new treatments enter the market, there are often many uncertainties for doctors and patients, such as how to employ these new treatments in clinical practice by integrating them with those already available, optimal dose and duration, and which patient population can derive the maximum benefit [150].

T. Spanic clarified how it is important to consider the patient's perspective within clinical trials. To do this, it would be useful, for example, to involve patients early in trial design, address patient-relevant questions, recognise differences between patient and physician perspectives (e.g., side effects and their impact on patients' daily lives), minimise the burden of hospital visits, incorporate meaningful QoL questionnaires and ensure treatment protocols align with real-world patient needs and preferences.

Session XI: Addressing the needs of young BC patients

C. Saura presented the topic of BC in pregnant patients. Pregnancy-associated cancer encompasses two different entities: BC diagnosed during pregnancy, with a prognosis comparable to non-pregnant patients according to age and stage; and BC diagnosed in the postpartum period, with a worse prognosis [151]. When possible, treatments for pregnant women with BC should be non-inferior to standard treatment, but dedicated considerations are necessary. For example, regarding imaging, we can perform: US, mammography and chest X-ray with abdominal shielding, and MRI without gadolinium. CT scans, bone scintigraphy and PET should be avoided; tumour markers are not informative during pregnancy [152]. Regarding surgery: BCS and mastectomy have essentially similar indications as in non-pregnant women. Reconstruction, preferably with an expander, can be safely performed. For SLN, the use of technetium with local injection 2 hours before surgery is recommended to minimise radiation exposure. Blue dye, however, should be avoided due to potential allergic reactions. RT in general is recommended to be postponed to the postpartum period; this should be considered in planning the surgical choice. CT is contraindicated in the first trimester due to the high risk of miscarriage and congenital malformation. In the second and third trimesters, standard anthracycline-taxane-based regimens can be administered as in the non-pregnancy setting. Carboplatin can be given safely. Immunotherapy for TNBC or anti-HER2 therapy for HER2+ BC should be deferred until after delivery. Supportive treatments such as ondansetron, metoclopramide and G-CSF can be used. Consider that after 35 weeks of gestation, weekly schedules are advisable and can be continued until closer to delivery. The use of genomic tests could be interesting to help identify low-risk BC, but studies are lacking in this setting. ET is contraindicated during pregnancy because it may induce abnormalities in the development and function of the reproductive tracts and congenital malformations [151, 152, 153]. Whenever possible, it is preferable to target full-term delivery (starting from the 37th week). Breastfeeding is contraindicated only if the patient has to continue systemic therapy or RT [154].

Fertility preservation and pregnancy after BC were the topics of discussion by M. Lambertini. All cancer patients of reproductive age should receive oncofertility counselling as early as possible in the treatment planning process, as there are several options to offer patients, such as embryo/oocyte cryopreservation, ovarian tissue cryopreservation and GnRHa during CT to reduce the rate of premature ovarian insufficiency [155, 156, 157]. Recent data have provided reassurance on the safety and feasibility of pregnancy in BC survivors, regardless of the hormone receptor status of the disease and even in BRCA carriers. It is necessary to consider that oncological treatments can be teratogenic, and therefore, contraception during treatments and an adequate period of washout are mandatory. Actual guidelines suggest waiting to try to conceive: at least 1 year after completion of CT, 7 months with trastuzumab, 3 months with TAM (although in some countries, this interval has been extended to 9 months); there is limited data available on immune checkpoint inhibitors (ICIs) and new agents [158, 159]. The POSITIVE trial evaluated the safety of suspending ET in patients after having completed more than 18 but less than 30 months of treatment. After 3 months of washout, women are allowed to conceive; it seems useful to consider a total-body restaging procedure before attempting pregnancy. The interruption was planned for a maximum of 24 months. In all these patients, resumption of ET after delivery is recommended [160, 161]. Breastfeeding appears to be oncologically safe after BC, even in BRCA mutation carriers [162, 163].

L. Michel discussed sexual health in BC survivors. What we must consider is that sexual health is an essential and often neglected aspect in BC patients. The prevalence of sexual concerns (poor body image, poor sexual functioning, poor sexual enjoyment, sexual inactivity) seems frequent, persistent and insufficiently addressed [164]. The main mechanisms causing sexual dysfunction in BC patients include emotional distress (such as anxiety and depression, potentially leading to restriction of sexual desire and self-esteem), body image alterations (surgery/RT, alopecia, loss of nipple/breast sensation and treatment-related weight gain) and premature menopause [165]. ET may lead to dysfunction, including vaginal dryness, reduced libido and dyspareunia [166]. There are various therapeutic strategies for genitourinary menopause symptoms, such as water/silicone-based vaginal products, vaginal laser, vaginal dilators, and, if these are ineffective, local estrogen therapy appears to be safe. However, it is recommended to use the lowest effective dosage and an appropriate individual risk-benefit assessment [167–172].

Session XII: Systemic therapy for early TNBC

S. Loi focused on the correct use of immunotherapy. Early-stage TNBC contains large amounts of T cell infiltrate. The use of PD-1/PD-L1 inhibitors with CT in both neoadjuvant and adjuvant settings, in some cases, improves pCR rate, EFS and OS [173]. Current evidence supports the use of Pembrolizumab in both settings, with ongoing studies examining de-escalation by not using adjuvant pembrolizumab for patients with pCR [174]. In the pure adjuvant setting, the addition of the immune therapy drug atezolizumab to CT after surgery did not provide benefit. This suggests that a lower micrometastatic tumour burden or the absence of residual cancer is not enough to trigger a T cell response [175]. The optimal duration of PD-1 inhibitors, both pre- and post-surgery, in early TNBC is an evolving field. In the neoadjuvant setting, the duration is probably less important than achieving pCR. In the post-surgery setting, for patients with pCR, there is no rationale for continuing immunotherapy. A longer duration of immunotherapy is associated with more immune-mediated adverse events, particularly endocrinopathies. The onset of immune-related adverse events can occur even long after (up to 41 months) the start of treatment with PD-1/PD-L1 inhibitors. Immune biomarkers can already help tailor shorter duration NACT + immunotherapy (Neo PACT, NeoN) that can achieve high pCR rates, and thus, de-escalation prospective studies should incorporate biomarkers (e.g., TILs and ctDNA). In the near future, strategies will probably be found to identify and mitigate immunotherapy-related toxicity, for example, using future PD-1 agents that target tumour cells and not normal cells.

W.F. Symmans discussed the important role of RCB. It would be necessary to standardise the routine quantification and reporting of RCB after NACT, as there is a long-linear relationship between RCB score and prognosis [45]. The prognostic surrogacy of RCB was irrespective of neoadjuvant treatment and provides an assessment of residual risk that appears to be clinically meaningful and could inform a patient’s subsequent adjuvant treatment. Furthermore, investigational treatments that shifted the distribution of RCB values in I-SPY2 suggested subtype-specific differences in patterns of RCB shift that are hypothesis-generating, and they also had longer EFS in an exploratory analysis. Thus, the survival benefit of a specific treatment may be reflected in changes to the RCB distribution, with a larger shift implying a greater probability of efficacy [176]. TILs RD (residual disease) levels in TNBC treated with NACT are significantly associated with improved RFS and OS and add further prognostic information to RCB class, particularly in patients with moderate RCB [177].

L. Carey attempted to answer three important questions. The first one: Is it possible to administer the ICI only in the adjuvant setting? Considering the results of the KEYNOTE-522 trial with a higher percentage of pCR among patients who received Pembrolizumab + CT in the neoadjuvant setting, the answer is probably ‘no’. The answer continues to be ‘no’ even when analysing two other trials: the A-BRAVE trial shows that the addition of ICI (Avelumab) for 1 year does not significantly increase DFS [178], similarly, the ALEXANDRA trial does not show an improvement in DFS with the addition of Atezolizumab in the adjuvant setting [175], for the mechanism already highlighted by Prof. Loi during her presentation. Turning to the second question: Is adjuvant therapy necessary in patients who achieved pCR? In GeparNuevo, the addition of Durvalumab to NACT, despite a modest pCR increase, significantly improved OS; in this case, ICI was not continued after surgery [179]. There are ongoing trials such as OPT-PEMBRO and OptimICE, whose primary endpoint is the evaluation of EFS in patients who achieved pCR with Pembrolizumab + CT in the neoadjuvant setting, without continuing pembrolizumab after surgery. Pending these data, the standard is the completion of adjuvant Pembrolizumab, if patients are tolerating it. Finally, the last question: are more drugs needed in residual disease? In these high-risk patients, probably yes. For example, in the CREATE-X trial, after standard NACT containing anthracycline, taxane or both, the addition of adjuvant capecitabine therapy at a dose of 1,250 mg per square meter of body-surface area, twice daily conventional schedule for 6 months, was safe and effective in prolonging DFS and OS among patients with HER2-negative BC who had RD [180], but other clinical trials such as GEICAM/2003 failed to show a statistically significant improvement in DFS by adding capecitabine in the adjuvant setting [181]. Among patients with high-risk, HER2-negative early BC and germline BRCA1 or BRCA2 PVs, adjuvant Olaparib was associated with significantly longer DFS [114]. In essence, for now, it is unknown whether adjuvant capecitabine adds benefit in patients receiving adjuvant continuation of their ICI or olaparib; no efficacy results are available for either of these combinations in the adjuvant setting [106]. There are several ongoing trials, such as OptimICE-RD (AFT-65)/ASCENT-05, SASCIA and TROPION-Breast03, that may help to clarify.

Do all TNBCs require CT? H. Rugo discussed this. CT is recommended for T1c/N0 or greater TNBC. Data in pT1b pN0 are unclear, but probably for most of them, adjuvant CT is suggested. The majority of patients with pT1a/N0 TNBC do not benefit from adjuvant CT, but probably, it is advised in highly selected patients, such as young patients with a high grade [182]. Patients with low-grade, good prognosis, rare TNBC subtypes (e.g., adenoid cystic, secretory carcinoma, apocrine, low-grade fibromatosis-like carcinoma and low-grade adenosquamous) do not need CT [106, 183]. At present, we are probably still over-treating at least some TNBC. Help to better stratify treatments could come from the use of biomarkers such as TILs levels, which have a prognostic value [184, 185]. There are ongoing trials, like, for example, NeoTRACT, which investigates de-escalating NACT based on the degree of pre-treatment TILs enrichment. In fact, this is positively associated with pCR in TNBC and may be useful to identify patients for whom de-escalation of NACT might be acceptable.

A. Tutt focused on PARP inhibitors (PARPi) and new approaches to homologous recombination deficiency (HRD). PARPi has been demonstrated to exhibit anti-tumour activity in individuals whose cancers have a defect in the HR DNA repair pathway. HRD populations may be larger than populations with BRCA1/2 mutations. For example, 60% of TNBC have HRD and could potentially benefit from PARPi [186]. The OlympiA trial showed that 1 year of adjuvant Olaparib in patients with germline mutations improves iDFS and OS [187], but resistance to PARPi can develop. For example, BRCA1/2 reversion mutations are observed in ctDNA in 60% of patients who develop resistance and were the most prevalent form of resistance. The cause of the reversion appears to be driven by a polymerase theta-mediated process, and this nature of the resistance mechanism may have implications for the use of DNA polymerase theta inhibitors and other agents that may be synthetic lethal with 53BP1/Shieldin complex mutations or non-HR-related aspects of BRCA1/2 deficiency [188]. There are ongoing trials testing polymerase theta inhibitors (e.g., MOMA 313, GSK4524101 and ART6043). Another potential target for new drugs is represented by USP1 inhibitors. USP1 is required for fork protection in BRCA1-deficient cells. There are trials testing these inhibitors (e.g., KSQ-4279). Finally, other potential drugs could be represented by ATR inhibitors (tuvusertib) and WEE1 inhibitors (azenosertib).

S. Dawood emphasised the side effects associated with the use of ICI. ICI is an increasingly important in BC treatment, and as more patients are treated with ICI and live longer, we will see an increasing incidence of both acute and chronic adverse events, which we need to manage. Most of the toxic effects are reversible, aside from effects on the endocrine system, which may be permanent [189]. Furthermore, ICI can impact immediate and future fertility, and therefore, fertility preservation should be strongly advised [190]. The precise pathophysiology underlying immune-related adverse events is unknown but is believed to be related to the role that immune checkpoints play in maintaining immunologic homeostasis [191]. More studies are needed to better elucidate the mechanisms underlying the development of these adverse factors, in order to identify and manage them multidisciplinary by developing personalised treatment strategies.

Conclusion

The final day focused on the consensus panel, the true highlight of the St. Gallen congress.

The purpose of this consensus, chaired by leading international experts, is to develop guidance for the majority of common presentations and clinical scenarios in early-stage BC. The various aspects of the diagnosis and treatment of BC were discussed. A summary of these discussions is presented below.

The conclusions are the most important and most-read part. To make it easier to read, I think it would be better to make the different sections more prominent. I leave the method up to you, but I'm underlining the sections in green. Whenever possible, in patients without high risk and without contraindications to RT, BCS is preferred instead of mastectomy. However, patient preference is also important in shared decision-making.

SLNB can be omitted in upfront surgery for postmenopausal patients with T1, N0, luminal BC. Currently, there is insufficient data to omit it in patients with TNBC and HER2+ BC, and also in ILC, even when preoperative axillary US is negative.

Following NACT, in the presence of MRD in the axilla, ITC or micrometastasis in favourable biology, the panel predominantly advises against ALND, instead recommending nodal irradiation. However, in the specific case of ITC in luminal BC, RT may be omitted.

We are less comfortable with a finding of 1/1 or 2/2 positive SLNs out of the total sampled, but in the case of 1 macrometastasis in 4 SLNs after NACT with a good clinical response, 58% of the panel expressed a preference for nodal irradiation over ALND especially in luminal BC or HER2+. For TNBC with residual macrometastases and in inflammatory BC ALND remains the gold standard.

The standard treatment schedule of RT should now be considered moderate hypofractionation with 15–16 fractions. Potential de-escalation with ultra-hypofractionation can be considered in post-menopausal patients with low-risk BC (FAST-FORWARD) and even a viable single-modality treatment, RT or ET (LUMINA, IDEA, EUROPA).

Post-mastectomy radiation therapy is recommended for high-risk BC, with irradiation of the chest wall and regional LN, if it is involved. According to the panel, RT is preferable to ALND for 1 or 2 macrometastatic SLNs in upfront surgery.

Hereditary BC: Genetic testing is an important tool, but it must be offered ‘judiciously’ and not routinely to all patients, for example, in women with newly diagnosed a high aggressive BC or in patients aged 50 or less, male BC or strong family history. Regarding risk-reduction surgery, the panel agrees for patients with PVs in BRCA1-2, PALB2 upto 50–55 years old. For older women or those with PVs of ATM, CHECK2, BARD1 or RAD51 genes, screening is preferred. NSM is the surgical procedure of choice, preferably performed by surgeons with high expertise.

Survivorship: Considerable emphasis was placed on patients' QoL. For example, to prevent neuropathy in women receiving taxane-based neo/adjuvant treatment, the majority of the panel recommends routinely offering cooling gloves. Compression gloves are also useful, but appear to be less effective. Alternatively, they can be used in combination.

DCIS: At present, the recommended treatment for G2 DCIS is surgery. In case of BCS, adjuvant therapies depend on age, DCIS size and HR status: in healthy non-elderly patients with DCIS ≥10 mm HR+, it is advisable to combine RT and ET. In women over 70, a de-escalation can be considered. Genomic testing for DCIS management is not routinely recommended at this time. Instead, it is preferred to base decisions on the presence/absence of necrosis, microcalcifications and grade.

ER+/HER2-BC: More than 60% of the panel recommends adjuvant CT if the likely benefit on distant recurrence-free survival is ≥5%. All panellists agree on requesting genomic risk assays for N0 tumours ≥10 mm, with 30% even recommending it for smaller sizes. For T2, N0 BC with a high RS (26–31), more than 70% of the panel favours the use of CT, particularly anthracycline-free regimens (docetaxel-cyclophosphamide) or even lower in the case of N1; taxane-anthracycline for RS ≥ 31. However, it is necessary to use clinical judgment to individualise therapy. For example, in premenopausal patients, consider CT in N0 even with RS lower than 26 and OFS if RS ≥ 16. In N+, 67% of the panel recommends CT in addition to ET for RS ≥16. Standard ET duration is 5 years, however, in high-risk BC, extending ET beyond 5 years should be considered: a treatment duration of 7 to 8 years appears sufficient for the majority of these patients, 10 years for ≥ 3 positive lymph nodes. Targeted therapy with CDK4/6i in addition to ET should be considered in higher aggressive BC.

HER2+ BC: In N0 disease, over 90% of the panel recommended NACT plus anti-HER2 therapy for tumours ≥ 20 mm, with 40% advocating this approach even for tumours ≥ 15 mm. In stages II and III disease, 75% of the panel agreed on an anthracycline-free regimen combined with dual blockade TCb/HP (Docetaxel, Carboplatin, Trastuzumab, Pertuzumab), with 60% supporting this even in cases of inflammatory BC. Patients with no-pCR after NACT plus anti-HER2 therapy should receive adjuvant treatment with T-DM1, according to over 70% of the panel.

For patients with T1b, N0 disease, upfront surgery followed by adjuvant 12 weeks of paclitaxel plus 1 year of trastuzumab was deemed the correct therapeutic choice by 90% of the panel, rising to unanimous agreement in cases of T1c, N0 disease. Pertuzumab addition is considered only in N+. In cases of only foci of microinvasive cancer, over half of the panel did not recommend paclitaxel/trastuzumab. For risk stratification, various tools are available, such as omics integration or HER2DX, which 50% of the panel found useful. However, these tools are not yet widely utilised in clinical practice.

TNBC: NACT is the standard of care for T1c-4/N0 or N+. Concerning immunotherapy, the addition of pembrolizumab, according to 70% of the panellists, is indicated when the tumour size is >20 mm and, pending the results of ongoing trials, is currently continued after surgery even in cases of pCR (approximately 90% of the panel). In the case of durvalumab, it is not continued in the adjuvant setting (GeparNuevo). Immunotherapy should not be used in the adjuvant setting alone. If patients, with stage 2 or 3, have contraindications to the use of checkpoint inhibitors, nearly 90% of the panel recommends TCb/AC (Docetaxel, Carboplatin, Anthracycline, Cyclophosphamide) administration. Patients with residual disease following NACT should receive adjuvant capecitabine for 6–8 cycles. Furthermore, 75% of the panel agrees to continue immunotherapy and add capacitabine. In BRCA1/2 BC immunotherapy and concurrent olaparib.

The panel, with 82% agreement, recommends treating ER-low tumours equivalently to TNBC, with the adjunct of pembrolizumab to NACT.

In N0, 100% of the panel recommends adjuvant CT for tumours >10 mm; 76% even if the size is >0.5 mm, excluding adjuvant CT only in cases of pT1a.

Oligometastatic BC: For limited metastatic disease with highly effective treatment options and/or a favourable initial response to therapy, nearly 90% of the panel agreed on considering definitive local-regional treatment. For patients presenting with de novo oligometastatic disease and a clinically negative axilla, 70% of the panel recommended performing SLNB.

The 19 St. Gallen Congress addressed the current standard of care while exploring emerging aspects of early BC treatment, highlighting the increasing importance of integrating genomic assays and AI in the near future. Our role, as physicians and researchers, must be to advance along this path and, as Dr. Giuliano emphasised at the outset, to embrace these new tools and not resist change, because ‘the fear of change is often worse than the change itself’.

Conflicts of interest

None.

Funding

None.

References

1. EBCTC (2024) Reductions in recurrence in women with early breast cancer entering clinical trials between 1990 and 2009: a pooled analysis of 155746 women in 151 trials Lancet 404(10461) 1407–1418

2. Blondeaux E, Xie W, and Carmisciano L, and et al (2024) Intermediate clinical endpoints in early-stage breast cancer: an analysis of individual patient data from the Gruppo Italiano Mammella and Mammella Intergruppo trials EClinicalMedicine 70 102501 https://doi.org/10.1016/j.eclinm.2024.102501

3. Conforti F, Nekljudova V, and Sala I, and et al (2025) Surrogate end points for overall survival in neoadjuvant randomized clinical trials for early breast cancer JCO 43(12) 1441–1452 https://doi.org/10.1200/JCO-24-01360

4. Ferreira AR, Di Meglio A, and Pistilli B, and et al (2019) Differential impact of endocrine therapy and chemotherapy on quality of life of breast cancer survivors: a prospective patient-reported outcomes analysis Ann Oncol 30(11) 1784–1795 https://doi.org/10.1093/annonc/mdz298

5. Pistilli B, Paci A, and Ferreira AR, and et al (2020) Serum detection of nonadherence to adjuvant tamoxifen and breast cancer recurrence risk JCO 38(24) 2762–2772 https://doi.org/10.1200/JCO.19.01758

6. Schiavon G, Hrebien S, and Garcia-Murillas I, and et al (2015) Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer Sci Transl Med 7(313) 313ra182 https://doi.org/10.1126/scitranslmed.aac7551

7. Jhaveri KL, Neven P, and Casalnuovo ML, and et al (2024) Immunestrant with or without abemaciclib in advanced breast cancer NEJM 392(12) 1189–1202

8. Oliveira M, Pominchuk D, and Nowecki Z, and et al (2024) Camizestrant, a next-generation oral SERD, versus fulvestrant in post-menopausal women with oestrogen receptor-positive, HER2-negative advanced breast cancer (SERENA-2): a multi-dose, open-label, randomised, phase 2 trial Lancet Oncol 25(11) 1424–1439 https://doi.org/10.1016/S1470-2045(24)00387-5

9. Hurvitz SA, Bardia A, and Quiroga V, and et al (2024) Neoadjuvant palbociclib plus either giredestrant or anastrozole in oestrogen receptor-positive, HER2-negative, early breast cancer (coopERA Breast Cancer): an open-label, randomised, controlled, phase 2 study Lancet Oncol 24(9) 1029–1041

10. Nitz U, Gluz O, and Graeser M, and et al (2022) De-escalated neoadjuvant pertuzumab plus trastuzumab therapy with or without weekly paclitaxel in HER2-positive, hormone receptor-negative, early breast cancer (WSG-ADAPT-HER2+/HR-): survival outcomes from a multicentre, open-label, randomised, phase 2 trial Lancet Oncol 23(5) 625–635 https://doi.org/10.1016/S1470-2045(22)00159-0

11. Piccart-Gebhart MJ, Procter M, and Leyland-Jones B, and et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer NEJM 353(16) 1659–72 https://doi.org/10.1056/NEJMoa052306

12. Baselga J, Cortés J, and Kim SB, and et al Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer NEJM 366(2) 109–19 https://doi.org/10.1056/NEJMoa1113216

13. Verma S, Miles D, and Gianni L, and et al (2012) Trastuzumab emtansine for HER2-positive advanced breast cancer NEJM 367(19) 1783-91 https://doi.org/10.1056/NEJMoa1209124 PMID: 23020162 PMCID: 5125250

14. Murthy RK, Loi S, and Okines A, and et al (2020) Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer NEJA 382(7) 597–609 https://doi.org/10.1056/NEJMoa1914609

15. Cortés J, Kim SB, and Chung WP, and et al (2022) Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer NEJM 386(12) 1143–1154 https://doi.org/10.1056/NEJMoa2115022

16. Garcia-Murillas I, Chopra N, and Comino-Méndez I, and et al (2019) Assessment of molecular relapse detection in early-stage breast cancer JAMA Oncol 5(10) 1473–1478 https://doi.org/10.1001/jamaoncol.2019.1838 PMCID: 6681568

17. Radovich M, Jiang G, and Hancock BA, and et al (2020) Association of circulating tumor DNA and circulating tumor cells after neoadjuvant chemotherapy with disease recurrence in patients with triple-negative breast cancer JAMA Oncol 6(9) 1410–1415 https://doi.org/10.1001/jamaoncol.2020.2295

18. Sparano J, O’Neill A, and Alpaugh K, and et al (2018) Association of circulating tumor cells with late recurrence of estrogen receptor-positive breast cancer: a secondary analysis of a randomized clinical trial Jama Oncol 4(12) 1700–1706 https://doi.org/10.1001/jamaoncol.2018.2574 PMID: 30054636 PMCID: 6385891

19. Razavi P, Li BT, and Brown DN, and et al (2019) High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants Nature Med 25(12) 1928–1937 https://doi.org/10.1038/s41591-019-0652-7 PMID: 31768066 PMCID: 7061455

20. Schrag D, Beer TM, and McDonnell III CH, and et al (2023) PATHFINDER: a prospective cohort study of blood-based multi-cancer early detection Lancet 402(10409) 1251–1260

21. Garcia-Murillas I, Abbott CW, and Cutts RJ, and et al (2025) Whole genome sequencing-powered ctDNA sequencing for breast cancer detection Ann Oncol 36(6) 673–681 https://doi.org/10.1016/j.annonc.2025.01.021 PMID: 39914664

22. Papakonstantinou A, Gonzalez NS, and Pimentel I, and et al (2022) Prognostic value of ctDNA detection in patients with early breast cancer undergoing neoadjuvant therapy: a systematic review and meta-analysis Cancer Treat Rev 104 102362 https://doi.org/10.1016/j.ctrv.2022.102362

23. Cameron D, Piccart M, and Gelber RD, and et al (2017) 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial Lancet 389(10075) 1195–1205 https://doi.org/10.1016/S0140-6736(16)32616-2

24. Romond EH, and et al (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer NEJM 353(16) 1673–84 https://doi.org/10.1056/NEJMoa052122 PMID: 16236738

25. Perez EA, Suman VJ, and Davidson NE, and et al (2011) Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer JCO 29(34) 4491–7 https://doi.org/10.1200/JCO.2011.36.7045

26. Slamon D, Eiermann W, and Robert N, and et al (2011) Adjuvant trastuzumab in HER2-positive breast cancer NEJM 365(14) 1273–83 https://doi.org/10.1056/NEJMoa0910383 PMID: 21991949 PMCID: 3268553

27. Earl HM, Hiller L, and Vallier AL, and et al (2019) 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomized phase 3 non-inferiority trial Lancet 393(10191) 2599–2612 https://doi.org/10.1016/S0140-6736(19)30650-6

28. Pivot X, Romieu G, and Debled M, and et al (2019) 6 months versus 12 months of adjuvant trastuzumab in early breast cancer (PHARE): final analysis of a multicentre, open-label, phase 3 randomised trial Lancet 393(10191) 2591–2598 https://doi.org/10.1016/S0140-6736(19)30653-1 PMID: 31178155

29. Mavroudis D, Saloustros E, and Malamos N, and et al (2015) Six versus 12 months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG) Ann Oncol 26(7) 1333–40 https://doi.org/10.1093/annonc/mdv213 PMID: 25935793

30. Pfitzner BM, Lederer B, and Lindner J, and et al (2018) Clinical relevance and concordance of HER2 status in local and central testing-an analysis of 1581 HER2-positive breast carcinomas over 12 years Mod Pathol 31(4) 607–615 https://doi.org/10.1038/modpathol.2017.171

31. Fehrenbacher L, Cecchini RS, and Geyer CE, and et al (2020) NSABP B-47/NRG oncology phase III randomized trial comparing adjuvant chemotherapy with or without trastuzumab in high-risk invasive breast cancer negative for HER2 by FISH and with IHC 1+ or 2 JCO 38(5) 444–453 https://doi.org/10.1200/JCO.19.01455

32. Modi S, Jacot W, and Yamashita T, and et al (2022) Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer NEJM 387(1) 9–20 https://doi.org/10.1056/NEJMoa2203690

33. Bardia A, Hu X, and Dent R, and et al (2022) Trastuzumab deruxtecan after endocrine therapy in metastatic breast cancer NEJM 391(22) 2110–2122

34. Rediti M, Venet D, and Joaquin Garcia A, and et al (2024) Identification of HER2-positive breast cancer molecular subtypes with potential clinical implications in the ALTTO clinical trial Nat Comm 15(1) 10402 https://doi.org/10.1038/s41467-024-54621-3

35. Tolaney SM, Tarantino P, and Graham N, and et al (2023) Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer: final 10-year analysis of the open-label, single-arm, phase 2 APT trial Lancet 24(3) 273–285 https://doi.org/10.1016/S1470-2045(23)00051-7

36. von Minckwitz G, Procter M, and De Azambuja E, and et al (2017) Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer NEJM 377(2) 122–131 https://doi.org/10.1056/NEJMoa1703643 PMID: 28581356 PMCID: 5538020

37. Loibl S, Jassem J, and Sonnenblick A, and et al (2024) Adjuvant pertuzumab and trastuzumab in early human epidermal growth factor receptor 2-positive breast cancer in the APHINITY Trial: third Interim overall survival analysis with efficacy update JCO 42(31) 3643–3651 https://doi.org/10.1200/JCO.23.02505

38. van Mackelenbergh MT, and Loibl S, Untch M, and et al (2023) Pathologic complete response and individual patient prognosis after neoadjuvant chemotherapy plus anti-human epidermal growth factor receptor 2 therapy of human epidermal growth factor receptor 2-positive early breast cancer JCO 41(16) 2998–3008 https://doi.org/10.1200/JCO.22.02241

39. Nitz U, Gluz O, and Graeser M, and et al (2022) De-escalated neoadjuvant pertuzumab plus trastuzumab therapy with or without weekly paclitaxel in HER2-positive, hormone receptor-negative, early breast cancer (WSG-ADAPT-HER2+/HR–): survival outcomes from a multicentre, open-label, randomised, phase 2 trial Lancet Oncol 23(5) 625–635 https://doi.org/10.1016/S1470-2045(22)00159-0

40. Pérez-García JM, Gebhart G, and Borrego MR, and et al (2024) Chemotherapy de-escalation using an 18F-FDG-PET-based pathological response-adapted strategy in patients with HER2-positive early breast cancer (PHERGain): a multicentre, randomised, open-label, non-comparative, phase 2 trial Lancet Oncol 22(6) 858–871 https://doi.org/10.1016/S0140-6736(24)00054-0

41. van der Voort A, Louis FM, and van Ramshorst MS, and et al (2024) MRI-guided optimisation of neoadjuvant chemotherapy duration in stage II-III HER2-positive breast cancer (TRAIN-3): a multicentre, single-arm, phase 2 study Lancet Oncol 25(5) 603–613 https://doi.org/10.1016/S1470-2045(24)00104-9 PMID: 38588682

42. von Minckwitz G, Huang CS, and Mano MS, and et al (2018) Trastuzumab emtansine for residual invasive HER2-positive breast cancer NEJM 380(7) 617–628

43. Geyer CE, Untch M, and Huang CS, and et al (2025) Survival with trastuzumab emtansine in residual HER2-Positive breast cancer NEJM 392(3) 249–257 https://doi.org/10.1056/NEJMoa2406070

44. Chan A, Moy B, and Mansi J, and et al (2021) Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET Trial 21(1) 80–91.e7 Clin Breast Cancer 2021

45. Yau C, Osdoit M, and van der Noordaa M, and et al (2021) Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer: a multicentre pooled analysis of 5161 patients Lancet Oncol 23(1) 149–160

46. Chan A, Moy B, and Mansi J, and et al (2020) Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET Trial Clin Breast Cancer 21(1) 80–91.e7 PMID: 33183970

47. Meattini I, De Santis MC, and Visani L, and et al (2025) Single-modality endocrine therapy versus radiotherapy after breast-conserving surgery in women aged 70 years and older with luminal A-like early breast cancer (EUROPA): a preplanned interim analysis of a phase 3, non-inferiority, randomised trial Lancet Oncol 26(1) 37–50 https://doi.org/10.1016/S1470-2045(24)00661-2

48. Whelan TJ, Smith S, Parpia S, and et al (2023) Omitting radiotherapy after breast-conserving surgery in luminal a breast cancer NEJM 389(7) 612–619 https://doi.org/10.1056/NEJMoa2302344

49. Jagsi R, Griffith KA, and Harris EE, and et al (2024) Omission of radiotherapy after breast-conserving surgery for women with breast cancer with low clinical and genomic risk: 5-year outcomes of IDEA J Clin Oncol 42(4) 390–398 https://doi.org/10.1200/JCO.23.02270

50. Elder K, Coles C, and Dodwell D, and et al (2025) SMALL: open surgery versus minimally invasive vacuum-assisted excision for small screen-detected breast cancer-protocol for a phase III randomised multicentre trial BMJ Open 15(4) e099702 https://doi.org/10.1136/bmjopen-2025-099702

51. Takayama s, Takahashi, and Fujisawa T, and et al (2024) Radiofrequency ablation without excision for breast cancer: 5-year results of ipsilateral breast tumor recurrence-free survival in the RAFAELO study (NCCH1409) J Clin Oncol 42(16) 578–578 https://doi.org/10.1200/JCO.2024.42.16_suppl.578

52. Fine RE, Gilmore RC, and Tomkovich KR, and et al (2024) Cryoablation without excision for early-stage breast cancer: ICE3 trial 5-year follow-up on ipsilateral breast tumor recurrence Ann Surg Oncol 31(11) 7273–7283 PMID: 39283572 PMCID: 11452421

53. Brouwers B, Hatse S, and Lago LD, and et al (2016) The impact of adjuvant chemotherapy in older breast cancer patients on clinical and biological aging parameters Oncotarget 7(21) 29977–88 https://doi.org/10.18632/oncotarget.8796 PMID: 27102154 PMCID: 5058657

54. Freyer G, Campone M, and Peron J, and et al (2011) Adjuvant docetaxel/cyclophosphamide in breast cancer patients over the age of 70: results of an observational study Crit Rev Oncol Hematol 80(3) 466–73 https://doi.org/10.1016/j.critrevonc.2011.04.001 PMID: 21565521

55. Sawaki M, Taira N, and Uemura Y, and et al (2020) Randomized controlled trial of trastuzumab with or without chemotherapy for HER2-positive early breast cancer in older patients JCO 38(32) 3743–3752 https://doi.org/10.1200/JCO.20.00184

56. Brain E, Caillet P, and De Glas N, and et al (2019) HER2-targeted treatment for older patients with breast cancer: an expert position paper from the International Society of Geriatric Oncology J Geriatr Oncol 10(6) 1003–1013 https://doi.org/10.1016/j.jgo.2019.06.004

57. Brain E, Viansone AA, and Bourbouloux E, and et al (2022) ASCO Annual Meeting Chicago J Clin Oncol 40 2022 (suppl 16; abstr 500) https://doi.org/10.1200/JCO.2022.40.16_suppl.500

58. De Boniface J, Szulkin R, and Johansson ALV (2022) Major surgical postoperative complications and survival in breast cancer: swedish population-based register study in 57 152 women Br J Surg 109(10) 977–983 https://doi.org/10.1093/bjs/znac275

59. Gulis K, Ellbrant J, and Bendahl PO, and et al (2024) Health-related quality of life by type of breast surgery in women with primary breast cancer: prospective longitudinal cohort study BJS Open 8(3) zrae042 PMID: 38829692 PMCID: 11146426

60. Davies C, Johnson L, and Conefrey C, and et al (2024) Clinical and patient-reported outcomes in women offered oncoplastic breast-conserving surgery as an alternative to mastectomy: aNTHEM multicentre prospective cohort study Br J Surg 112(1) znae306 https://doi.org/10.1093/bjs/znae306 PMID: 39718969 PMCID: 11668256

61. Haussmann J, Budach W, and Corradini S, and et al (2023) Comparison of adverse events in partial- or whole breast radiotherapy: investigation of cosmesis, toxicities and quality of life in a meta-analysis of randomized trials Radiat Onoclogy 18(1) 181 https://doi.org/10.1186/s13014-023-02365-7

62. Shaitelman SF, Anderson BM, and Arthur DW, and et al (2024) Partial breast irradiation for patients with early-stage invasive breast cancer or ductal carcinoma in situ: an ASTRO Clinical Practice Guideline Prac Radi Onco 14(2) 112–132 https://doi.org/10.1016/j.prro.2023.11.001

63. Curigliano, Burstein HJ, and Winer EP, and et al (2017) De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017 Ann Oncol 28(8) 1700–1712 https://doi.org/10.1093/annonc/mdx308

64. Burstein HJ, Curigliano G, and Loibl S, and et al (2019) Estimating the benefits of therapy for early-stage breast cancer: the St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019 Ann Oncol 30(10) 1541–1557 https://doi.org/10.1093/annonc/mdz235

65. Di Lena E, Iny E, and Wong SM, and et al (2024) Impact of margin status on local recurrence in patients with breast cancer undergoing breast-conserving surgery after neoadjuvant chemotherapy: a retrospective multi-institutional cohort study Ann Surg Oncol 31(10) 6786–6794 PMID: 38969849

66. Feliciano Y, Mamtani A, and Morrow M, and et al (2017) Do calcifications seen on mammography after neoadjuvant chemotherapy for breast cancer always need to be excised? Ann Surg Oncol 24(6) 1492–1498 https://doi.org/10.1245/s10434-016-5741-y PMID: 28058550 PMCID: 5485840

67. Allotey J, Ruparel V, and McCallum A, and et al (2025) Residual microcalcifications after neoadjuvant systemic therapy for early breast cancer: implications for surgical planning and long-term outcomes EJCO 51(1) 108781

68. Spring LM, Fell G, and Arfe A, and et al (2020) Pathological complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and survival: a comprehensive meta-analysis Clin Cancer Res 26(12) 2838–2848 https://doi.org/10.1158/1078-0432.CCR-19-3492

69. Netti S, D’Ecclesiis O, and Corso F, and et al (2024) Methodological issues in radiomics: impact on accuracy of MRI for predicting response to neoadjuvant chemotherapy in breast cancer Eur Radiol 35(7) 4325–4334 https://doi.org/10.1007/s00330-024-11260-y PMID: 39702630

70. Tasoulis MK, Lee HB, and Yang W, and et al (2020) Accuracy of post-neoadjuvant chemotherapy image-guided breast biopsy to predict residual cancer JAMA Surg 155(12) e204103 https://doi.org/10.1001/jamasurg.2020.4103 PMID: 33026457 PMCID: 7542519

71. Kuerer HM, Rauch G, and Krishnamurthy S, and et al (2023) 243MO Omission of breast surgery after neoadjuvant systemic therapy for invasive cancer: three-year preplanned primary-endpoint on a phase II multicentre prospective trial Ann Oncol 34 S280 https://doi.org/10.1016/j.annonc.2023.09.441

72. Sparano JA, Gray JG, and Makower DF, and et al (2018) Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer NEJM 379(2) 111–121 https://doi.org/10.1056/NEJMoa1804710 PMID: 29860917 PMCID: 6172658

73. Sparano JA, Gray RJ, and Makower DF, and et al (2019) Clinical outcomes in early breast cancer with a high 21-gene recurrence score of 26 to 100 assigned to adjuvant chemotherapy plus endocrine therapy a secondary analysis of the TAILORx randomized clinical trial JAMA Oncol 6(3) 367–374

74. Chen N (2024) Impact of Anthracyclines in High Genomic Risk Node-Negative HR+/HER2- Breast Cancer (San Antonio: SABCS)

75. Kalinsky K, Barlow WE, and Gralow JR, and et al (2021) 21-gene assay to inform chemotherapy benefit in node-positive breast cancer NEJM 385(25) 2336–2347 21 2021

76. Kalinsky K, Barlow WE, and Pathak HB, and et al (2024) Correlation of serum anti-Müllerian hormone (AMH) levels on identification of premenopausal patients (pts) with hormone receptor positive (HR+), HER2-negative, node-positive breast cancer most likely to benefit from adjuvant chemotherapy in SWOG S1007 (RxPONDER) ASCO J Clin Oncol 42 505 https://doi.org/10.1200/JCO.2024.42.16_suppl.505

77. Piccart M, van 't Veer LJ, and Poncet C, and et al 2021) 70-gene signature as an aid for treatment decisions in early breast cancer: updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age Lancet Oncol 22(4) 476–488 https://doi.org/10.1016/S1470-2045(21)00007-3 PMID: 33721561

78. Pusztai L, Hoag JR, and Albain KS, and et al (2025) Development and validation of the RSClinN+ tool to predict prognosis and chemotherapy benefit for hormone receptor-positive, node-positive breast cancer JCO 43(8) 919–928

79. Francis PA, Fleming GF, and Láng I, and et al (2022) Adjuvant endocrine therapy in premenopausal breast cancer: 12-year results from SOFT JCO 41(7) 1370–1375

80. Paluch-Shimon S, Neven P, and Huober J, and et al (2023) Efficacy and safety results by menopausal status in monarchE: adjuvant abemaciclib combined with endocrine therapy in patients with HR+, HER2-, node-positive, high-risk early breast cancer Ther Adv Med Oncol 15 17588359231151840 https://doi.org/10.1177/17588359231151840 PMID: 36756142 PMCID: 9900651

81. Pan H, Gray R, and Braybrooke J, and et al (2017) 20-Year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years NEJM 377(19) 1836–1846 https://doi.org/10.1056/NEJMoa1701830 PMID: 29117498 PMCID: 5734609

82. Dowsett M, Sestak I, and Regan MM, and et al (2018) Integration of clinical variables for the prediction of late distant recurrence in patients with estrogen receptor-positive breast cancer treated with 5 years of endocrine therapy JCO 36(19) 1941–1948 https://doi.org/10.1200/JCO.2017.76.4258

83. Naito Y, Ozaki Y, and Tsuda H, and et al (2024) CtDNA monitoring for breast cancer at high risk of recurrence: interim analysis of JCOG1204A1 J Clin Oncol 42 518(2024) https://doi.org/10.1200/JCO.2024.42.16_suppl.518

84. Noordhoek I, Treuner K, and Putter H, and et al (2021) Breast cancer index predicts extended endocrine benefit to individualize selection of patients with HR+ early-stage breast cancer for 10 years of endocrine therapy Clin Cancer Res 2021 27(1) 311–319 https://doi.org/10.1158/1078-0432.CCR-20-2737

85. Bartlett JMS, Sgroi DC, and Treuner K, and et al (2019) Breast Cancer Index and prediction of benefit from extended endocrine therapy in breast cancer patients treated in the Adjuvant Tamoxifen-To Offer More? (aTTom) trial Ann Oncol 30(11) 1776–1783 https://doi.org/10.1093/annonc/mdz289 PMID: 31504126 PMCID: 6927322

86. Rastogi P, Bandos H, and Lucas PC, and et al (2024) Utility of the 70-gene mammaprint assay for prediction of benefit from extended letrozole therapy in the NRG Oncology/NSABP B-42 Trial J Clin Oncol 42(30) 3561–3569 https://doi.org/10.1200/JCO.23.01995 PMID: 39047219 PMCID: 11469649

87. Van Baelen K, Geukens T, and Maetens M, and et al (2022) Current and future diagnostic and treatment strategies for patients with invasive lobular breast cancer et al Ann Oncol 33(8) 769–785 https://doi.org/10.1016/j.annonc.2022.05.006

88. Cozzi A, Di Leo G, and Houssami N, and et al (2025) Preoperative breast MRI reduces reoperations for unilateral invasive lobular carcinoma: a patient-matched analysis from the MIPA study Eur Radiol 35(7) 3990–4000 https://doi.org/10.1007/s00330-024-11338-7

89. Van Hemert A, Van Loevezijn AA, and Bosman A, and et al (2024) Breast surgery after neoadjuvant chemotherapy in patients with lobular carcinoma: surgical and oncologic outcome Breast Cancer Res Treatment 204(3) 497–507 https://doi.org/10.1007/s10549-023-07192-8

90. Kim SY, Cho N, and Park IA, and et al (2024) Dynamic contrast-enhanced breast MRI for evaluating residual tumor size after neoadjuvant chemotherapy Breast Cancer Res Treatment 289(2) 327–334

91. Ulaner GA, Jhaveri K, and Chandarlapaty S, and et al (2021) Head-to-head evaluation of 18F-FES and 18F-FDG PET/CT in metastatic invasive lobular breast cancer J Nucl Med 62(3) 326–331 https://doi.org/10.2967/jnumed.120.247882 PMCID: 8049349

92. Weiser R, Polychronopoulou E, and Hatch SS, and et al 2022) Adjuvant chemotherapy in patients with invasive lobular carcinoma and use of the 21-gene recurrence score: A National Cancer Database analysis Cancer 128(9) 1738–1747 https://doi.org/10.1002/cncr.34127

93. Jiang YZ, Ma D, and Jin X, and et al (2024) Integrated multiomic profiling of breast cancer in the Chinese population reveals patient stratification and therapeutic vulnerabilities Nat Cancer 5(4) 673–690

94. Jin X, Zhou YF, and Ma D, and et al (2023) Molecular classification of hormone receptor-positive HER2-negative breast cancer Nat Genet 55(10) 1696–1708 https://doi.org/10.1038/s41588-023-01507-7 PMID: 37770634 PMCID: 10562210

95. Fasching PA, Stroyakovskiy D, and Yardley D, and et al (2024) LBA13 Adjuvant ribociclib (RIB) plus nonsteroidal aromatase inhibitor (NSAI) in patients (Pts) with HR+/HER2− early breast cancer (EBC): 4-year outcomes from the NATALEE trial Abstract Book of the ESMO Congress 2024 (Barcelona) 35(2) https://doi.org/10.1016/j.annonc.2024.08.2251

96. Rastogi P, O'Shaughnessy J, and Martin M, and et al (2024) Adjuvant abemaciclib plus endocrine therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative, high-risk early breast cancer: results from a preplanned monarche overall survival interim analysis, including 5-year efficacy outcomes JCO 42(9) 987–993 https://doi.org/10.1200/JCO.23.01994

97. Cardoso F, O’Shaughnessy J, and Liu Z, and et al (2025) Pembrolizumab and chemotherapy in high-risk, early-stage, ER+/HER2- breast cancer: a randomized phase 3 trial Nat Med 31(2) 442–448 https://doi.org/10.1038/s41591-024-03415-7

98. Loi S, Salgado R, and Curigliano G, and et al (2025) Neoadjuvant nivolumab and chemotherapy in early estrogen receptor-positive breast cancer: a randomized phase 3 trial Nat Med 31(2) 433–441 PMID: 39838118 PMCID: 11835735

99. Pusztai L, Yau C, and Wolf DM, and et al (2021) Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: results from the adaptively randomized I-SPY2 trial Cancer Cell 39(7) 989–998.e5 https://doi.org/10.1016/j.ccell.2021.05.009 PMID: 34143979 PMCID: 11064785

100. Perez-Lopez R, Laleh NG, and Mahmood F, et al (2024) A guide to artificial intelligence for cancer researchers Nat Rev Cancer 24(6) 427-441 https://doi.org/10.1038/s41568-024-00694-7 PMID: 38755439

101. Boehm KM, El Nahhas OSM, and Marra A, and et al (2025) Multimodal histopathologic models stratify hormone receptor-positive early breast cancer Nat Commun 16(1) 2106 https://doi.org/10.1038/s41467-025-57283-x

102. Huynh E, Hosny A, and Guthier C, and et al (2020) Artificial intelligence in radiation oncology Nat Rev Clin Oncol 17(12) 771–781 https://doi.org/10.1038/s41571-020-0417-8 PMID: 32843739

103. Vaz SC, Woll JPP, and Cardoso F, and et al (2024) Joint EANM-SNMMI guideline on the role of 2-18FFDG PET/CT in no special type breast cancer : (endorsed by the ACR, ESSO, ESTRO, EUSOBI/ESR, and EUSOMA) Eur J Nucl Med Mol Imag 51(9) 2706–2732 https://doi.org/10.1007/s00259-024-06696-9

104. Groheux D, Vaz SC, and Poortmans P, and et al (2024) Role of 18FFDG PET/CT in patients with invasive breast carcinoma of no special type: literature review and comparison between guidelines Breast 78 103806 https://doi.org/10.1016/j.breast.2024.103806

105. Van Hemert AKE, Van Duijnhoven FH, and Vrancken Peeters MJTFD (2023) This house believes that: mARI/TAD is better than sentinel node biopsy after PST for cN+ patients Breast 71 89–95 https://doi.org/10.1016/j.breast.2023.06.011 PMID: 37562108 PMCID: 10432821

106. Loibl S, André F, and Bachelot T, and et al (2024) Early breast cancer: eSMO Clinical Practice Guideline for diagnosis, treatment and follow-up Ann Oncol 35(2) 159–182 https://doi.org/10.1016/j.annonc.2023.11.016

107. Moloney BM, McAnena PF, and Ryan EJ, and et al (2020) The impact of preoperative breast magnetic resonance imaging on surgical management in symptomatic patients with invasive lobular carcinoma Breast Cancer 14 1178223420948477 PMCID: 7430084

108. Park AR, Chae EY, and Kim HJ, and et al (2023) Effects of preoperative breast MRI on breast cancer survival outcomes in women aged 35 years and younger Radiology 307(4) e221797 https://doi.org/10.1148/radiol.221797

109. Zeng Z, Amin A, and Roy A, and et al (2020) Preoperative magnetic resonance imaging use and oncologic outcomes in premenopausal breast cancer patients NPJ Breast Cancer 6 49 eCollection 2020 https://doi.org/10.1038/s41523-020-00192-7 PMID: 33083528 PMCID: 7532157

110. Rosselli Del Turco M, Palli D, and Cariddi A, and et al (1994) Intensive diagnostic follow-up after treatment of primary breast cancer. A randomized trial JAMA 271(20) 1593–7 https://doi.org/10.1001/jama.1994.03510440053032

111. Ghezzi P, Magnanini S, and Rinaldini M, and et al (1994) Impact of follow-up testing on survival and health-related quality of life in breast cancer patients. A multicenter randomized controlled trial JAMA 271(20) 1587–92 https://doi.org/10.1001/jama.1994.03510440047031

112. Buys SS, Sandbach JF, and Gammon A, and et al (2017) A study over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes Cancer 123(10) 1721–1730 https://doi.org/10.1002/cncr.30498

113. Sun L, Brentnall A, and Patel S, and et al (2019) A cost-effectiveness analysis of multigene testing for all patients with breast cancer Jama Oncol 5(12) 1718–1730 https://doi.org/10.1001/jamaoncol.2019.3323 PMCID: 6777250

114. Tutt ANJ, Garber JE, and Kaufman B, and et al (2021) Adjuvant olaparib for patients with BRCA1 or BRCA-mutated breast cancer NEJM 384(25) 2394–2405 https://doi.org/10.1056/NEJMoa2105215

115. Allen I, Hassan H, and Walburga Y, and et al (2025) Second primary cancer risks after breast cancer in BRCA1 and BRCA2 pathogenic variant carriers JCO 43(6) 651–661 https://doi.org/10.1200/JCO.24.01146

116. Metcalfe K, Huzarski T, and Gronwald J, and et al (2023) Risk-reducing mastectomy and breast cancer mortality in women with a BRCA1 or BRCA2 pathogenic variant: an international analysis Br J Cancer 130(2) 269–274 PMID: 38030749 PMCID: 10803363

117. Blondeaux E, Sonnenblick A, and Agostinetto E, and et al (2025) Association between risk-reducing surgeries and survival in young BRCA carriers with breast cancer: an international cohort study Lancet Oncol 26(6):759–770 https://doi.org/10.1016/S1470-2045(25)00152-4

118. Metcalfe K, Huzarski T, and Gronwald J, and et al (2024) Risk-reducing mastectomy and breast cancer mortality in women with a BRCA1 or BRCA2 pathogenic variant: an international analysis Br J Cancer 130(2):269–274 https://doi.org/10.1038/s41416-023-02503-8

119. Yadav S, Boddicker NJ, and Na J, and et al (2023) Contralateral breast cancer risk among carriers of germline pathogenic variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 JCO 41(9) 1703–1713 https://doi.org/10.1200/JCO.22.01239

120. Galimberti G, Corso G, and Morigi C, and et al (2017) Nipple-sparing and skin-sparing mastectomy: reviews of aims, oncological safety and contra-indications Breast 34 Suppl 1(Suppl 1) S82–S84

121. Hammond JB, Kandi LA, and Armstrong VL, and et al (2022) Long-term breast and nipple sensation after nipple-sparing mastectomy with implant reconstruction: relevance to physical, psychosocial, and sexual well-being J Plast Reconstr Aesthet Surg 75(9) 2914–2919 https://doi.org/10.1016/j.bjps.2022.06.034 PMID: 35915018

122. Peled AW, Von Eyben R, and Peled ZM (2023) Sensory outcomes after neurotization in nipple-sparing mastectomy and implant-based breast reconstruction Plast Reconstr Surg Glob Open 11(12) e5437 https://doi.org/10.1097/GOX.0000000000005437 PMID: 38074501 PMCID: 10703124

123. Sessa C, Balmaña J, and Bober SL, and et al (2023) Risk reduction and screening of cancer in hereditary breast-ovarian cancer syndrome: eSMO clinical practice guidelines Ann Oncol 34(1) 33–47 https://doi.org/10.1016/j.annonc.2022.10.004

124. Lubinski J, Kotsopoulos J, and Moller P, and et al (2024) MRI surveillance and breast cancer mortality in women with BRCA1 and BRCA2 sequence variations JAMA Oncol 10(4) 493–499 https://doi.org/10.1001/jamaoncol.2023.6944 PMCID: 10905376

125. Kotsopoulos J, Gronwald J, and Huzarski T, and et al (2023) Tamoxifen and the risk of breast cancer in women with a BRCA1 or BRCA2 mutation Breast Cancer Res Treat 201(2) 257–264 https://doi.org/10.1007/s10549-023-06991-3 PMID: 37432545

126. Blondeaux E, Sonnenblick A, and Agostinetto E, and et al (2025) Association between risk-reducing surgeries and survival in young BRCA carriers with breast cancer: an international cohort study Lancet Oncol 26(6) 759–770 https://doi.org/10.1016/S1470-2045(25)00152-4

127. Daniele A, Divella R, and Pilato B, and et al (2021) Can harmful lifestyle, obesity and weight changes increase the risk of breast cancer in BRCA1 and BRCA2 mutation carriers? A mini review Hered Cancer Clin Pract 19(1) 45 https://doi.org/10.1186/s13053-021-00199-6

128. Bucy AM, Valencia CI, and Howe CL, and et al (2022) Physical activity in young BRCA carriers and reduced risk of breast cancer Am J Prev Med 837–845 https://doi.org/10.1016/j.amepre.2022.04.022 PMID: 35738959 PMCID: 9900869

129. Jozsa F, Ahmed M, and Baker R, and et al (2019) Is sentinel node biopsy necessary in the radiologically negative axilla in breast cancer? Breast Cancer Res Treatment 177(1) 1–4 https://doi.org/10.1007/s10549-019-05299-5

130. Banys-Paluchowski M, Rubio IT, and Ditsch N, and et al (2023) Real de-escalation or escalation in disguise? Breast 69 249–257 https://doi.org/10.1016/j.breast.2023.03.001 PMID: 36898258 PMCID: 10017412

131. Grova MM, Strassle PD, and Navajas EE, and et al (2021) The prognostic value of axillary staging following neoadjuvant chemotherapy in inflammatory breast cancer Ann Surg Oncol 28(4) 2182–2190 https://doi.org/10.1245/s10434-020-09152-8

132. Lu X, He M, and Yu L, and et al (2023) Is repeat sentinel lymph node biopsy possible for surgical axillary staging among patients with ipsilateral breast tumor recurrence? Cancer 129(10) 1492–1501

133. Poodt IGM, Vugts G, and Schipper RJ, and et al (2018) Repeat sentinel lymph node biopsy for ipsilateral breast tumor recurrence: a systematic review of the results and impact on prognosis Ann Surg Oncol 25(5) 1329–1339

134. Lisboa FCAP, Silva RB, and De Andrade KRC, and et al (2020) Axillary surgical approach in metastatic breast cancer patients: a systematic review and meta-analysis Ecancermedicalscience 14 1117 https://doi.org/10.3332/ecancer.2020.1117

135. Geng C, Chen X, and Pan X, and et al (2016) The feasibility and accuracy of sentinel lymph node biopsy in initially clinically node-negative breast cancer after neoadjuvant chemotherapy: a systematic review and meta-analysis PLoS One 11(9) e0162605 https://doi.org/10.1371/journal.pone.0162605

136. Khaler-Ribeiro Fontana S, Pagan E, and Magnoni F, and et al (2021) Long-term standard sentinel node biopsy after neoadjuvant treatment in breast cancer: a single institution ten-year follow-up EJCO 47(4) 804–812

137. Samiei S, de Mooij CM, and Lobbes MBI, and et al (2021) Diagnostic performance of noninvasive imaging for assessment of axillary response after neoadjuvant systemic therapy in clinically node-positive breast cancer: a systematic review and meta-analysis Ann Surg 273(4) 694–700 https://doi.org/10.1097/SLA.0000000000004356

138. van Hemert AKE, van Loevezijn AA, and Baas MSPD, and et al (2025) Omitting axillary lymph node dissection in breast cancer patients with extensive nodal disease and excellent response to primary systemic therapy using the MARI protocol Breast 80 104411 https://doi.org/10.1016/j.breast.2025.104411 PMID: 39954569 PMCID: 11872389

139. Barrio AV, Montagna G, and Mamtani A, and et al (2021) Nodal recurrence in patients with node-positive breast cancer treated with sentinel node biopsy alone after neoadjuvant chemotherapy-a rare event JAMA Oncol 7(12) 1851–1855 https://doi.org/10.1001/jamaoncol.2021.4394 PMID: 34617979 PMCID: 8498932

140. Montagna G, Mrdutt MM, and Sun SX, and et al (2024) Omission of axillary dissection following nodal downstaging with neoadjuvant chemotherapy JAMA Oncol 10(6) 793–798 PMCID: 11046400

141. Boughey JC, Yu H, and Switalla K, and et al (2025) Oncologic Outcomes with De-Escalation of Axillary Surgery After Neoadjuvant Chemotherapy for Breast Cancer: results from u003e 1500 Patients on the I-SPY2 Clinical Trial Ann Surg Oncol 32(5) 3278–3291

142. Muslumanoglu M, Mollavelioglu B, and Cabioglu N, and et al (2024) Axillary lymph node dissection is not required for breast cancer patients with minimal axillary residual disease after neoadjuvant chemotherapy WJSO 22(1) 286

143. Cabıoğlu N, Karanlık H, and Yıldırım N, and et al (2021) Favorable outcome with sentinel lymph node biopsy alone after neoadjuvant chemotherapy in clinically node positive breast cancer at diagnosis: turkish Multicentric NEOSENTI-TURK MF-18-02-study Eur J Surg Oncol 47(10) 2506–2514 https://doi.org/10.1016/j.ejso.2021.06.024

144. Montagna G, Laws A, and Ferrucci M, and et al (2024) Nodal burden and oncologic outcomes in patients with residual isolated tumor cells after neoadjuvant chemotherapy (ypN0i+): the OPBC-05/ICARO Study JCO 43(7) 810–820

145. Kaidar-Person O, Pfob A, and Gentilini OD, and et al (2023) The Lucerne Toolbox 2 to optimize axillary management for early breast cancer: a multidisciplinary expert consensus Lancet 61 102085

146. Haviland JS, Owen JR, and Dewar JA, and et al (2013) The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials Lancet 14(11) 1086–1094 https://doi.org/10.1016/S1470-2045(13)70386-3

147. Brunt AM, Haviland JS, and Wheatley DA, and et al (2020) Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial Lancet 395(10237) 1613–1626

148. Richardson WS, Wilson MC, and Nishikawa J, and et al (1995) The well-built clinical question: a key to evidence-based decisions ACP J ACP J 123(3) A12-3

149. Postmus D, Litiere S, and Bogaerts J, and et al (2024) Attitudes of healthcare professionals and drug regulators about progression-free survival as endpoint in the advanced cancer setting Eur J Cancer 197 113496 https://doi.org/10.1016/j.ejca.2023.113496

150. Saesen R, Espinasse C, and Pignatti F, and et al (2022) Advancing academia-driven treatment optimisation in oncology: launch of the EMA Cancer Medicines Forum Eur J Cancer 168 77–79 https://doi.org/10.1016/j.ejca.2022.03.025 PMID: 35462319

151. Loibl S, Azim HA, and Bachelot T, and et al (2023) ESMO Expert Consensus Statements on the management of breast cancer during pregnancy (PrBC) Ann Oncol 34(10) 849–866 https://doi.org/10.1016/j.annonc.2023.08.001

152. Peccatori FA, Azim HA, and Orecchia R, and et al (2013) Cancer, pregnancy and fertility: eSMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 24 Suppl 6 vi160-70 https://doi.org/10.1093/annonc/mdt199 PMID: 23813932

153. Loibl S, Schmidt A, and Gentilini O, and et al (2015) Breast cancer diagnosed during pregnancy: adapting recent advances in breast cancer care for pregnant patients JAMA Oncol 1(8) 1145–53 https://doi.org/10.1001/jamaoncol.2015.2413 PMID: 26247818

154. Amant F, Vandenbroucke T, and Verheecke M, and et al (2015) Pediatric outcome after maternal cancer diagnosed during pregnancy NEJM 373(19) 1824–1834 https://doi.org/10.1056/NEJMoa1508913 PMID: 26415085

155. Razeti MG, Soldato D, and Arecco L, and et al (2023) Approaches to Fertility Preservation for Young Women With Breast Cancer Clin Breast Cancer 23(3) 241–248 https://doi.org/10.1016/j.clbc.2023.01.006 PMID: 36710145

156. Zong X, Yu Y, and Yang H, and et al (2022) Effects of Gonadotropin-Releasing Hormone Analogs on Ovarian Function Against CT-Induced Gonadotoxic Effects in Premenopausal Women With Breast Cancer in China: a Randomized Clinical Trial JAMA Oncol 8(2) 252–258

157. Von Wolff M, Germeyer A, and Liebenthron J, and et al (2017) Practical recommendations for fertility preservation in women by the FertiPROTEKT network. Part II: fertility preservation techniques Arch Gynecol Obstet 297(1) 257–267

158. Perachino M, Poggio F, and Arecco L, and et al (2022) Update on Pregnancy Following Breast Cancer Diagnosis and Treatment Cancer J 28(3) 176–182 https://doi.org/10.1097/PPO.0000000000000599 PMID: 35594464

159. Lambertini M, Peccatori FA, and Demeestere I, and et al (2020) Fertility preservation and post-treatment pregnancies in post-puberal cancer patients: eSMO clinical practice guidelines Ann Oncol 31(12) 1664–1678 https://doi.org/10.1016/j.annonc.2020.09.006

160. Pagani O, Ruggeri M, and Manunta S, and et al (2015) Pregnancy after breast cancer: are young patients willing to participate in clinical studies? Breast 24(3):201–7 https://doi.org/10.1016/j.breast.2015.01.005 PMID: 25662412

161. Arecco L and Lambertini M (2023) Safety of interrupting adjuvant endocrine therapy to conceive: early data are POSITIVE Nat Rev Clin Oncol 20(10) 662–663 https://doi.org/10.1038/s41571-023-00797-4 PMID: 37414910

162. Peccatori FA, Prosperi Porta R, and Azim HA, and et al (2025) Reproductive autonomy and breastfeeding in young breast cancer survivors Cancer 131(1) e35602 https://doi.org/10.1002/cncr.3560

163. Blondeaux E, and et al (2024) Breastfeeding after breast cancer in young BRCA carriers: results from an international cohort study (Barcelona: ESMO 2024) 35 pp 2S1076–S1077 https://doi.org/10.1016/j.annonc.2024.08.1911

164. Franzoi MA, Aupomerol M, and Havas J, and et al (2024) Investigating sexual health after breast cancer by longitudinal assessment of patient-reported outcomes ESMO Open 9(2) 102236 https://doi.org/10.1016/j.esmoop.2024.102236

165. Cucciniello L, Miglietta F, and Guarneri V, and et al (2024) Managing sexual health challenges in breast cancer survivors: a comprehensive review Breast 76 103754 https://doi.org/10.1016/j.breast.2024.103754 PMCID: 11170478

166. Francis PA, Pagani O, and Fleming GF, and et al (2018) Tailoring adjuvant endocrine therapy for premenopausal breast cancer NEJM 379(2) 122–137 https://doi.org/10.1056/NEJMoa1803164

167. Beste ME, Kaunitz AM, and Mckinney JA, and et al (2025) Vaginal estrogen use in breast cancer survivors: a systematic review and meta-analysis of recurrence and mortality risks Am J Obstet Gynecol 232(3) 262–270.e1 https://doi.org/10.1016/j.ajog.2024.10.054

168. Partridge AH, Hughes ME, and Warner ET, and et al (2016) Subtype-dependent relationship between young age at diagnosis and breast cancer survival J Clin Oncol 34(27) 3308–3314 https://doi.org/10.1200/JCO.2015.65.8013

169. Lambertini M, Kim HJ, and Poorvu P (2022) Editorial: breast Cancer in Young Women: Dedicated Research Efforts Are Needed Front Oncol 12 913167 https://doi.org/10.3389/fonc.2022.913167 PMID: 35719912 PMCID: 9198590

170. Howard-Anderson J, Ganz PA, and Bower JE, and et al 2012) Quality of life, fertility concerns, and behavioral health outcomes in younger breast cancer survivors: a systematic review J Natl Cancer Inst 104(5) 386–405 https://doi.org/10.1093/jnci/djr541 PMID: 22271773

171. Kent EE, Smith AW, and Keegan THM, and et al (2018) Talking about cancer and meeting peer survivors: social information needs of adolescents and young adults diagnosed with cancer Adolesc Young Adult Oncol 2(2) 44–52

172. Zebrack BJ, Block R, and Hayes‐Lattin B, and et al (2013) Psychosocial service use and unmet need among recently diagnosed adolescent and young adult cancer patients Cancer 119(1) 201–14 https://doi.org/10.1002/cncr.27713

173. Schmid P, Cortes J, and Dent R, and et al (2024) Overall survival with pembrolizumab in early-stage triple-negative breast cancer NEJM 391(21):1981–1991 https://doi.org/10.1056/NEJMoa2409932

174. Sharma P, Stecklein SR, and Yoder R, and et al (2024) Clinical and biomarker findings of neoadjuvant pembrolizumab and carboplatin plus docetaxel in triple-negative breast cancer: neoPACT phase 2 clinical trial JAMA Oncol 10(2) 227–235 https://doi.org/10.1001/jamaoncol.2023.5033

175. Ignatiadis M, Bailey A, and Mcarthur H, and et al (2025) Adjuvant atezolizumab for early triple-negative breast cancer: the ALEXANDRA/IMpassion030 Randomized Clinical Trial JAMA 333(13) 1150–1160 https://doi.org/10.1001/jama.2024.26886 PMID: 39883436 PMCID: 11783246

176. Symmans WF, Yau C, and Chen YY, and et al (2021) Assessment of residual cancer burden and event-free survival in neoadjuvant treatment for high-risk breast cancer: an analysis of data from the i-SPY2 randomized clinical trial JAMA Oncol 7(11) 1654–1663 https://doi.org/10.1001/jamaoncol.2021.3690 PMID: 34529000 PMCID: 8446908

177. Luen SJ, Salgado R, and Dieci MV, and et al (2019) Prognostic implications of residual disease tumor-infiltrating lymphocytes and residual cancer burden in triple-negative breast cancer patients after neoadjuvant chemotherapy Ann Oncol 30(2) 236–242

178. Conte PF, and et al (2024) A-BRAVE trial: a phase III randomized trial with avelumab in early triple-negative breast cancer with residual disease after neoadjuvant chemotherapy or at high risk after primary surgery and adjuvant chemotherapy In ASCO 2024

179. Loibl S, Schneeweiss A, and Huober J, and et al (2022) Neoadjuvant durvalumab improves survival in early triple-negative breast cancer independent of pathological complete response Ann Oncol 33(11) 1149–1158 https://doi.org/10.1016/j.annonc.2022.07.1940

180. Masuda N, Lee SJ, and Ohtani S, and et al (2017) Adjuvant capecitabine for breast cancer after preoperative chemotherapy NEJM 376(22) 2147–2159 https://doi.org/10.1056/NEJMoa1612645

181. Lluch A, Barrios CH, and Torrecillas L, and et al (2019) Phase III trial of adjuvant capecitabine after standard neo-/adjuvant chemotherapy in patients with early triple-negative breast cancer (GEICAM/2003-11_CIBOMA/2004-01) J Clin Oncol 38(3) 203–213

182. Tarantino P, Leone J, and Vallejo CT, and et al (2024) Prognosis and treatment outcomes for patients with stage IA triple-negative breast cancer NPJ Breast Cancer 10(1) 26 https://doi.org/10.1038/s41523-024-00634-6 PMID: 38575691 PMCID: 10995121

183. Thomas A, Reis-Filho JS, and Geyer CE, and et al (2023) Rare subtypes of triple negative breast cancer: current understanding and future directions NPJ Breast Cancer 9(1) 55 https://doi.org/10.1038/s41523-023-00554-x PMID: 37353557 PMCID: 10290136

184. Leon-Ferre RA, Jonas SF, and Salgado R, and et al (2024) Tumor-infiltrating lymphocytes in triple-negative breast cancer JAMA 331(13) 1135–1144 PMCID: 10988354

185. Geurts VCM, Balduzzi S, and Steenbruggen TG, and et al (2024) Tumor-infiltrating lymphocytes in patients with stage I triple-negative breast cancer untreated with chemotherapy JAMA Oncol 10(8) 1077–1086 https://doi.org/10.1001/jamaoncol.2024.1917 PMID: 38935352 PMCID: 11211993

186. Staaf J, Glodzik D, and Bosch A, and et al (2019) Whole-genome-sequencing of triple negative breast cancers in a population-based clinical study Nat Med 25(10) 1526–1533 https://doi.org/10.1038/s41591-019-0582-4 PMCID: 6859071

187. Garner JE (2024) PARP inhibition shows long-term survival benefits for patients with high-risk, BRCA-positive breast cancer in olympia trial (San Antonio: SABCS 2024)

188. Harvey-Jones E, Raghunandan M, and Robbez-Masson L, and et al (2024) Longitudinal profiling identifies co-occurring BRCA1/2 reversions, TP53BP1, RIF1 and PAXIP1 mutations in PARP inhibitor-resistant advanced breast cancer Ann Oncol 35(4) 364–380 https://doi.org/10.1016/j.annonc.2024.01.003 PMID: 38244928

189. Johnson DB, Nebhan CA, and Moslehi JJ, and et al (2022) Immune-checkpoint inhibitors: long-term implications of toxicity Nat Rev Clin Oncol 19(4) 254–267 https://doi.org/10.1038/s41571-022-00600-w PMID: 35082367 PMCID: 8790946

190. Winship AL, Alesi LR, and Sant S, and et al (2022) Checkpoint inhibitor immunotherapy diminishes oocyte number and quality in mice Nat Cancer 3(8) 1–13 https://doi.org/10.1038/s43018-022-00413-x PMID: 36008687

191. Postow MA, Sidlow R, and Hellmann MD, and et al (2018) Immune-related adverse events associated with immune checkpoint blockade NEJM 378(2) 158–168 https://doi.org/10.1056/NEJMra1703481