Third national surgical consensus conference of the Italian Association of Breast Surgeons (ANISC) on management after neoadjuvant chemotherapy: The difficulty in reaching a consensus.

INTRODUCTION: Neoadjuvant chemotherapy (NAC) has a profound impact on surgical management of breast cancer. For this reason, the Italian Association of Breast Surgeons (ANISC) promoted the third national Consensus Conference on this subject, open to multidisciplinary specialists. MATERIALS AND METHODS: The Consensus Conference was held on-line in November 2022, and after an introductory session with five core-team experts, participants were asked to vote on eleven controversial issues, while results were collected in real-time with a polling system. RESULTS: A total of 164 dedicated specialists from 74 Breast Centers participated. Consensus was reached for only three of the eleven issues, including: 1) the indication to assess the response with Magnetic Resonance Imaging (79 %); 2) the need to re-assess the biological factors of the residual tumor if present (96 %); 3) the possibility of omitting a formal axillary node dissection for cN1 patients if a pathologic Complete Response (pCR) was confirmed with analysis of one or more sentinel lymph nodes (82 %). The majority voted in favor of mapping both the breast and nodal lesions pre-NAC (59 %), and against the omission of sentinel lymph node biopsy in cN0 patients in the case of pathologic or clinical Complete Response (69 %). In cases of cT3/cN1+ tumors with pCR, only 8 % of participants considered appropriate the omission of Post-Mastectomy Radiation Therapy. CONCLUSION: There is still a wide variability in surgical approaches after NAC in the "real world". As NAC is increasingly used, multidisciplinary teams should be attuned to conforming their procedures to the rapid advances in this field.

"Positioning of tucatinib in the new clinical scenario of HER2-positive metastatic breast cancer: An Italian and Spanish consensus paper".

INTRODUCTION: Advancements in monoclonal antibodies, tyrosine kinase inhibitors, and antibody drug conjugates (ADCs) have notably enhanced outcomes for metastatic HER2-positive breast cancer patients. Despite the expanding treatment options and clinical complexities, determining the optimal sequence of HER2-targeted therapies remains partly uncertain, influenced by various factors. METHODS: To refine HER2-positive metastatic breast cancer management, particularly regarding tucatinib's position, a Steering Committee of leading oncologists in breast cancer care devised a panel of statements via a Delphi approach, focusing on five key topics: general clinical management, therapeutic approaches for patients with HER2-positive breast cancer and brain metastases, treatment sequence, and tucatinib's safety and efficacy. RESULTS: A total of 29 statements were deliberated, with strong consensus achieved for most. However, no consensus emerged regarding the management of brain progression alongside stable extracranial disease: 48 % advocated for switching to tucatinib, while 53 % favored a stereotactic brain radiotherapy (SBRT) approach if feasible. CONCLUSION: The unanimous consensus attained in this Delphi panel, particularly regarding tucatinib's efficacy and safety, underscores oncologists' recognition of its clinical significance based on existing trial data. These findings align closely with current literature, shedding light on areas necessitating further investigation, not thoroughly explored in prior studies. Moreover, the results underscore the scarcity of data on managing brain progression alongside stable extracranial disease, emphasizing the imperative for dedicated research to address these gaps and yield definitive insights.

Intermediate clinical endpoints in early-stage breast cancer: an analysis of individual patient data from the Gruppo Italiano Mammella and Mammella Intergruppo trials.

Background: Intermediate clinical endpoints (ICEs) are frequently used as primary endpoint in randomised trials (RCTs). We aim to assess whether changes in different ICEs can be used to predict changes in overall survival (OS) in adjuvant breast cancer trials. Methods: Individual patient level data from adjuvant phase III RCTs conducted by the Gruppo Italiano Mammella (GIM) and Mammella Intergruppo (MIG) study groups were used. ICEs were computed according to STEEP criteria. Using a two-stage meta-analytic model, we assessed the surrogacy of each ICE at both the outcome (i.e., OS and ICE are correlated irrespective of treatment) and trial (i.e., treatment effects on ICE and treatment effect on OS are correlated) levels. The following ICEs were considered as potential surrogate endpoints of OS: disease-free survival (DFS), distant disease-free survival (DDFS), distant relapse-free survival (DRFS), recurrence-free survival (RFS), recurrence-free interval (RFI), distant recurrence-free interval (DRFI), breast cancer-free interval (BCFI), and invasive breast cancer-free survival (IBCFS). The estimates of the degree of correlation were obtained by copula models and weighted linear regression. Kendall's τ and R2 ≥ 0.70 were considered as indicators of a clinically relevant surrogacy. Findings: Among the 12,397 patients enrolled from November 1992 to July 2012 in six RCTs, median age at enrolment was 57 years (interquartile range (IQR) 49-65). After a median follow-up of 10.3 years (IQR 6.4-14.5), 2131 (17.2%) OS events were observed, with 1390 (65.2%) attributed to breast cancer. At the outcome-level, Kendall's τ ranged from 0.69 for BCFI to 0.84 for DRFS. For DFS, DDFS, DRFS, RFS, RFI, DRFI, BCFI, and IBCFS endpoints, over 95% of the 8-year OS variability was attributable to the variation of the 5-year ICE. At the trial-level, treatment effects for the different ICEs and OS were strongly correlated, with the highest correlation for RFS and DRFS and the lowest for BCFI. Interpretation: Our results provide evidence supporting the use of DFS, DDFS, DRFS, RFS, RFI, DRFI, and IBCFS as primary endpoint in breast cancer adjuvant trials. Funding: This analysis was supported by the Italian Association for Cancer Research ("Associazione Italiana per la Ricerca sul Cancro", AIRC; IG 2017/20760) and by Italian Ministry of Health-5 × 1000 funds (years 2021-2022).

Gender minorities in breast cancer - Clinical trials enrollment disparities: Focus on male, transgender and gender diverse patients.

BACKGROUND: The last years have seen unprecedented improvement in breast cancer (BC) survival rates. However, this entirely apply to female BC patients, since gender minorities (male, transgender/gender-diverse) are neglected in BC phase III registration clinical trials. METHODS: We conducted a scoping review of phase III clinical trials of agents with a current positioning within the therapeutic algorithms of BC. RESULTS: We selected 51 phase III trials. Men enrollment was allowed in 35.3% of trials. In none of the trial inclusion/exclusion criteria referred to transgender/gender-diverse people. A numerical higher rate of enrolled men was observed in the contemporary as compared to historical group. We found a statistically significant association between the drug class and the possibility of including men: 100%, 80%, 50%, 33.3%, 25%, 10% and 9.1% of trials testing ICI/PARP-i, ADCs, PI3K/AKT/mTOR-i, anti-HER2 therapy, CDK4/6-i, ET alone, and CT alone. Overall, 77409 patients were enrolled, including 112 men (0.2%). None of the trial reported transgender/gender-diverse people proportion. Studies investigating PARP-i were significantly associated with the highest rate of enrolled men (1.42%), while the lowest rates were observed for trials of CT (0.13%), ET alone (0.10%), and CDK 4/6-I (0.08%), p < 0.001. CONCLUSIONS: We confirmed that gender minorities are severely underrepresented among BC registration trials. We observed a lower rate of men in trials envisaging endocrine manipulation or in less contemporary trials. This work sought to urge the scientific community to increase the awareness level towards the issue of gender minorities and to endorse more inclusive criteria in clinical trials.

Identification of Patients with Early HR+ HER2- Breast Cancer at High Risk of Recurrence.

Breast cancer incidence has increased in the last two decades and, simultaneously, survival has improved due to earlier detection and improved treatment options. Despite this improvement, locoregional recurrences and distant metastases occur in up to 10 and 30% of women diagnosed with early breast cancer, respectively. Around 70% of breast cancers are hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), and associated with a persistent risk of relapse up to 20 years after diagnosis/initial treatment. We conducted a narrative review by combining PubMed searches with our clinical experience to describe patient characteristics, biomarkers, and genomic profiling tools available to clinicians for the identification of patients with HR+, HER2- early breast cancer at high risk of recurrence and to provide recommendations to classify patients into recurrence risk categories. National and international treatment guidelines are also summarised. Accurate assessment of the risk of recurrence in these patients is crucial as the predicted risk guides treatment decisions; imprecise estimations can result in over- or undertreatment, with either scenario having negative consequences for patients. Multiple prognostic tools and factors are recommended for early breast cancer, and no single test provides accurate prognosis in isolation. Since no single test can provide accurate prognosis in isolation, a combination of tools should be used. Risk thresholds are important to guide optimised and balanced therapeutic decisions in HR+, HER2- early breast cancer. However, prognostic assessment should be performed on a case-by-case basis, making patient-specific prognostic approaches essential to avoid over- or undertreatment.

Pregnancy After Breast Cancer in Young BRCA Carriers: An International Hospital-Based Cohort Study.

Importance: Young women with breast cancer who have germline pathogenic variants in BRCA1 or BRCA2 face unique challenges regarding fertility. Previous studies demonstrating the feasibility and safety of pregnancy in breast cancer survivors included limited data regarding BRCA carriers. Objective: To investigate cumulative incidence of pregnancy and disease-free survival in young women who are BRCA carriers. Design, Setting, and Participants: International, multicenter, hospital-based, retrospective cohort study conducted at 78 participating centers worldwide. The study included female participants diagnosed with invasive breast cancer at age 40 years or younger between January 2000 and December 2020 carrying germline pathogenic variants in BRCA1 and/or BRCA2. Last delivery was October 7, 2022; last follow-up was February 20, 2023. Exposure: Pregnancy after breast cancer. Main Outcomes and Measures: Primary end points were cumulative incidence of pregnancy after breast cancer and disease-free survival. Secondary end points were breast cancer-specific survival, overall survival, pregnancy, and fetal and obstetric outcomes. Results: Of 4732 BRCA carriers included, 659 had at least 1 pregnancy after breast cancer and 4073 did not. Median age at diagnosis in the overall cohort was 35 years (IQR, 31-38 years). Cumulative incidence of pregnancy at 10 years was 22% (95% CI, 21%-24%), with a median time from breast cancer diagnosis to conception of 3.5 years (IQR, 2.2-5.3 years). Among the 659 patients who had a pregnancy, 45 (6.9%) and 63 (9.7%) had an induced abortion or a miscarriage, respectively. Of the 517 patients (79.7%) with a completed pregnancy, 406 (91.0%) delivered at term (≥37 weeks) and 54 (10.4%) had twins. Among the 470 infants born with known information on pregnancy complications, 4 (0.9%) had documented congenital anomalies. Median follow-up was 7.8 years (IQR, 4.5-12.6 years). No significant difference in disease-free survival was observed between patients with or without a pregnancy after breast cancer (adjusted hazard ratio, 0.99; 95% CI, 0.81-1.20). Patients who had a pregnancy had significantly better breast cancer-specific survival and overall survival. Conclusions and Relevance: In this global study, 1 in 5 young BRCA carriers conceived within 10 years after breast cancer diagnosis. Pregnancy following breast cancer in BRCA carriers was not associated with decreased disease-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT03673306.

Breaking barriers in triple negative breast cancer (TNBC) - Unleashing the power of antibody-drug conjugates (ADCs).

Antibody-drug conjugates (ADCs) represent a novel class of molecules composed of a recombinant monoclonal antibody targeted to a specific cell surface antigen, conjugated to a cytotoxic agent through a cleavable or non-cleavable synthetic linker. The rationale behind the development of ADCs is to overcome the limitations of conventional chemotherapy, such as the narrow therapeutic window and the emergence of resistance mechanisms. ADCs had already revolutionized the treatment algorithm of HER2-positive breast cancer. Currently, emergent non-HER2 targeted ADCs are gaining momentum, with special focus on triple-negative disease therapeutic landscape. Sacituzumab govitecan (SG) is an ADC consisting of a humanized monoclonal antibody hRS7 targeting trophoblast cell surface antigen 2 (Trop2), linked to the topoisomerase I inhibitor SN-38 by a hydrolysable linker. It currently stands as the only non-HER2 targeted ADC that already received approval for the treatment of unresectable locally advanced or metastatic triple negative breast cancer (TNBC) in patients who had received two or more prior systemic therapies, with at least one for advanced disease. The purpose of these review is to analyze the available evidence regarding ADCs in TNBC, alongside with providing an overview on the ongoing and future research horizons in this field.

Essential requirements for reporting radiation therapy in breast cancer clinical trials: An international multi-disciplinary consensus endorsed by the European Society for Radiotherapy and Oncology (ESTRO).

The European Society for Radiotherapy and Oncology (ESTRO) has advocated the establishment of guidelines to optimise precision radiotherapy (RT) in conjunction with contemporary therapeutics for cancer care. Quality assurance in RT (QART) plays a pivotal role in influencing treatment outcomes. Clinical trials incorporating QART protocols have demonstrated improved survival rates with minimal associated toxicity. Nonetheless, in routine clinical practice, there can be variability in the indications for RT, dosage, fractionation, and treatment planning, leading to uncertainty. In pivotal trials reporting outcomes of systemic therapy for breast cancer, there is limited information available regarding RT, and the potential interaction between modern systemic therapy and RT remains largely uncharted. This article is grounded in a consensus recommendation endorsed by ESTRO, formulated by international breast cancer experts. The consensus was reached through a modified Delphi process and was presented at an international meeting convened in Florence, Italy, in June 2023. These recommendations are regarded as both optimal and essential standards, with the latter aiming to define the minimum requirements. A template for a case report form (CRF) has been devised, which can be utilised by all clinical breast cancer trials involving RT. Optimal requirements include adherence to predefined RT planning protocols and centralised QART. Essential requirements aim to reduce variations and deviations from the guidelines in RT, even when RT is not the primary focus of the trial. These recommendations underscore the significance of implementing these practices in both clinical trials and daily clinical routines to generate high-quality data.

Adjuvant treatment in hormone receptor-positive early breast cancer: New approaches of endocrine therapy.

Breast cancer is the most common cancer in women, and luminal breast cancer is the predominant subtype, characterized by the presence of estrogen receptors and/or progesterone receptors in tumor cells. Adjuvant endocrine therapy is the pivotal approach in the management of luminal early breast cancer. Hence, new therapeutic approaches have been studied during the last few years, especially in patients with high risk of recurrence.Here we provide a summary of the most recent clinical trials evaluating adjuvant treatment in hormone-receptors-positive early breast cancer. First, the main cornerstone is related to the role of extended endocrine treatment, which has been widely investigated to access a benefit in disease-free survival and overall survival (only the GIM4 trial has positive feedback about survival) and to tailor the treatment according to patient compliance. The results highlighted an advantage in extending the use of endocrine treatment for at least seven full years, considering aromatase inhibitors as principal drugs. Second, the shift of CDK4/6 inhibitors (CDK4/6i) from advanced to early setting reported positive outcomes, with favorable results from MonarchE and NATALEE trials, using Abemaciclib and Ribociclib respectively, even if non-negligible toxicities have been reported. Last, the use of PARP inhibitors for BRCA1/2 mutated patients has been evaluated in the OlympiA trial (Olaparib), observing a comparable benefit between hormone-receptors-positive and triple-negative early breast cancer.However, more data are still required to better select patients that could benefit more from CDK4/6i considering side effects too, and sequential treatments are still not codified.

Diagnosis of lung cancer following emergency admission: Examining care pathways, clinical outcomes, and advanced NSCLC treatment in an Italian cancer Center.

Background: Lung cancer patients diagnosed following emergency admission often present with advanced disease and poor performance status, leading to suboptimal treatment options and outcomes. This study aimed to investigate the clinical and molecular characteristics, treatment initiation, and survival outcomes of these patients. Methods: We retrospectively analyzed data from 124 patients diagnosed with lung cancer following emergency admission at a single institution. Clinical characteristics, results of molecular analyses for therapeutic purpose, systemic treatment initiation, and survival outcomes were assessed. Correlations between patients' characteristics and treatment initiation were analyzed. Results: Median age at admission was 73 years, and 79.0 % had at least one comorbidity. Most patients (87.1 %) were admitted due to cancer-related symptoms. Molecular analyses were performed in 89.5 % of advanced non-small cell lung cancer (NSCLC) cases. In this subgroup, two-thirds (66.2 %) received first-line therapy. Median overall survival (OS) was 3.9 months for the entire cohort, and 2.9 months for patients with metastatic lung cancer. Among patients with advanced NSCLC, OS was significantly longer for those with actionable oncogenic drivers and those who received first-line therapy. Improvement of performance status during hospitalization resulted in increased probability of receiving first-line systemic therapy. Discussion: Patients diagnosed with lung cancer following emergency admission demonstrated poor survival outcomes. Treatment initiation, particularly for patients with actionable oncogenic drivers, was associated with longer OS. These findings highlight the need for proactive medical approaches, including improving access to molecular diagnostics and targeted treatments, to optimize outcomes in this patient population.

Evolving treatments and outcomes in HER2-Positive metastatic breast cancer: Data from the GIM14/BIOMETA study.

BACKGROUND: Treatment for HER2-positive (+) metastatic breast cancer has improved in the last decade. We analyzed treatment changes over time and their impact on patients outcomes in a real-world dataset. METHODS: Data from 637 HER2+ patients with metastatic breast cancer enrolled in the multicenter Italian GIM14/BIOMETA study were retrieved. Progression-free survival (PFS) over time was evaluated according to the type of anti-HER2 therapy, disease onset (de novo vs. relapsing), metastatic site, and year of treatment (2000-2013 vs. 2014-2020). RESULTS: Median follow-up was 64.4 months. Overall, for first-line therapies, mPFS was 16.5 vs 19.5 months for patients treated in 2000-2013 vs 2014-2020 (HR: 0.78, 95% CI:0.65-0.94, P = 0.008). mPFS improved over time in all patients except for those with brain metastasis. Interestingly mPFS was 17.4 vs13.4 months (HR, 1.49; 95% CI, 1.13-1.98, P = 0.005) in 2000-2013 and 24.4 vs 20.9 months (HR 1.04; 95% CI 0.78-1.40 p = 0.77) in 2014-2020 in pts without vs with liver metastases. For second line therapies, the overall median PFS was 9.6 months (95% CI, 8.31-10.97) and did not change over time. CONCLUSION: Median first-line PFS improved since 2014, mainly due to the introduction of pertuzumab. The outcome of patients with liver metastases appears to have improved in recent years. Patients with brain metastases had the worst PFS, which also did not improve over time.

SNP of Aromatase Predict Long-term Survival and Aromatase Inhibitor Toxicity in Patients with Early Breast Cancer: A Biomarker Analysis of the GIM4 and GIM5 Trials.

PURPOSE: In estrogen receptor-positive (ER+) breast cancer, single-nucleotide polymorphisms (SNP) in the aromatase gene might affect aromatase inhibitors (AI) metabolism and efficacy. Here, we assessed the impact of SNP on prognosis and toxicity of patients receiving adjuvant letrozole. EXPERIMENTAL DESIGN: We enrolled 886 postmenopausal patients in the study. They were treated with letrozole for 2 to 5 years after taking tamoxifen for 2 to 6 years, continuing until they completed 5 to 10 years of therapy. Germline DNA was genotyped for SNP rs4646, rs10046, rs749292, and rs727479. Log-rank test and Cox model were used for disease-free survival (DFS) and overall survival (OS). Cumulative incidence (CI) of breast cancer metastasis was assessed through competing risk analysis, with contralateral breast cancer, second malignancies and non-breast cancer death as competing events. CI of skeletal and cardiovascular events were assessed using DFS events as competing events. Subdistribution HR (sHR) with 95% confidence intervals were calculated through Fine-Gray method. RESULTS: No SNP was associated with DFS. Variants rs10046 [sHR 2.03, (1.04-2.94)], rs749292 [sHR 2.11, (1.12-3.94)], and rs727479 [sHR 2.62, (1.17-5.83)] were associated with breast cancer metastasis. Three groups were identified on the basis of the number of these variants (0, 1, >1). Variant-based groups were associated with breast cancer metastasis (10-year CI 2.5%, 7.6%, 10.7%, P = 0.035) and OS (10-year estimates 96.5%, 93.0%, 89.6%, P = 0.030). Co-occurrence of rs10046 and rs749292 was negatively associated with 10-year CI of skeletal events (3.2% vs. 10%, P = 0.033). A similar association emerged between rs727479 and cardiovascular events (0.3% vs. 2.1%, P = 0.026). CONCLUSIONS: SNP of aromatase gene predict risk of metastasis and AI-related toxicity in ER+ early breast cancer, opening an opportunity for better treatment individualization.

Estrogen deprivation effects of endocrine therapy in breast cancer patients: Incidence, management and outcome.

Endocrine therapy is one of the standard adjuvant treatments to reduce the risk of recurrence and mortality in patients with hormone receptor positive early breast cancer. Despite its proven efficacy, ET side effects, which persist over time even if low grade, may deteriorate quality of life. During follow-up visits, emphasis is generally placed on the risk of disease recurrence, while the topic of ET side effects is commonly neglected and discussed only briefly. This could lead to poor adherence to therapy and early treatment discontinuation, resulting in worse survival outcomes. The aim of this review is to provide an overview of the available evidence on the incidence and reporting of ET-related side effects (including vasomotor symptoms, musculoskeletal disorders and genitourinary syndrome of menopause, as well as fatigue, psychological and ocular disorders, dysmetabolic effects and loss of bone density) and of the pharmacological and non-pharmacological strategies available to mitigate symptom burden.

Spatial predictors of immunotherapy response in triple-negative breast cancer.

Immune checkpoint blockade (ICB) benefits some patients with triple-negative breast cancer, but what distinguishes responders from non-responders is unclear1. Because ICB targets cell-cell interactions2, we investigated the impact of multicellular spatial organization on response, and explored how ICB remodels the tumour microenvironment. We show that cell phenotype, activation state and spatial location are intimately linked, influence ICB effect and differ in sensitive versus resistant tumours early on-treatment. We used imaging mass cytometry3 to profile the in situ expression of 43 proteins in tumours from patients in a randomized trial of neoadjuvant ICB, sampled at three timepoints (baseline, n = 243; early on-treatment, n = 207; post-treatment, n = 210). Multivariate modelling showed that the fractions of proliferating CD8+TCF1+T cells and MHCII+ cancer cells were dominant predictors of response, followed by cancer-immune interactions with B cells and granzyme B+ T cells. On-treatment, responsive tumours contained abundant granzyme B+ T cells, whereas resistant tumours were characterized by CD15+ cancer cells. Response was best predicted by combining tissue features before and on-treatment, pointing to a role for early biopsies in guiding adaptive therapy. Our findings show that multicellular spatial organization is a major determinant of ICB effect and suggest that its systematic enumeration in situ could help realize precision immuno-oncology.

Toxicity profile of antibody-drug conjugates in breast cancer: practical considerations.

Antibody-drug conjugates (ADCs) represent a novel and evolving class of antineoplastic agents, constituted by monoclonal antibody linked to biologically active drugs, delivering cytotoxic compounds at the tumor site, reducing the likelihood of systemic exposure and toxicity. They are generally well tolerated, nevertheless some predictable adverse reactions need careful monitoring and timely approach. These include neutropenia, nausea and vomiting, alopecia, diarrhea, left ventricular dysfunction, ILD/pneumonitis. The mechanisms leading to drug-associated toxicities are summarized, and prophylaxis protocols and appropriate management strategies are proposed, based on current literature. This review aims to collect the most updated evidence on toxicities potentially occurring during breast cancer treatment with approved or under clinical investigation (advanced stage) ADCs. A focus is dedicated to monitoring protocols and clinical management, aimed at preventing and/or promptly address relevant problems, in order to avoid premature discontinuation or improper dose reduction.

Tucatinib's journey from clinical development to clinical practice: New horizons for HER2-positive metastatic disease and promising prospects for brain metastatic spread.

Approximately 20% of breast cancers (BCs) overexpress human epidermal growth factor receptor 2 (HER2), a transmembrane glycoprotein with tyrosine kinase activity, encoded by ERBB2 gene. Historically, HER2 overexpression has been linked with increased disease recurrence and a worse prognosis. However, the increasing availability of different anti-HER2 compounds and combinations is progressively improving HER2-positive BC outcome, thus requiring expertise to prioritize both overall survival (OS) prolongation and quality of life, without neglecting the accessibility to further treatment lines with a low attrition rate. In this context, tucatinib, an oral tyrosine kinase inhibitor, has recently been granted approval by regulatory agencies based on evidence from the HER2CLIMB, a clinical trial which randomized patients with metastatic BC to receive trastuzumab and capecitabine with either tucatinib or placebo. A distinctive feature of this study was the inclusion of patients with new or active brain metastases (BMs) at study entry, a population traditionally excluded from clinical trials. Thus, HER2CLIMB provides the first solid evidence of an OS benefit in patients with BC and BMs, addressing a long standing unmet medical need, especially given the high incidence of central nervous system metastatic spread in patients with HER2-positive disease. This review provides an overview of the molecular and clinical landscape of tucatinib for the treatment of advanced BC. It focuses on the technological journey that drove the development of this therapeutic innovation, from preclinical data to clinical practice.

Platinum-based chemotherapy and PARP inhibitors for patients with a germline BRCA pathogenic variant and advanced breast cancer (LATER-BC): retrospective multicentric analysis of post-progression treatments.

INTRODUCTION: Patients with breast cancer (BC) harbouring a germinal BRCA pathogenic variant (gBRCA-PV) may have an enhanced sensitivity to platinum-based chemotherapy (PBC) and PARP inhibitors (PARPi). As reported in ovarian cancer, however, sensitivity and resistance to these treatments could partially overlap. In patients with a gBRCA-PV and advanced BC (aBC), it remains unclear whether prior exposure to PARPi/PBC affects tumour response to subsequent PBC/PARPi, respectively. METHODS: We conducted a retrospective, multicentric study to investigate the clinical benefit of post-PBC PARPi and vice versa in patients with a gBRCA-PV and aBC. Patients included had received (neo)adjuvant PBC and then PARPi in advanced setting (group 1), PBC followed by PARPi (group 2) or PARPi followed by PBC (group 3), both in advanced setting. We reported median progression-free survival (mPFS) and disease control rate (DCR) in each group. RESULTS: A total of 67 patients from six centres were included. PARPi-mPFS in advanced setting was 6.1 months in patients in group 1 (N = 12), while PARPi-DCR was 67%. In group 2 (N = 36), PARPi-mPFS was 3.4 months and PARPi-DCR was 64%. Age < 65 years and platinum-free interval (PFI) > 6 months were associated with longer PARPi-PFS; previous PBC-PFS > 6 months and PBC in first to second line were associated with longer PARPi-DCR. Patients in group 3 (N = 21) reported a PBC-mPFS of 1.8 months and a PBC-DCR of 14%. PARPi-PFS ≥ 9 months and PARPi-FI ≥ 6 months were associated with better PBC-DCR. CONCLUSIONS: Sensitivity and resistance to PARPi and PBC partially overlap in patients with a gBRCA-PV and aBC. Evidence of PARPi activity emerged in patients who progressed on previous PBC.