Neoadjuvant chemotherapy for breast cancer in Italy: A Senonetwork analysis of 37,215 patients treated from 2017 to 2022.

BACKGROUND: Adoption of neoadjuvant chemotherapy (NACT) in the "real world" has been poorly investigated. Aim of this study was to examine the rate of NACT in Italy, trends over time and determinants of therapeutic choices. METHODS: Senonetwork, the recognized network of Breast Centers in Italy, has developed a voluntary national data warehouse with the aim to monitor and improve treatments quality. A retrospective analysis was conducted among 58,661 breast cancer (BC) patients treated between 2017 and 2022 by 24 high-volume Breast Centers participating in the project. RESULTS: After subset exclusion, 37,215 primary BC patients were analysed, 32,933 underwent primary-breast-surgery and 4,282 underwent NACT. From 2017 to 2022, the overall NACT incidence increased particularly for HR-/HER2+, Triple-Negative, and HR+/HER2+ BC (p < 0.001). In cN + patients the recommendation to axillary lymph-node dissection after NACT decreased over time along with an increase of <4 lymph-nodes removed (p < 0.001). Immediate breast reconstruction and indication for nipple sparing mastectomy increased significantly over time (OR = 1.10, p = 0.011 and OR 1.14, p < 0.001, respectively). On multivariate analysis, there was a trend towards an increased adoption of conservative treatment for HR-/HER2+ (p = 0.01) and Triple Negative tumors (p = 0.06). Implementation of NACT varied significantly among Breast-Centers from 3.8 to 17.7 % (p < 0.001). CONCLUSION: The impact of NACT on the subsequent surgical management is substantial and continues to evolve over time, resulting in less-extensive surgery. Even among high-volume Centers NACT implementation rate is still highly variable. Although we registered a significant increase in its use during the study period, these results need to be further improved.

Liquid biopsy in triple-negative breast cancer: unlocking the potential of precision oncology.

In the era of precision oncology, the management of triple-negative breast cancer (TNBC) is rapidly changing and becoming more complicated with a variety of chemotherapy, immunotherapy, and targeted treatment options. Currently, TNBC treatment is based on prognostic and predictive factors including immunohistochemical biomarkers [e.g. programmed death-ligand 1 (PD-L1)] and germline BRCA mutations. Given the current limitation of existing biomarkers, liquid biopsies may serve as clinically useful tools to determine treatment efficacy and response in both the (neo)adjuvant and metastatic settings, for detecting early relapse, and for monitoring clonal evolution during treatment. In this review, we comprehensively summarize current and future liquid biopsy applications. Specifically, we highlight the role of circulating tumor cell characterization, circulating tumor DNA, and other preclinical liquid biopsy technologies including circulating exosomes, RNA liquid biopsy, and circulating immune-based biomarkers. In the near future, these biomarkers may serve to identify early disease relapse, therapeutic targets, and disease clonality for patients with TNBC in the clinical setting.

Characteristics and clinical outcomes of breast cancer in young BRCA carriers according to tumor histology.

BACKGROUND: Young women with breast cancer (BC) have an increased chance of carrying germline BRCA pathogenic variants (PVs). Limited data exist on the prognostic impact of tumor histology (i.e. ductal versus lobular) in hereditary breast cancer. METHODS: This multicenter retrospective cohort study included women aged ≤40 years with early-stage breast cancer diagnosed between January 2000 and December 2020 and known to carry germline PVs in BRCA1/2. Histology was locally assessed in each center. The Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival and overall survival. RESULTS: Of 4628 patients included from 78 centers worldwide, 3969 (86%) had pure ductal, 135 (3%) pure lobular, and 524 (11%) other histologies. Compared with ductal tumors, lobular tumors were more often grade 1/2 (57.7% versus 22.1%), stage III (29.6% versus 18.5%), and luminal A-like (42.2% versus 12.2%). Lobular tumors were more often associated with BRCA2 PVs (71.1% BRCA2), while ductal tumors were more often associated with BRCA1 PVs (65.7% BRCA1). Patients with lobular tumors more often had mastectomy (68.9% versus 58.3%), and less often received chemotherapy (83.7% versus 92.9%). With a median follow-up of 7.8 years, no significant differences were observed in disease-free survival (adjusted hazard ratio 1.01, 95% confidence interval 0.74-1.37) or overall survival (hazard ratio 0.96, 95% confidence interval 0.62-1.50) between patients with ductal versus lobular tumors. No significant survival differences were observed according to specific BRCA gene, breast cancer subtype, or body mass index. CONCLUSIONS: In this large global cohort of young BRCA carriers with breast cancer, the incidence of pure lobular histology was low and associated with higher disease stage at diagnosis, luminal-like disease and BRCA2 PVs. Histology did not appear to impact prognosis.

Efficacy of adjuvant chemotherapy schedules for breast cancer according to body mass index: results from the phase III GIM2 trial.

BACKGROUND: The phase III GIM2 trial showed improved disease-free survival (DFS) and overall survival (OS) with adjuvant dose-dense (DD) as compared with standard-interval (SI) chemotherapy in women with node-positive early-stage breast cancer (BC). This exploratory analysis aimed to investigate the benefit of different schedules according to body mass index (BMI) in this trial. PATIENTS AND METHODS: This analysis explored the efficacy, in terms of DFS and OS, of different chemotherapy schedules according to BMI. Univariate and multivariable Cox proportional hazard models, adjusted for relevant prognostic factors, were used. RESULTS: Out of 2091 patients enrolled, 1925 with known baseline BMI were randomized in the DD versus SI comparison and therefore included in this analysis: 31.6% were overweight and 19.3% obese. Overweight and obesity were significantly associated with postmenopausal status, pT >2, and pN >2 tumors. After a median follow-up of 15.0 years (interquartile range 8.4-16.3 years), multivariable Cox survival models demonstrated no association of different BMI categories on DFS [adjusted hazard ratio (adjHR) 0.96, 95% confidence interval (CI) 0.80-1.15 and adjHR 1.11, 95% CI 0.91-1.35 for overweight and obese patients, respectively, compared to patients with normal BMI] or OS (adjHR 0.90, 95% CI 0.71-1.14 and adjHR 1.18, 95% CI 0.92-1.52 for overweight and obese patients, respectively). No significant interaction was found between BMI and treatment schedule in terms of DFS (Pfor interaction = 0.56) or OS (Pfor interaction = 0.19). The survival benefit of DD chemotherapy was observed irrespective of different BMI categories, with a more pronounced benefit for overweight and obese patients. CONCLUSION: In node-positive BC patients, DD schedule should be considered the preferred schedule irrespective of BMI.

Impact of hormone receptor status and tumor subtypes of breast cancer in young BRCA carriers.

BACKGROUND: Hormone receptor expression is a known positive prognostic and predictive factor in breast cancer; however, limited evidence exists on its prognostic impact on prognosis of young patients harboring a pathogenic variant (PV) in the BRCA1 and/or BRCA2 genes. PATIENTS AND METHODS: This international, multicenter, retrospective cohort study included young patients (aged ≤40 years) diagnosed with invasive breast cancer and harboring germline PVs in BRCA genes. We investigated the impact of hormone receptor status on clinical behavior and outcomes of breast cancer. Outcomes of interest [disease-free survival (DFS), breast cancer-specific survival (BCSS), and overall survival (OS)] were first investigated according to hormone receptor expression (positive versus negative), and then according to breast cancer subtype [luminal A-like versus luminal B-like versus triple-negative versus human epidermal growth factor receptor 2 (HER2)-positive breast cancer]. RESULTS: From 78 centers worldwide, 4709 BRCA carriers were included, of whom 2143 (45.5%) had hormone receptor-positive and 2566 (54.5%) hormone receptor-negative breast cancer. Median follow-up was 7.9 years. The rate of distant recurrences was higher in patients with hormone receptor-positive disease (13.1% versus 9.6%, P < 0.001), while the rate of second primary breast cancer was lower (9.1% versus 14.7%, P < 0.001) compared to patients with hormone receptor-negative disease. The 8-year DFS was 65.8% and 63.4% in patients with hormone receptor-positive and negative disease, respectively. The hazard ratio of hormone receptor-positive versus negative disease changed over time for DFS, BCSS, and OS (P < 0.05 for interaction of hormone receptor status and survival time). Patients with luminal A-like breast cancer had the worst long-term prognosis in terms of DFS compared to all the other subgroups (8-year DFS: 60.8% in luminal A-like versus 63.5% in triple-negative versus 65.5% in HER2-positive and 69.7% in luminal B-like subtype). CONCLUSIONS: In young BRCA carriers, differences in recurrence pattern and second primary breast cancer among hormone receptor-positive versus negative disease warrant consideration in counseling patients on treatment, follow-up, and risk-reducing surgery.

Discontinuation rate and serious adverse events of chemoimmunotherapy as neoadjuvant treatment for triple-negative breast cancer: a systematic review and meta-analysis.

BACKGROUND: The use of combination of chemotherapy with immune checkpoint inhibitors (ICIs) has shown efficacy in triple-negative breast cancer (TNBC), and chemoimmunotherapy has been introduced in clinical practice. However, limited data are available on the discontinuation rate and serious adverse events of these treatments, particularly in the neoadjuvant setting. Herein, we carried out a comprehensive systematic review and meta-analysis to assess discontinuation rate and serious adverse events of chemoimmunotherapy compared to chemotherapy alone in phase II and III neoadjuvant clinical trials in TNBC. MATERIALS AND METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, EMBASE, Cochrane Library, and PubMed/Medline were searched for articles published from June 2008 to May 2023. The outcomes of interest were the discontinuation rate, serious adverse events, and grade 3-4 adverse events. RESULTS: Four studies were included in the analysis. The pooled odds ratios (ORs) for discontinuation rate and serious adverse events were 1.26 [95% confidence interval (CI) 0.78-2.06] and 1.79 (95% CI 1.4-2.28), respectively, in patients receiving chemoimmunotherapy compared to chemotherapy alone as neoadjuvant treatment for TNBC. The chemoimmunotherapy group had a higher risk of grade 3-4 adverse events (OR 1.30, 95% CI 1.07-1.59). The analysis showed substantial heterogeneity, and the risk of discontinuation rate was heavily influenced by the KEYNOTE-522 trial. CONCLUSIONS: Our findings highlight the need for clinical trials specifically focused on safety, quality of life, and treatment adherence in TNBC patients receiving neoadjuvant treatment. Close monitoring of tolerability remains crucial in this clinical setting.

Second-line treatment strategies for RAS wild-type colorectal cancer: A systematic review and Network Meta-analysis (NMA).

BACKGROUND: The optimal strategy for second-line (IIL) treatment in KRAS wt metastatic colorectal cancer (mCRC) is not determined yet. METHODS: A random-effect NMA of phase II/III RCTs was conducted to evaluate IIL treatment for all-RAS wt mCRC, comparing anti-EGFR or anti-VEGF, and chemotherapy (CT). RESULTS: Overall, 11 RCTs (3613 patients) were included. In KRAS wt patients, PFS was improved with anti-VEGF (HR 0.43) and anti-EGFR (HR 0.63) vs CT. However, anti-VEGF based therapy had the highest likelihood of being ranked as the best treatment in terms of PFS (SUCRA 99.3%) and OS (SUCRA 99.4%). Bevacizumab-based treatment is most likely to be the best treatment in terms of PFS (SUCRA 89.1%) and OS (SUCRA 86.7%). CONCLUSIONS: Second line treatment with anti-VEGF and anti-EGFR improved PFS in mCRC patients, however, anti-VEGF based therapy, particularly CT plus bevacizumab, is the best treatment according to SUCRA in terms of PFS and OS.

Optimizing choices and sequences in the diagnostic-therapeutic landscape of advanced triple-negative breast cancer: An Italian consensus paper and critical review.

Triple-negative (TN) metastatic breast cancer (mBC) represents the most challenging scenario withing mBC framework, and it has been only slightly affected by the tremendous advancements in terms of drug availability and survival prolongation we have witnessed in the last years for advanced disease. However, although chemotherapy still represents the mainstay of TN mBC management, in the past years, several novel effective agents have been developed and made available in the clinical practice setting. Within this framework, a panel composed of a scientific board of 17 internationally recognized breast oncologists and 42 oncologists working within local spoke centers, addressed 26 high-priority statements, including grey areas, regarding the management of TN mBC. A structured methodology based on a modified Delphi approach to administer the survey and the Nominal Group Technique to capture perceptions and preferences on the management of TN mBC within the Italian Oncology community were adopted. The Panel produced a set of prioritized considerations/consensus statements reflecting the Panel position on diagnostic and staging approach, first-line and second-line treatments of PD-L1-positive/germline BRCA (gBRCA) wild-type, PD-L1-positive/gBRCA mutated, PD-L1-negative/gBRCA wild-type and PD-L1-negative/gBRCA mutated TN mBC. The Panel critically and comprehensively discussed the most relevant and/or unexpected results and put forward possible interpretations for statements not reaching the consensus threshold.

Health-related quality of life in breast cancer patients treated with CDK4/6 inhibitors: a systematic review.

BACKGROUND: Evaluation of health-related quality of life (HR-QoL) among cancer patients has gained an increasing importance and is now a key determinant of anticancer treatments' value. HR-QoL has been assessed in trials testing cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in breast cancer (BC), using various questionnaires at different timepoints. HR-QoL reports from BC patients treated with CDK4/6i in the real-world setting are also available. METHODS: We systematically reviewed the literature, searching for full-length articles, and selected conference abstracts reporting data on HR-QoL in BC patients at any stage and of any molecular subtype treated with abemaciclib, palbociclib or ribociclib. RESULTS: A total of 533 full-length articles and 143 abstracts were retrieved. After screening for eligibility, 38 records were included (31 clinical trials; 7 real-world reports). Assessment methods were heterogeneous across studies in terms of questionnaires, evaluation timepoints and endpoints. Overall, adding CDK4/6i to endocrine therapy did not worsen patients' HR-QoL, with a positive trend towards pain improvement. Gastrointestinal scores (diarrhea, nausea and appetite loss) statistically favored the control arm among metastatic BC patients receiving abemaciclib, whereas they were superimposable in the early setting. The combination of palbociclib and endocrine therapy showed similar HR-QoL outcomes compared with endocrine therapy alone, but determined better scores compared with chemotherapy. HR-QoL was specifically assessed in premenopausal patients treated with ribociclib, showing similar scores compared with postmenopausal patients. CONCLUSIONS: Despite methodological heterogeneity does not allow a proper comparison, HR-QoL was generally maintained with CDK4/6i. However, differences between abemaciclib, palbociclib and ribociclib exist and mainly rely on the distinct safety profiles of the compounds. These differences should be acknowledged and taken into account in the clinical practice.

Safety of assisted reproductive techniques in young women harboring germline pathogenic variants in BRCA1/2 with a pregnancy after prior history of breast cancer.

BACKGROUND: Knowledge is growing on the safety of assisted reproductive techniques (ART) in cancer survivors. No data exist, however, for the specific population of breast cancer patients harboring germline BRCA1/2 pathogenic variants. PATIENTS AND METHODS: This is a multicenter retrospective cohort study across 30 centers worldwide including women diagnosed at ≤40 years with stage I-III breast cancer, between January 2000 and December 2012, harboring known germline BRCA1/2 pathogenic variants. Patients included in this analysis had a post-treatment pregnancy either achieved through use of ART (ART group) or naturally (non-ART group). ART procedures included ovulation induction, ovarian stimulation for in vitro fertilization or intracytoplasmic sperm injection, and embryo transfer under hormonal replacement therapy. RESULTS: Among the 1424 patients registered in the study, 168 were eligible for inclusion in the present analysis, of whom 22 were in the ART group and 146 in the non-ART group. Survivors in the ART group conceived at an older age compared with those in the non-ART group (median age: 39.7 versus 35.4 years, respectively). Women in the ART group experienced more delivery complications compared with those in the non-ART group (22.1% versus 4.1%, respectively). No other apparent differences in obstetrical outcomes were observed between cohorts. The median follow-up from pregnancy was 3.4 years (range: 0.8-8.6 years) in the ART group and 5.0 years (range: 0.8-17.6 years) in the non-ART group. Two patients (9.1%) in the ART group experienced a disease-free survival event (specifically, a locoregional recurrence) compared with 40 patients (27.4%) in the non-ART group. In the ART group, no patients deceased compared with 10 patients (6.9%) in the non-ART group. CONCLUSION: This study provides encouraging safety data on the use of ART in breast cancer survivors harboring germline pathogenic variants in BRCA1/2, when natural conception fails or when they opt for ART in order to carry out preimplantation genetic testing.

Emerging molecular alterations leading to histology-specific targeted therapies in ovarian cancer beyond PARP inhibitors.

After more than 30 years of a one-size-fits-all approach in the management of advanced ovarian cancer, in 2018 the SOLO1 trial results have introduced a new era of personalized medicine. A deeper knowledge of ovarian cancer biology and the development of new drugs targeting specific molecular pathways have led to biomarker-driven phase 3 trials with practice changing results. Thereafter, platinum-based combinations are no longer the only therapeutic options available in first line setting and poly-ADP ribose polymerase inhibitors maintenance therapy has become the mainstay in patients with tumor harboring a homologous recombination defect. However, most of the recent therapeutic breakthroughs regard high grade serous carcinoma, the most frequent ovarian cancer subtype, and only few improvements have occurred in the management of less common histotypes. Moving towards the next challenges, we aimed to investigate and review new potential molecular targets in ovarian cancer, according to histotype, starting from promising molecular drivers and matched drugs that have been investigated in early and late-stage clinical trials or conceptualized in preclinical studies.

Checkpoint inhibitors, fertility, pregnancy, and sexual life: a systematic review.

Immune checkpoint inhibitors (i.e. anti-PD1, anti-PDL1, and anti-CTLA4) have revolutionized the therapeutic approach of several cancer types. In a subset of metastatic patients, the duration of the response is so long that a cure might be hypothesized, and a treatment discontinuation strategy could be proposed. Considering that long-term efficacy, some patients could also plan to have a child. Moreover, immunotherapy is moving to the early setting in several diseases including melanoma and breast cancer that are common cancers in young patients. However, there is a paucity of data about their potential detrimental effect on fertility, pregnancy, or sexuality. Herein, we conducted a systematic review with the aim to comprehensively collect the available evidence about fertility, pregnancy, and sexual adverse effects of checkpoint inhibitors in order to help clinicians in daily practice and trialists to develop future studies.

Transformation of Cancer Care during and after the COVID Pandemic, a point of no return. The Experience of Italy.

Policymakers everywhere struggle to introduce therapeutic innovation while controlling costs, a particular challenge for the universal Italian National Healthcare System (SSN), which spends only 8.8% of GDP to care for one of the world's oldest populations. Oncology provides a telling example, where innovation has dramatically improved care and survival, transforming cancer into a chronic condition. However, innovation has also increased therapy duration, adverse event management, and service demand. The SSN risks collapse unless centralized cancer planning changes gear, particularly with Covid-19 causing treatment delays, worsening patient prognosis and straining capacity. In view of the 750 billion Euro "Next Generation EU", released by the European Union to relieve Member States hit by the pandemic, the SSN tapped a multidisciplinary research team to identify key strategies for equitable uptake of innovations in treatment and delivery, with emphasis on data-driven technological and managerial advancements - and lessons from Covid-19.

Final results from the PERUSE study of first-line pertuzumab plus trastuzumab plus a taxane for HER2-positive locally recurrent or metastatic breast cancer, with a multivariable approach to guide prognostication.

BACKGROUND: The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. PATIENTS AND METHODS: Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. RESULTS: Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade ≥3 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). CONCLUSIONS: Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design.

T-DM1 versus pertuzumab, trastuzumab and a taxane as first-line therapy of early-relapsed HER2-positive metastatic breast cancer: an Italian multicenter observational study.

BACKGROUND: The current standard first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive (+) metastatic breast cancer is the combination of pertuzumab, trastuzumab and a taxane (P + T + taxane), while standard second-line is ado-trastuzumab-emtansine (T-DM1). The registration trial of pertuzumab, however, did not include early-relapsing patients, defined as patients experiencing tumor relapse ≤12 months from the end of (neo)adjuvant anti-HER2 therapy. Conversely, the pivotal trial of T-DM1 included some patients relapsing ≤6 months after the end of (neo)adjuvant trastuzumab. Thus, a proportion of early-relapsing patients are currently eligible to receive T-DM1 as first-line treatment. Nevertheless, no direct comparison exists between the two regimens in this clinical setting. PATIENTS AND METHODS: We retrospectively compared T-DM1 versus P + T + taxane as first-line treatment in two cohorts of early-relapsing patients in an Italian 'real-world' setting, involving 14 public health care institutions. The primary endpoint was progression-free survival. Secondary endpoints included patients' characterization, overall survival and post-progression survival. Univariate and multivariate analyses were carried out. All tests were two-sided and a P ≤ 0.05 was considered statistically significant. RESULTS: Among 1252 screened patients, 75 met the inclusion criteria. Forty-four (58.7%) received P + T + taxane and 31 (41.3%) received T-DM1. The two cohorts showed similar characteristics of aggressiveness and no significant differences in treatment history. T-DM1, compared with P + T + taxane was associated with worse progression-free survival (adjusted hazard ratio: 2.26, 95% confidence interval: 1.13-4.52, P = 0.021) and overall survival (adjusted hazard ratio: 3.95, 95% confidence interval: 1.38-11.32, P = 0.010), irrespective of previous (neo)adjuvant treatment, age, hormone receptors status, time-to-relapse (≤6 months or within 6-12 months) and presence of visceral/brain metastases. No differences were observed in post-progression survival (P = 0.095). CONCLUSIONS: Our study suggests superiority for P + T + taxane over T-DM1 as up-front treatment of early-relapsing HER2+ metastatic breast cancer, which merits further assessment in larger and prospective trials.