Unlocking the potential of Molecular Tumor Boards: from cutting-edge data interpretation to innovative clinical pathways.

The emerging era of precision medicine is characterized by an increasing availability of targeted anticancer therapies and by the parallel development of techniques to obtain more refined molecular data, whose interpretation may not always be straightforward. Molecular tumor boards gather various professional figures, in order to leverage the analysis of molecular data and provide prognostic and predictive insights for clinicians. In addition to healthcare development, they could also become a tool to promote knowledge and research spreading. A growing body of evidence on the application of molecular tumor boards to clinical practice is forming and positive signals are emerging, although a certain degree of heterogeneity exists. This work analyzes molecular tumor boards' potential workflows, figures involved, data sources, sample matrices and eligible patients, as well as available evidence and learning examples. The emerging concept of multi-institutional, disease-specific molecular tumor boards is also considered by presenting two ongoing nationwide experiences.

Gene-expression assays to tailor adjuvant endocrine therapy for HR+/HER2- breast cancer.

Adjuvant endocrine therapy represents the standard of care for almost all HR+/HER2- breast cancers and different agents and durations are currently available. In this context, the tailoring and optimization of adjuvant endocrine treatment by reducing unnecessary toxic treatment while taking into account the biological heterogeneity of HR+/HER2- breast cancer represents a clinical priority. There is therefore a significant need for the integration of biological biomarkers in the choice of adjuvant endocrine therapy beyond currently used clinicopathological characteristics. Several gene-expression assays have been developed to identify patients with HR+/HER2- breast cancer who will not derive benefit from the addition of adjuvant chemotherapy. By enhancing risk stratification and predicting therapeutic response, genomic assays have also shown to be a promising tool for optimizing endocrine treatment decision. We here review evidence supporting the use of most common commercially available gene-expression assays (Oncotype DX, MammaPrint, Breast Cancer Index, Prosigna and EndoPredict) in tailoring adjuvant endocrine therapy. Available data on the use of genomic tests to inform extended adjuvant treatment choice based on the risk of late relapse and on the estimated benefit of a prolonged endocrine therapy are discussed. Moreover, preliminary evidence regarding the use of genomic assays to inform de-escalation of endocrine treatment, such as shorter durations or omission, for low risk patients are reviewed. Overall, gene expression assays are emerging as potential tools to further personalize adjuvant treatment for patients with HR+/HER2- breast cancers.

Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer.

Importance: The association of tumor-infiltrating lymphocyte (TIL) abundance in breast cancer tissue with cancer recurrence and death in patients with early-stage triple-negative breast cancer (TNBC) who are not treated with adjuvant or neoadjuvant chemotherapy is unclear. Objective: To study the association of TIL abundance in breast cancer tissue with survival among patients with early-stage TNBC who were treated with locoregional therapy but no chemotherapy. Design, Setting, and Participants: Retrospective pooled analysis of individual patient-level data from 13 participating centers in North America (Rochester, Minnesota; Vancouver, British Columbia, Canada), Europe (Paris, Lyon, and Villejuif, France; Amsterdam and Rotterdam, the Netherlands; Milan, Padova, and Genova, Italy; Gothenburg, Sweden), and Asia (Tokyo, Japan; Seoul, Korea), including 1966 participants diagnosed with TNBC between 1979 and 2017 (with follow-up until September 27, 2021) who received treatment with surgery with or without radiotherapy but no adjuvant or neoadjuvant chemotherapy. Exposure: TIL abundance in breast tissue from resected primary tumors. Main Outcomes and Measures: The primary outcome was invasive disease-free survival [iDFS]. Secondary outcomes were recurrence-free survival [RFS], survival free of distant recurrence [distant RFS, DRFS], and overall survival. Associations were assessed using a multivariable Cox model stratified by participating center. Results: This study included 1966 patients with TNBC (median age, 56 years [IQR, 39-71]; 55% had stage I TNBC). The median TIL level was 15% (IQR, 5%-40%). Four-hundred seventeen (21%) had a TIL level of 50% or more (median age, 41 years [IQR, 36-63]), and 1300 (66%) had a TIL level of less than 30% (median age, 59 years [IQR, 41-72]). Five-year DRFS for stage I TNBC was 94% (95% CI, 91%-96%) for patients with a TIL level of 50% or more, compared with 78% (95% CI, 75%-80%) for those with a TIL level of less than 30%; 5-year overall survival was 95% (95% CI, 92%-97%) for patients with a TIL level of 50% or more, compared with 82% (95% CI, 79%-84%) for those with a TIL level of less than 30%. At a median follow-up of 18 years, and after adjusting for age, tumor size, nodal status, histological grade, and receipt of radiotherapy, each 10% higher TIL increment was associated independently with improved iDFS (hazard ratio [HR], 0.92 [0.89-0.94]), RFS (HR, 0.90 [0.87-0.92]), DRFS (HR, 0.87 [0.84-0.90]), and overall survival (0.88 [0.85-0.91]) (likelihood ratio test, P < 10e-6). Conclusions and Relevance: In patients with early-stage TNBC who did not undergo adjuvant or neoadjuvant chemotherapy, breast cancer tissue with a higher abundance of TIL levels was associated with significantly better survival. These results suggest that breast tissue TIL abundance is a prognostic factor for patients with early-stage TNBC.

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.

Metastatic site patterns by intrinsic subtype and HER2DX in early HER2-positive breast cancer.

BACKGROUND: Even with contemporary treatment strategies, more than 10% of HER2-positive early stage breast cancer patients may experience distant metastasis as first event during follow-up. Tools for predicting unique patterns of metastatic spread are needed to plan personalized surveillance. We evaluated how molecular heterogeneity affects the pattern of distant relapse in HER2-positive breast cancer. METHODS: A total of 677 HER2-positive stage I-III breast cancer patients from ShortHER trial, Cher-LOB trial, and 2 institutional cohorts were included. PAM50 molecular subtypes and research-based HER2DX scores were evaluated. The cumulative incidence of distant relapse as the first event (any site and site specific) was evaluated using competing risk analysis. Median follow-up was 8.4 years. Tests of statistical significance are 2-sided. RESULTS: Stage III and high HER2DX risk score identified patients at the highest risk of distant relapse as first event (10-year incidence 24.5% and 19.7%, respectively). Intrinsic molecular subtypes were associated with specific patterns of metastatic spread: compared with other subtypes, HER2-enriched tumors were more prone to develop brain metastases (10-year incidence 3.8% vs 0.6%, P = .005), basal-like tumors were associated with an increased risk of lung metastases (10-year incidence 11.1% vs 2.6%, P = .001), and luminal tumors developed more frequently bone-only metastases (10-year incidence 5.1% vs 2.0%, P = .042). When added to stage or HER2DX risk score in competing risk regression models, intrinsic subtype maintained an independent association with site-specific metastases. CONCLUSIONS: The integration of intrinsic molecular subtypes with stage or HER2DX risk score predicts site-specific metastatic risk in HER2-positive breast cancer, with potential implications for personalized surveillance and clinical trials aimed at preventing site-specific recurrence.

Peripheral blood lymphocytes predict clinical outcomes in hormone receptor-positive HER2-negative advanced breast cancer patients treated with CDK4/6 inhibitors.

Background: Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) combined with Endocrine Therapy (ET) are the standard treatment for patients with Hormone Receptor-positive/HER2-negative advanced breast cancer (HR+/HER2- aBC). Objectives: While CDK4/6i are known to reduce several peripheral blood cells, such as neutrophils, lymphocytes and platelets, the impact of these modulations on clinical outcomes is unknown. Design: A multicenter, retrospective-prospective Italian study. Methods: We investigated the association between baseline peripheral blood cells, or their early modifications (i.e. 2 weeks after treatment initiation), and the progression-free survival (PFS) of HR+/HER2- aBC patients treated with ETs plus CDK4/6i. Random Forest models were used to select covariates associated with patient PFS among a large list of patient- and tumor-related variables. Results: We evaluated 638 HR+/HER2- aBC patients treated with ET plus CDK4/6i at six Italian Institutions between January 2017 and May 2021. High baseline lymphocyte counts were independently associated with longer PFS [median PFS (mPFS) 20.1 versus 13.2 months in high versus low lymphocyte patients, respectively; adjusted Hazard Ratio (aHR): 0.78; 95% confidence interval (CI): 0.66-0.92; p = 0.0144]. Moreover, patients experiencing a lower early reduction of lymphocyte counts had significantly longer PFS when compared to patients undergoing higher lymphocyte decrease (mPFS 18.1 versus 14.5 months; aHR: 0.82; 95% CI: 0.73-0.93; p = 0.0037). Patients with high baseline lymphocytes and undergoing a lower reduction, or even an increase, of lymphocyte counts during CDK4/6i therapy experienced the longest PFS, while patients with lower baseline lymphocytes and undergoing a higher decrease of lymphocytes had the lowest PFS (mPFS 21.4 versus 11 months, respectively). Conclusion: Baseline and on-treatment modifications of peripheral blood lymphocytes have independent prognostic value in HR+/HER2- aBC patients. This study supports the implementation of clinical strategies to boost antitumor immunity in patients with HR+/HER2- aBC treated with ETs plus CDK4/6i.

Association of tumor-infiltrating lymphocytes with recurrence score in hormone receptor-positive/HER2-negative breast cancer: Analysis of four prospective studies.

BACKGROUND: The clinical value of tumor infiltrating lymphocytes (TILs) in hormone receptor-positive (HR+)/HER2- breast cancer (BC) may be unearthed by focusing on more biologically aggressive tumors. Here we deepen and describe the correlation between RS and TILs, proposing an immuno-genomic model for HR+ /HER2- BC. METHODS: We enrolled T1-T3, N0-N1 BC patients with available RS® and TILs in the context of four multicenter, prospective studies. RS® and TILs were considered as continuous and categorical variables. RS® was categorized into: 0-10 (low risk), 11-25 (intermediate risk) and 26-100 (high risk); TILs were categorized into: low TILs (0-10%), intermediate TILs (11-59%) and high TILs (60-100%). RESULTS: 811 patients were included. RS distribution was (n = 810): low risk 22.0%, intermediate risk 61.2%, high risk 16.8%. TIL distribution was (n = 455): low TILs 84.6%, intermediate TILs 13.6% and high TILs 1.8%. A significant, weak positive, linear correlation was found between continuous TILs and RS (Pearson coefficient=0.223, p < 0.001). When considering RS and TILs categories, tumors with intermediate/high TIL levels significantly enriched the high RS subgroup (p = 0.006). This was confirmed both within Luminal A and Luminal B cohorts. Among high-RS patients, 16.7% of Luminal A and 26.7% of Luminal B tumors had intermediate/high TILs. CONCLUSIONS: We observed that RS® and TILs capture only slightly overlapping information on the biology of HR+ /HER2- tumor microenvironment. We demonstrated the feasibility of combining RS and TILs into a composite immuno-genomic model, which may serve the purpose of guiding and focalizing patient selection in the further development of immunotherapy strategies for Luminal-like disease.

Multidisciplinary management of HER2-positive breast cancer with brain metastases: An evidence-based pragmatic approach moving from pathophysiology to clinical data.

INTRODUCTION: About 30-50 % of stage IV HER2+ breast cancers (BC) will present brain metastases (BMs). Their management is based on both local treatment and systemic therapy. Despite therapeutic advances, BMs still impact on survival and quality of life and the development of more effective systemic therapies represents an unmet clinical need. MATERIALS AND METHODS: A thorough analysis of the published literature including ongoing clinical trials has been performed, investigating concepts spanning from the pathophysiology of tumor microenvironment to clinical considerations with the aim to summarize the current and future locoregional and systemic strategies. RESULTS: Different trials have investigated monotherapies and combination treatments, highlighting how the blood-brain barrier (BBB) represents a major problem hindering diffusion and consequently efficacy of such options. Trastuzumab has long been the mainstay of systemic therapy and over the last two decades other HER2-targeted agents including lapatinib, pertuzumab, and trastuzumab emtansine, as well as more recently neratinib, tucatinib, and trastuzumab deruxtecan, have been introduced in clinical practice after showing promising results in randomized controlled trials. CONCLUSIONS: We ultimately propose an evidence-based treatment algorithm for clinicians treating HER2 + BCs patients with BMs.

Nine-Week Versus One-Year Trastuzumab for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: 10-Year Update of the ShortHER Phase III Randomized Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We present the final analysis of the phase III noninferiority, randomized ShortHER trial comparing 9 weeks versus 1 year of adjuvant trastuzumab with chemotherapy in patients with human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (BC). Women with HER2+ BC were randomly assigned to anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or 9-week trastuzumab (arm B, short). Here, we report the second coprimary end point overall survival (OS), updated disease-free survival (DFS), and outcomes according to hormone receptor status, age, and nodal status. At a median follow-up of 9 years, 10-year DFS is 77% versus 78% in the long versus short arm, respectively. Ten-year OS is 89% versus 88% in the long versus short arm, respectively. 10-year DFS rates in the long versus short arm according to nodal status are N0 81% versus 85%; N1-3 77% versus 79%; and N4+ 63% versus 53%. Ten-year OS rates in long versus short arm according to nodal status are N0 89% versus 95%%; N1-3 92% versus 89%; and N4+ 84% versus 64%. The updated analysis of the ShortHER trial shows that 1-year trastuzumab is the standard treatment for patients with HER2+ early BC as noninferiority cannot be claimed. However, numerically, the differences for the patients at low or intermediate risk (N0/N1-3) is negligible, while patients with N4+ have a clear benefit with 1-year trastuzumab.

The Impact of COVID-19 on Treatment Practices for Patients With Early Breast Cancer: A Cross-Sectional Study From a Large Cancer Center in Italy.

INTRODUCTION: The Coronavirus Disease 2019 (COVID-19) has disrupted health services worldwide. The evidence on the impact of the pandemic on cancer care provision, however, is conflicting. We aimed to audit the management of patients diagnosed with early breast cancer (EBC) during the pandemic in a large, tertiary-level cancer center in Italy. METHODS: We conducted a cross-sectional study to track the route to first treatment for patients diagnosed with EBC during 2019, 2020, and 2021. We abstracted data for all consecutive patients referred to the Veneto Institute of Oncology (Padua, Italy). We defined as point of contact (POC) the date of the first consultation with a breast cancer specialist of the breast unit. First treatment was defined as either upfront surgery or neoadjuvant chemotherapy (NACT). RESULTS: We reviewed medical records for 878 patients for whom an MDT report during 2019-2021 (April through June) was available. Of these, 431 (49%) were eligible. The proportion of screen-detected tumors was larger in 2019 and 2021 than in 2020 (59%). Conversely, the proportion of screen-detected tumors was offset by the proportion of palpable tumors in 2020 (P = .004). Distribution of tumor and nodal stage was unchanged over time, but in situ tumors were slightly fewer in 2020 than in 2019 or 2021. The adjusted odds ratio for treatment delay (45 days or more) was 0.87 for 2020 versus 2019 (95% CI, 0.5-1.53) and 0.9 for 2021 versus 2019 (95% CI, 0.52-1.55). CONCLUSIONS: There was no evidence for major changes in the management of patients with EBC during 2019-2021 and no treatment delays were observed. Our findings suggest that more women presented with palpable nodules at diagnosis, but the stage distribution did not change over time. Validation on a larger cohort of patients is warranted to robustly assess the impact of the COVID-19 pandemic on treatment practices for patients with EBC.

A Prognostic Model Based on Residual Cancer Burden and Tumor-Infiltrating Lymphocytes on Residual Disease after Neoadjuvant Therapy in HER2+ Breast Cancer.

PURPOSE: We aim to evaluate the prognostic significance of tumor-infiltrating lymphocyte on residual disease (RD-TIL) in HER2+ patients with breast cancer who failed to achieve pathologic complete response (pCR) after anti-HER2+ chemotherapy (CT)-based neoadjuvant treatment (NAT). We assessed the feasibility of combining the prognostic information provided by residual cancer burden (RCB) and RD-TILs into a composite score (RCB+TIL). EXPERIMENTAL DESIGN: HER2+ patients with breast cancer treated with CT+anti-HER2-based NAT at three institutions were retrospectively included. RCB and TIL levels were evaluated on hematoxylin and eosin-stained slides from surgical samples according to available recommendations. Overall survival (OS) was used as an outcome measure. RESULTS: A total of 295 patients were included, of whom 195 had RD. RCB was significantly associated with OS. Higher RD-TILs were significantly associated with poorer OS as compared with lower RD-TILs (15% cutoff). In multivariate analysis, both RCB and RD-TIL maintained their independent prognostic value. A combined score, RCB+TIL, was calculated from the estimated coefficient of RD-TILs and the RCB index in a bivariate logistic model for OS. The RCB+TIL score was significantly associated with OS. The C-index for OS of the RCB+TIL score was numerically higher than that of RCB and significantly higher than that of RD-TILs. CONCLUSIONS: We have reported an independent prognostic impact of RD-TILs after anti-HER2+CT NAT, which might underlie an imbalance of the RD microenvironment towards immunosuppressive features. We provided a new composite prognostic score based on RCB+TIL, which was significantly associated with OS and proved to be more informative than the isolated evaluation of RCB and RD-TILs.

PI3K/PTEN/mTOR pathway dynamic tracking and prognostic value in HR+/HER2- BC patients with residual disease after neoadjuvant chemotherapy: a cohort study.

AIMS: Hormone receptor-positive (HR)+/HER2- breast cancer (BC) is highly heterogeneous, with PI3K/PTEN/mTOR pathway alterations emerging as possible players within this complexity. We longitudinally tracked PI3K/PTEN/mTOR pathway dynamics from baseline biopsy to residual disease (RD)-and to metastases in case of relapse-in HR+/HER2- BC patients receiving neoadjuvant chemotherapy (NACT). METHODS: HR+/HER2- BC patients with RD after NACT were identified. We assessed PIK3CA mutational, Pten-loss and phosphorylation levels of mTOR and its substrates (p70S6K and 4EBP1) on baseline biopsies and matched RD samples; in case of disease relapse, we also assessed PIK3CA mutational status on metastatic samples. Recurrence-free survival (RFS) was adopted as endpoint. RESULTS: 92 patient were included. The conversion rate of PIK3CA mutational status was 12.8%; 1 patient acquired PIK3CA mutation at relapse; the rate of Pten conversion was 33.3%; mTOR phosphorylation levels significantly increased from baseline biopsy to RD, while its substrates significantly decreased. Baseline phosphorylated-mTOR significantly predicted poorer RFS in patients with PIK3CA wild-type status; baseline phosphorylated-70S6K was positively associated with RFS. CONCLUSIONS: We observed that PI3K/PTEN/mTOR pathway is highly dynamic under NACT exposure and the assessment of PIK3CA mutations may capture only a small fraction of such complexity. In this context, mTOR activation trough alternative pathways with respect to PIK3CA signalling may have a crucial role in shaping the molecular landscape of HR+/HER2- BC with RD after NACT. It is imperative to further elucidate the role of PIK3CA and mTOR-dependent pathways in shaping chemoresistance and endocrine resistance in high-risk HR+/HER2- early/locally advanced BC patients.

Radiological response of leptomeningeal metastases according to revised RANO criteria is associated with overall survival in breast cancer patients.

Assessment of treatment response in patients (pts) with leptomeningeal metastases (LM) represents a significant challenge and standardized criteria are needed. In 2017, the RANO LM Working Group proposed a standardized scorecard to evaluate MRI findings (further simplified in 2019). Here, we aim to validate the prognostic impact of response to treatment assessed using this tool in a multicentric cohort of breast cancer (BC) pts. Pts with BC-related LM diagnosed at two institutions between 2005 and 2018 were identified. Baseline and follow-up MRI scans were centrally reviewed and response assessment was evaluated using 2019 revised RANO LM criteria. A total of 142 pts with BC-related LM and available baseline brain MRI imaging were identified; 60 of them had at least one follow-up MRI. In this subgroup, median overall survival (OS) was 15.2 months (95%CI 9.5-21.0). At first re-evaluation, radiological response by RANO criteria was: complete response (CR) in 2 pts (3%), partial response (PR) in 12 (20%), stable disease (SD) in 33 (55%) and progression of disease (PD) in 13 (22%). Median OS was 31.1 months (HR 0.10, 95%CI 0.01-0.78) in pts with CR, 16.1 months (HR 0.41, 95%CI 0.17-0.97) in pts with PR, 17.9 months (HR 0.45, 95%CI 0.22-0.91) in pts with SD and 9.5 months in pts with PD (P = .029). A second blinded evaluation showed a moderate interobserver agreement (K = 0.562). Radiological response according to 2019 RANO criteria is significantly associated with OS in pts with BC-related LM, thus supporting the use of this evaluation tool both in trials and clinical practice.

Prognostic significance of HER2-low status in HR-positive/HER2-negative advanced breast cancer treated with CDK4/6 inhibitors.

Whether Human Epidermal growth factor Receptor 2 (HER2)-low status has prognostic significance in HR + /HER2- advanced Breast Cancer (aBC) patients treated with first-line Endocrine Therapy plus CDK 4/6 inhibitors remains unclear. In 428 patients evaluated, HER2-low status was independently associated with significantly worse PFS and OS when compared with HER2-0 status. Based on our findings, HER2-low status could become a new prognostic biomarker in this clinical setting.

Economic Evaluation for Palbociclib Plus Fulvestrant vs Ribociclib Plus Fulvestrant and Abemaciclib Plus Fulvestrant in Endocrine-Resistant Advanced or Metastatic Breast Cancer in Italy.

Background: To date, no study evaluated the cost-effectiveness of palbociclib (PAL) plus fulvestrant (FUL) vs ribociclib (RIB) plus FUL and abemaciclib (ABM) plus FUL in Italy. Cost-effectiveness analysis comparing the three cyclin-dependent 4/6 kinase inhibitors in combination with endocrine therapies for the management of postmenopausal women with HR+, HER2- advanced or metastatic breast cancer in Italy was developed. Material and Methods: To assess the cost-effectiveness of PAL plus FUL vs RIB plus FUL and ABM plus FUL, a cost-minimization has been carried out with a conservative scenario considering three CDK4/6 inhibitors with equal effectiveness in terms of overall survival (OS) (MAIC, Rugo et al 2021). Adverse events (AEs) associated with all therapies were obtained from clinical trials. Ad-hoc analysis was performed to estimate the cost-effectiveness considering the quality-of-life (QoL) data (Lloyd et al 2006). Results: Cost-minimization inputs were drugs, visits and exams, AE monitoring and best supportive care (BSC) before the progression state, active and BSC in the progression and terminal phase of the last two weeks of life. Given the comparability of PAL, RIB and ABM in terms of efficacy, this analysis demonstrated slight economic savings over a lifetime for PAL. Results showed saving per patient of €305 (lifetime) when PAL is compared with RIB; for PAL vs ABM a saving of €243 (lifetime) in a conservative scenario. Results of a budget impact analysis showed a potential savings of €319,563 for PAL vs RIB and €297,544 for PAL vs ABM. When QoL data were considered, results may favor PAL due to the lower impact of AE with savings and improvement in the QoL related to fewer AE. Conclusion: From the Italian perspective, a cost-saving profile associated with the use of PAL+FUL for the management of advanced/metastatic HR+/HER2- breast cancer compared to RIB+FUL and ABM+FUL emerged.

Development of a nomogram for predicting pathological complete response in luminal breast cancer patients following neoadjuvant chemotherapy.

Background: Given the low chance of response to neoadjuvant chemotherapy (NACT) in luminal breast cancer (LBC), the identification of predictive factors of pathological complete response (pCR) represents a challenge. A multicenter retrospective analysis was performed to develop and validate a predictive nomogram for pCR, based on pre-treatment clinicopathological features. Methods: Clinicopathological data from stage I-III LBC patients undergone NACT and surgery were retrospectively collected. Descriptive statistics was adopted. A multivariate model was used to identify independent predictors of pCR. The obtained log-odds ratios (ORs) were adopted to derive weighting factors for the predictive nomogram. The receiver operating characteristic analysis was applied to determine the nomogram accuracy. The model was internally and externally validated. Results: In the training set, data from 539 patients were gathered: pCR rate was 11.3% [95% confidence interval (CI): 8.6-13.9] (luminal A-like: 5.3%, 95% CI: 1.5-9.1, and luminal B-like: 13.1%, 95% CI: 9.8-13.4). The optimal Ki67 cutoff to predict pCR was 44% (area under the curve (AUC): 0.69; p < 0.001). Clinical stage I-II (OR: 3.67, 95% CI: 1.75-7.71, p = 0.001), Ki67 ⩾44% (OR: 3.00, 95% CI: 1.59-5.65, p = 0.001), and progesterone receptor (PR) <1% (OR: 2.49, 95% CI: 1.15-5.38, p = 0.019) were independent predictors of pCR, with high replication rates at internal validation (100%, 98%, and 87%, respectively). According to the nomogram, the probability of pCR ranged from 3.4% for clinical stage III, PR > 1%, and Ki67 <44% to 53.3% for clinical stage I-II, PR < 1%, and Ki67 ⩾44% (accuracy: AUC, 0.73; p < 0.0001). In the validation set (248 patients), the predictive performance of the model was confirmed (AUC: 0.7; p < 0.0001). Conclusion: The combination of commonly available clinicopathological pre-NACT factors allows to develop a nomogram which appears to reliably predict pCR in LBC.

Characterization of Gut Microbiome Composition in Patients with Triple-Negative Breast Cancer Treated with Neoadjuvant Chemotherapy.

INTRODUCTION: Patients with triple-negative breast cancer (TNBC) achieving a pathological complete response (pCR) after neoadjuvant chemotherapy have a better event-free survival. The role of gut microbiome in early TNBC is underexplored. METHODS: Microbiome was analyzed by 16SrRNA sequencing. RESULTS: Twenty-five patients with TNBC treated with neoadjuvant anthracycline/taxane-based chemotherapy were included. Fifty-six percent achieved a pCR. Fecal samples were collected before (t0), at 1 (t1), and 8 weeks (t2) from chemotherapy. Overall, 68/75 samples (90.7%) were suitable for microbiome analysis. At t0, pCR group showed a significantly higher α-diversity as compared with no-pCR, (P = .049). The PERMANOVA test on ß-diversity highlighted a significant difference in terms of BMI (P = 0.039). Among patients with available matched samples at t0 and t1, no significant variation in microbiome composition was reported over time. CONCLUSIONS: Fecal microbiome analysis in early TNBC is feasible and deserves further investigation in order to unravel its complex correlation with immunity and cancer.

Type of adjuvant endocrine therapy and disease-free survival in patients with early HR-positive/HER2-positive BC: analysis from the phase III randomized ShortHER trial.

The optimal adjuvant endocrine therapy for HR-positive/HER2-positive breast cancer patients is unknown. We included in this analysis 784 patients with HR-positive/HER2-positive BC from the randomized ShortHER trial of adjuvant trastuzumab (1 year vs 9 weeks) + chemotherapy. At a median follow-up of 8.7 years, patients who received AI had a significantly better DFS vs patients who received TAM or TAM-AI: 8-yr DFS 86.4 vs 79.7%, log-rank P = 0.013 (HR 1.52, 95% CI 1.09-2.11). In multivariate analysis, the type of endocrine therapy maintained a significant association with DFS (HR 1.64, 95% CI 1.07-2.52, p = 0.025 for TAM/TAM-AI vs AI). Among premenopausal patients aged ≤45 years, the use of GnRHa was associated with longer DFS: 8-yr DFS rate 85.2 vs 62.6% (log-rank p = 0.019, HR 0.41, 95% CI 0.19-0.88). In this post-hoc analysis of the ShortHER trial adjuvant treatment with AI was independently associated with improved DFS. Subgroup analysis in premenopausal patients suggests benefits with ovarian suppression.Trial registration: NCI ClinicalTrials.gov number: NCT00629278.