Real-World Evidence of Ribociclib Plus Aromatase Inhibitors as First-Line Treatment in Advanced Breast Cancer: The BrasiLEEira Study.

PURPOSE: Cyclin inhibitors plus endocrine therapy represent the reference standard for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) locally advanced or metastatic breast cancer (ABC). Efficacy results on hard end points such as overall survival come from well-designed randomized clinical trials (RCTs). However, a limitation of RCTs is the low external results validity, and their extrapolation to a broader population may not be appropriate. Real-world studies can overcome these limitations, also increasing the reliability of RCTs. MATERIALS AND METHODS: The BrasiLEEira was an observational, longitudinal, retrospective, multicenter study to evaluate the effectiveness and safety of ribociclib plus nonsteroidal aromatase inhibitors in Brazilian women age 18 years or older with HR+/HER2- ABC. The study was approved by the institutional review boards of all 11 hospitals. Data were collected anonymously from medical records using an electronic case report form designed by an independent academic research organization, which conducted the study considering all recommendations of international guidelines. The primary end point was 1-year progression-free survival (PFS) rate. Secondary end points included mortality, dose reduction, and safety. RESULTS: The mean age of 76 patients was 57 years, and 28.9% were Black/Brown. The most prevalent comorbidity was arterial hypertension (34.7%). About 26.0% had endocrine-resistant disease, and 54.1% had more than three metastatic sites. The PFS rate was 77.6%. Three patients died (3.9%). Dose reductions occurred in 37.7% of patients. The most common adverse event was neutropenia (68.4%). CONCLUSION: The high-quality evidence from the BrasiLEEira study corroborates the RCTs' findings, expanding its validity to a broader spectrum and underrepresented population who may benefit from ribociclib treatment.

Nuclear and Cytoplasmic hTERT, Tumor-Infiltrating Lymphocytes, and Telomere Elongation Leukocytes Are Independent Factors in the Response to Neoadjuvant Treatment in HER2-Enriched Breast Cancer.

HER2-enriched tumors are responsible for 20% of breast tumors and have high rates of immune infiltrates in the tumor stroma that respond favorably to neoadjuvant chemotherapy. In the context of tumors, telomeres control cell death and prevent tumor cells from replicating discontinuously, leading to their immortalization. This study aimed to evaluate the presence of tumor-infiltrating lymphocytes, hTERT expression, hTERT promoter mutation, and leukocyte telomere length in HER2-enriched breast tumors. A total of 103 cases were evaluated, 19 with pathologic complete response. The TILs percentage was above ≥10 in 44 cases (43%) and significantly present in patients ≥50 years of age. hTERT staining positivity was mostly nuclear, significantly present in the non-pCR group, and associated with a lower survival rate. Leukocyte telomeres were elongated for HER2-enriched tumors, and in multivariate analysis, shortening was associated with an increased risk of death. Overall, our results show that the nuclear and cytoplasmic presence of hTERT may indicate a worse prognosis and that leukocyte telomere elongation is a protective factor.

Time interval between diagnosis to treatment of breast cancer and the impact of health insurance coverage: a sub analysis of the AMAZONA III Study (GBECAM 0115).

PURPOSE: Breast cancer (BC) is the most common type of cancer among women in Brazil. Evidence shows that delayed treatment onset is associated with increased mortality. This study aimed to evaluate median days between diagnosis and treatment and factors associated with delayed start of treatment (> 60 days after diagnosis): stage, treatment received, subtype, epidemiological characteristics, and type of healthcare coverage. METHODS: This analysis included 1709 stage I-III BC patients from AMAZONA III, a prospective, observational study, diagnosed from January 2016 to March 2018 in 22 centers in Brazil. RESULTS: The median number of days from diagnosis to beginning of first oncologic treatment was 46 days (IQR 28-75) overall, 43 days (IQR 25-75) for stage I disease, 49 days (IQR 28-81) for stage II, and 44 days (IQR 30-68) for stage III, (p = 0.1180). According to first treatment received, diagnosis-to-treatment interval was 43 days (IQR 29-65) for neoadjuvant chemotherapy and 48 days (IQR 26-81) for surgery. Diagnosis-to-treatment interval was higher in women treated in the public system versus the private system (56 vs. 34 days, p < 0.0001). Patients in the public system had an increased odds of delayed treatment initiation (OR 4.74 95% CI 3.09-7.26, p < .0001). The longer interval from diagnosis to treatment in the public system was independent of clinical stage, type of treatment (systemic vs surgery first), subtype and region of the country. CONCLUSION: By characterizing the delays in care delivery, our study will aid stakeholders to better design interventions and allocate resource to improve timely treatment for breast cancer in Brazil. CLINICALTRIALS: gov Identifier: NCT02663973, registered on January, 26th, 2016.

Triple-Negative PAM50 Non-Basal Breast Cancer Subtype Predicts Benefit from Extended Adjuvant Capecitabine.

PURPOSE: Predictive biomarkers for capecitabine benefit in triple-negative breast cancer (TNBC) have been recently proposed using samples from phase III clinical trials, including non-basal phenotype and biomarkers related to angiogenesis, stroma, and capecitabine activation genes. We aimed to validate these findings on the larger phase III GEICAM/CIBOMA clinical trial. EXPERIMENTAL DESIGN: Tumor tissues from patients with TNBC randomized to standard (neo)adjuvant chemotherapy followed by capecitabine versus observation were analyzed using a 164-gene NanoString custom nCounter codeset measuring mRNA expression. A prespecified statistical plan sought to verify the predictive capacity of PAM50 non-basal molecular subtype and tested the hypotheses that breast tumors with increased expression of (meta)genes for cytotoxic cells, mast cells, endothelial cells, PDL2, and 38 individual genes benefit from adjuvant capecitabine for distant recurrence-free survival (DRFS; primary endpoint) and overall survival. RESULTS: Of the 876 women enrolled in the GEICAM/CIBOMA trial, 658 (75%) were evaluable for analysis (337 with capecitabine and 321 without). Of these cases, 553 (84%) were profiled as PAM50 basal-like whereas 105 (16%) were PAM50 non-basal. Non-basal subtype was the most significant predictor for capecitabine benefit [HRcapecitabine, 0.19; 95% confidence interval (CI), 0.07-0.54; P < 0.001] when compared with PAM50 basal-like (HRcapecitabine, 0.9; 95% CI, 0.63-1.28; P = 0.55; Pinteraction<0.001, adjusted P value = 0.01). Analysis of biological processes related to PAM50 non-basal subtype revealed its enrichment for mast cells, extracellular matrix, angiogenesis, and features of mesenchymal stem-like TNBC subtype. CONCLUSIONS: In this prespecified correlative analysis of the GEICAM/CIBOMA trial, PAM50 non-basal status identified patients with early-stage TNBC most likely to benefit from capecitabine.

Is there a window of opportunity to optimize trastuzumab cardiac monitoring?

BACKGROUND: It remains unclear whether the current arbitrary screening recommendations of trastuzumab-related cardiotoxicity provides an adequate balance between preventing heart damage and curtailing a curative treatment. AIM: To determine the incidence rate and consequences of trastuzumab-induced cardiotoxicity as adjuvant treatment in a real-world scenario. METHODS: We present a retrospective analysis of cardiac function measured by echocardiogram at baseline and every 3 mo during trastuzumab treatment. Cardiotoxicity was defined as a drop in left ventricular ejection fraction (LVEF) ≥ 10% from baseline and/or any drop < 50%. RESULTS: Between January 2011 and December 2014, 407 patients were selected. Most (93.6%) were treated with an anthracycline followed by a taxane-based regimen and trastuzumab for 12 mo. Forty patients (9.8%) had cardiotoxicity. None of them were symptomatic, and 28 (72.5%) completely recovered LVEF. Cardiotoxicity happened early as shown by LVEF measured on echocardiogram 2 to 4 as compared to 5 to 7 (odds ratio = 2.47, 95% confidence interval: 1.09, 5.63, P = 0.024). There were 54 deaths (13.3%) during the 70-mo follow-up period; 1 (0.2%) was attributed to late cardiotoxicity (4 years after treatment). The absence of symptomatic cardiotoxicity during trastuzumab treatment and moreover the early occurrence on the treatment period may translate into a strategy to evaluate less frequently. CONCLUSION: We observed a 10% rate of asymptomatic cardiotoxicity, which mirrors the results from the large adjuvant trials. Despite being transient, an LVEF drop led to frequent treatment delays and interruptions. It remains unclear whether LVEF decline is predictive of late cardiotoxicity, and treatment efficacy is compromised.

Timelines to initiate a phase III trial across the globe: a sub-analysis of the APHINITY trial.

Background: Geographic location and national income may influence access to innovation in healthcare. We aimed to study if geographical location and national income influenced the timelines to activate the global phase III APHINITY trial, evaluating adjuvant pertuzumab in patients with HER2-positive early breast cancer. Methods: Time from regulatory authority (RA) submission to approval (RAA), time to Ethics Committee/Institutional Review Board (EC/IRB) approval, time from study approval by EC/IRB to first randomised patient and from first to last randomised patient were collected. Analyses were conducted grouping countries by geographical region or economic income classification. Results: Forty-one countries (of 42) had data available regarding all relevant timelines. No statistical difference was observed between the time to RAA and geographical region (p = 0.47), although there was a trend to longer time to RAA in upper middle-income economies (p = 0.07). Except for time from first to last patient randomised, there was wide variation in timelines overall and within geographical regions and economic income groups. Conclusions: Geographical location and income classification did not appear to be the major drivers influencing time for clinical trial activation. Wide variability in activation timelines within geographical regions and income groups exists and is worthy of further investigation.

Impact of Age on Clinical Outcomes and Efficacy of Adjuvant Dual Anti-HER2 Targeted Therapy.

BACKGROUND: Young age at breast cancer (BC) diagnosis has historically been a rationale for overtreatment. Limited data with short follow-up exist on the prognostic value of age at diagnosis in HER2-positive BC and the benefit of anti-HER2 therapy in young patients. METHODS: APHINITY (NCT01358877) is an international, placebo-controlled, double-blind randomized phase III trial in HER2-positive early BC patients investigating the addition of pertuzumab to adjuvant chemotherapy plus trastuzumab. The prognostic and predictive value of age on invasive disease-free survival (IDFS) as continuous and dichotomous variable (aged 40 years or younger and older than 40 years) was assessed. A subpopulation treatment effect pattern plot analysis was conducted to illustrate possible treatment-effect heterogeneity based on age as a continuous factor. RESULTS: Of 4804 included patients, 768 (16.0%) were aged 40 years or younger at enrollment. Median follow-up was 74 (interquartile range = 62-75) months. Young age was not prognostic either as dichotomous (hazard ratio [HR] = 1.06, 95% confidence interval [CI] = 0.84 to 1.33) or continuous (HR = 1.00, 95% CI = 1.00 to 1.01) variable. Lack of prognostic effect of age was observed irrespective of hormone receptor status and treatment arm. No statistically significant interaction was observed between age and pertuzumab effect (Pinteraction = 0.61). Adding pertuzumab improved IDFS for patients in the young (HR = 0.86, 95% CI = 0.56 to 1.32) and older (HR = 0.75, 95% CI = 0.62 to 0.92) cohorts. Similar results were observed irrespective of hormone receptor status. Subpopulation treatment effect pattern plot analysis confirmed the benefit of pertuzumab in 6-year IDFS across age subpopulations. CONCLUSIONS: In patients with HER2-positive early BC treated with modern anticancer therapies, young age did not demonstrate either prognostic or predictive value, irrespective of hormone receptor status.

Six-year absolute invasive disease-free survival benefit of adding adjuvant pertuzumab to trastuzumab and chemotherapy for patients with early HER2-positive breast cancer: A Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of the APHINITY (BIG 4-11) trial.

AIM: The APHINITY trial showed that adding adjuvant pertuzumab (P) to trastuzumab and chemotherapy, compared with adding placebo (Pla), significantly improved invasive disease-free survival (IDFS) for patients with HER2+ early breast cancer both overall and for the node-positive (N+) cohort. We explored whether adding P could benefit some N- subpopulations and whether to consider de-escalation for some N+ subpopulations. METHODS: Subpopulation Treatment Effect Pattern Plot (STEPP) is an exploratory, graphical method that plots estimates of treatment effect for overlapping patient subpopulations defined by a covariate of interest. We used STEPP to estimate Kaplan-Meier differences in 6-year IDFS percentages (P minus Pla: Δ ± standard error [SE]), both overall and by nodal status, for overlapping subpopulations defined by (1) a clinical composite risk score, (2) tumour infiltrating lymphocytes (TILs) percentage, and (3) human epidermal growth factor receptor 2 (HER2) FISH copy number. Because of multiplicity, a Δ of at least three SE is required to warrant attention. RESULTS: The average absolute gains in 6-year IDFS percentages were 2.8 ± 0.9 overall; 4.5 ± 1.2 for N+ and 0.1 ± 1.1 for N-. Largest gains were for patients with intermediate clinical composite risk (5.3 ± 1.9 overall; 6.9 ± 2.3 N+; 4.0 ± 3.0 N-), highest TILs percentage (6.3 ± 1.7 overall; 7.4 ± 2.4 N+; 3.2 ± 1.7 N-), and intermediate HER2 copy number (2.8 ± 1.9 overall; 7.4 ± 2.5 N+; -1.3 ± 1.9 N-), but clear evidence indicating a pattern of differential subpopulation treatment effects was lacking. CONCLUSIONS: STEPP plots for N- did not identify subpopulations clearly benefiting from adding P, and those for N+ did not identify subpopulations warranting de-escalation. TILs percentage appeared to be more predictive of P treatment effect than clinical composite risk score. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT01358877.

Breast Cancer Treatment Delay in SafetyNet Health Systems, Houston Versus Southeast Brazil.

BACKGROUND: Breast cancer outcomes among patients who use safety-net hospitals in the highly populated Harris County, Texas and Southeast Brazil are poor. It is unknown whether treatment delay contributes to these outcomes. METHODS: We conducted a retrospective cohort analysis of patients with non-metastatic breast cancer diagnosed between January 1, 2009 and December 31, 2011 at Harris Health Texas and Unicamp's Women's Hospital, Barretos Hospital, and Brazilian National Institute of Cancer, Brazil. We used Cox proportional hazards regression to evaluate association of time to treatment and risk of recurrence (ROR) or death. RESULTS: One thousand one hundred ninety-one patients were included. Women in Brazil were more frequently diagnosed with stage III disease (32.3% vs. 21.1% Texas; P = .002). Majority of patients in both populations had symptom-detected disease (63% in Brazil vs. 59% in Texas). Recurrence within 5 years from diagnosis was similar 21% versus 23%. Median time from diagnosis to first treatment defined as either systemic therapy (chemotherapy or endocrine therapy) or surgery, were comparable, 9.9 weeks versus 9.4 weeks. Treatment delay was not associated with increased ROR or death. Higher stage at diagnosis was associated with both increased ROR and death. CONCLUSION: Time from symptoms to treatment was considerably long in both populations. Treatment delay did not affect outcomes. IMPACT: Access to timely screening and diagnosis of breast cancer are priorities in these populations.

Cost-effectiveness analysis of Oncotype DX from a Brazilian private medicine perspective: a GBECAM multicenter retrospective study.

Background: Oncotype DX (ODX) is a validated assay for the prediction of risk of recurrence and benefit of chemotherapy (CT) in both node negative (N0) and 1-3 positive nodes (N1), hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) early breast cancer (eBC). Due to limited access to genomic assays in Brazil, treatment decisions remain largely driven by traditional clinicopathologic risk factors. ODX has been reported to be cost-effective in different health system, but limited data are available considering the reality of middle-income countries such as Brazil. We aim to evaluate the cost-effectiveness of ODX across strata of clinical risk groups using data from a dataset of patients from Brazilian institutions. Methods: Clinicopathologic and ODX information were analyzed for patients with T1-T3, N0-N1, HR+/HER2- eBC who had an ODX performed between 2005 and 2020. Projections of CT indication by clinicopathologic criteria were based on binary clinical risk categorization based on the Adjuvant! Algorithm. The ODX score was correlated with the indication of CT according to TAILORx and RxPONDER data. Two decision-tree models were developed. In the first model, low and high clinical risk patients were included while in the second, only high clinical risk patients were included. The cost for ODX and CT was based on the Brazilian private medicine perspective. Results: In all, 645 patients were analyzed; 411 patients (63.7%) had low clinical risk and 234 patients (36.3%) had high clinical risk disease. The ODX indicated low (<11), intermediate (11-25), and high (>25) risk in 119 (18.4%), 415 (64.3%), and 111 (17.2%) patients, respectively. Among 645 patients analyzed in the first model, ODX was effective (5.6% reduction in CT indication) though with an incremental cost of United States Dollar (US$) 2288.87 per patient. Among 234 patients analyzed in the second model (high clinical risk only), ODX led to a 57.7% reduction in CT indication and reduced costs by US$ 4350.66 per patient. Conclusions: Our study suggests that ODX is cost-saving for patients with high clinical risk HR+/HER2- eBC and cost-attractive for the overall population in the Brazilian private medicine perspective. Its incorporation into routine practice should be strongly considered by healthcare providers.

Patient-reported function, health-related quality of life, and symptoms in APHINITY: pertuzumab plus trastuzumab and chemotherapy in HER2-positive early breast cancer.

BACKGROUND: We assessed health-related quality of life (symptoms of therapy/patient functioning/global health status), in APHINITY (pertuzumab/placebo, trastuzumab, and chemotherapy as adjuvant HER2-positive early breast cancer therapy). METHODS: Patients received 1 year/18 cycles of pertuzumab/placebo with trastuzumab and chemotherapy and completed EORTC QLQ-C30 and BR23 questionnaires until 36 months post-randomisation/disease recurrence. Changes ≥10 points from baseline were considered clinically meaningful. RESULTS: 87-97% of patients completed questionnaires. In the pertuzumab versus placebo arms, mean decrease in physical function scores (baseline → end of taxane) was -10.7 (95% CI -11.4, -10.0) versus -10.6 (-11.4, -9.9), mean decrease in global health status was -11.2 (-12.2, -10.2) versus -10.2 (-11.1, -9.2), and mean increase in diarrhoea scores (baseline → end of taxane) was +22.3 (21.0, 23.6) versus +9.2 (8.2, 10.2). Diarrhoea scores remained elevated versus baseline in the pertuzumab arm throughout HER2-targeted treatment (week 25: +13.2; end of treatment: +12.2). Role functioning was maintained in both arms. CONCLUSIONS: Improved invasive disease-free survival achieved by adding pertuzumab to trastuzumab and chemotherapy did not adversely affect the ability to conduct activities of daily living versus trastuzumab and chemotherapy alone. Patient-reported diarrhoea worsened during taxane therapy in both arms, persisting during HER2-targeted treatment in the pertuzumab arm. CLINICALTRIALS.GOV: NCT01358877.

Challenge of Incorporating New Drugs for Breast Cancer in Brazil: A Proposed Framework for Improving Access to Innovative Therapies.

PURPOSE: The objective of this review is to address the barriers limiting access to treatment of advanced metastatic breast cancer (mBC) in Brazil, specifically for patients in the public health care system, arguably those with the least access to innovation. MATERIALS AND METHODS: A selected panel of Brazilian experts in BC were provided with a series of relevant questions to address in a multiday conference. During the conference, responses were discussed and edited by the entire group through numerous drafts and rounds of discussion until a consensus was achieved. RESULTS: The authors propose specific and realistic recommendations for implementing access to new drugs in cancer care in Brazil. Moreover, in creating these recommendations and framework, the authors strive to address the most important barriers and impediments for technology incorporation. A feasible and specific multidisciplinary process is proposed, which is based on the collective participation of all involved stakeholders. CONCLUSION: Given the current benefits and likely future developments, there is a great need to expand treatments for mBC not only in Brazil but also in most other countries in the world where access issues remain an unresolved demand. Adapting the current framework is essential for accomplishing this goal. The recommendations in this review can serve as a framework for adoption of new technologies in countries with limited resources.

Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up.

PURPOSE: APHINITY, at 45 months median follow-up, showed that pertuzumab added to adjuvant trastuzumab and chemotherapy significantly improved invasive disease-free survival (IDFS) (hazard ratio 0.81 [95% CI, 0.66 to 1.00], P = .045) for patients with early human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC), specifically those with node-positive or hormone receptor (HR)-negative disease. We now report the preplanned second interim overall survival (OS) and descriptive updated IDFS analysis with 74 months median follow-up. METHODS: After surgery and central HER2-positive confirmation, 4,805 patients with node-positive or high-risk node-negative BC were randomly assigned (1:1) to either 1-year pertuzumab or placebo added to standard adjuvant chemotherapy and 1-year trastuzumab. RESULTS: This interim OS analysis comparing pertuzumab versus placebo did not reach the P = .0012 level required for statistical significance (P = .17, hazard ratio 0.85). Six-year OS were 95% versus 94% with 125 deaths (5.2%) versus 147 (6.1%), respectively. IDFS analysis based on 508 events (intent-to-treat population) showed a hazard ratio of 0.76 (95% CI, 0.64 to 0.91) and 6-year IDFS of 91% and 88% for pertuzumab and placebo groups, respectively. The node-positive cohort continues to derive clear IDFS benefit from pertuzumab (hazard ratio 0.72 [95% CI, 0.59 to 0.87]), 6-year IDFS being 88% and 83%, respectively. Benefit was not seen in the node-negative cohort. In a subset analysis, IDFS benefit from pertuzumab showed a hazard ratio of 0.73 (95% CI, 0.59 to 0.92) for HR-positive disease and a hazard ratio of 0.83 (95% CI, 0.63 to 1.10) for HR-negative disease. Primary cardiac events remain < 1% in both the treatment groups. No new safety signals were seen. CONCLUSION: This analysis confirms the IDFS benefit from adding pertuzumab to standard adjuvant therapy for patients with node-positive HER2-positive early BC. Longer follow-up is needed to fully assess OS benefit.

Practical considerations for expediting breast cancer treatment in Brazil.

Patients in Brazil continue to present with late-stage breast cancer. Notwithstanding these figures, policies and programs to overcome this long-lasting scenario have had limited results. We enlist the main barriers for advancing breast cancer diagnosis in Brazil, based on the available evidence, and we propose feasible strategies that may serve as a platform to address this major public health challenge.

The impact of sociodemographic factors and health insurance coverage in the diagnosis and clinicopathological characteristics of breast cancer in Brazil: AMAZONA III study (GBECAM 0115).

PURPOSE: In Brazil, the available cancer registries are deficient in number and quality and, hence, little information is known regarding sociodemographic, clinicopathological characteristics, treatment patterns, and outcomes of breast cancer (BC) patients. We performed the AMAZONA III/ GBECAM 0115 study and in this analysis, we describe patients' characteristics at diagnosis and their association with health insurance type. METHODS: This is a prospective cohort study developed in 23 sites in Brazil including women with newly diagnosed invasive BC from January 2016 to March 2018. In order to compare healthcare insurance type, we considered patients who were treated under the Brazilian public health system as publicly insured, and women who had private insurance or paid for their treatment as privately insured. RESULTS: A total of 2950 patients were included in the study. Median age at diagnosis was 53.9 years; 63.1% were publicly insured. The majority of patients (68.6%) had stage II-III breast cancer and ductal carcinoma histology (80.9%). The most common breast cancer subtype was luminal A-like (48.0%) followed by luminal B-HER2 positive-like (17.0%) and triple-negative (15.6%). Luminal A was more frequent in private (53.7% vs. 44.2%, p < .0001) than public, whereas Luminal B HER2-positive (19.2% vs. 14.2%, p = 0.0012) and HER2-positive (8.8% vs. 5.1%, p = 0.0009) were more common in patients with public health system coverage. Only 34% of patients were diagnosed by screening exams. Privately insured patients were more frequently diagnosed with stage I disease when compared to publicly insured patients; publicly insured patients had more stage III (33.5% vs. 14.7%; p-value < 0.0001) disease than privately insured ones. Breast cancer was detected by symptoms more frequently in publicly than in privately insured patients (74.2% vs 25.8%, respectively; p-value < 0.0001). CONCLUSIONS: Patients with public health coverage were diagnosed with symptomatic disease, later stages and more aggressive subtypes when compared to privately insured patients.

Does the Sequence of Anthracycline and Taxane Matter? The NeoSAMBA Trial.

BACKGROUND: Taxanes usually follow anthracyclines in breast cancer neo/adjuvant treatment, likely because of their later introduction into clinical practice. However, there is no biological rationale that justifies this current standard of care. We compared a taxane followed by an anthracycline-based regimen with the reverse sequence in the neoadjuvant setting. PATIENTS AND METHODS: In a randomized, open-label, single-center phase II trial, women with inoperable, locally advanced, HER2-negative breast cancer were stratified by hormone receptor status and randomized to three cycles of docetaxel (T) followed by three cycles of fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus three cycles of FAC followed by three cycles of docetaxel. Surgery, radiotherapy, and adjuvant hormonal therapy were administered as per local guidelines. The primary endpoint was pathological complete response (pCR), and secondary endpoints included toxicity, event-free survival (EFS), and overall survival (OS). RESULTS: Treatment sequence did not improve pCR, which was 7% with T-FAC and 3% with FAC-T. However, after a median follow-up of 79 months, the 5-year EFS rate was 75.7% (95% confidence interval [CI], 65.4%-87.7%) with T-FAC and 48.2% (95% CI, 37.0%-62.7%) with FAC-T (hazard ratio [HR], 0.46; 95% CI, 0.26-0.81; log-rank p = .0054), and the 5-year OS rate was 89.7% (95% CI, 82.2%-97.8%) with T-FAC and 64.7% (95% CI, 53.6%-78.1%) with FAC-T (HR, 0.41; 95% CI, 0.22-0.78; p = .0052). There were no unexpected toxicities. CONCLUSION: We showed for the first time an improvement in EFS and OS with taxane-first compared with anthracycline-first sequencing chemotherapy in HER2-negative, locally advanced breast cancer. Confirmation of these results may have implications for clinical practice. This trial was registered with Clinicatrials.gov identifier NCT01270373. IMPLICATIONS FOR PRACTICE: The NeoSAMBA trial showed a benefit for taxane-first sequencing chemotherapy consistent with the systematic review of the literature as well as the larger Neo-tAnGo study. Many recent and current ongoing clinical trials have already followed this treatment strategy. As a taxane-before-anthracycline sequence carries neither an incremental cost nor an increased toxicity, and given the available literature on this issue, reinforced that taxane-first regimen can be easily incorporated into daily clinical practice while awaiting confirmation of these findings from larger trials.

Cell free DNA biology and its involvement in breast carcinogenesis.

Liquid biopsy represents a procedure for minimally invasive analysis of non-solid tissue, blood and other body fluids. It comprises a set of analytes that includes circulating tumor cells (CTCs) and circulating free DNA (cfDNA), RNA, long noncoding RNA (lncRNA) and micro RNA (miRNA), as well as extracellular vesicles. These novel analytes represent an alternative tool to complement diagnosis and monitor and predict response to treatment of the tumoral process and may be used for other disease processes such viral and parasitic infection. This review focuses on the biologic and molecular characteristics of cfDNA in general and the molecular changes (mutational and epigenetic) proven useful in oncologic practice for diagnosis, monitoring and treatment of breast cancer specifically.

ESR1 Mutations Are Not a Common Mechanism of Endocrine Resistance in Patients With Estrogen Receptor-Positive Breast Cancer Treated With Neoadjuvant Aromatase Inhibitor Therapy.

Introduction: Mutations in the ESR1 gene (ESR1m) are important mechanisms of resistance to endocrine therapy in estrogen receptor-positive (ER+) metastatic breast cancer and have been studied as a potential therapeutic target, as well as a predictive and prognostic biomarker. Nonetheless, the role of ESR1m as a possible mechanism of primary endocrine resistance, as well as whether it also occurs in tumors that are resistant to ET administered in early-stage disease as (neo)adjuvant, has not been adequately studied. In this study, we evaluated the prevalence of ESR1m in tumor samples from patients with ER+ breast cancer resistant to neoadjuvant aromatase inhibitor therapy. Methods: We followed a prospective cohort of patients with ER+ HER2- stages II and III breast cancer treated with neoadjuvant endocrine therapy (NET). Tumor samples from patients with a pattern of primary endocrine resistance [defined as a Preoperative Endocrine Prognostic Index (PEPI) score of ≥4] were identified and analyzed for the presence of ESR1m. Results: One hundred twenty-seven patients were included in the cohort, of which 100 (79%) had completed NET and underwent surgery. Among these patients, the PEPI score ranged from 0 to 3 in 70% (70/100), whereas 30% (30/100) had a PEPI score of 4 or more. Twenty-three of these patients were included in the analysis. ESR1 mutations were not identified in any of the 23 patients with early-stage ER+ breast cancer resistant to NET. Discussion: Growing evidence supports the notion that there are different mechanisms for primary and secondary endocrine resistance. Our study suggests that ESR1 mutations do not evolve rapidly and do not represent a common mechanism of primary endocrine resistance in the neoadjuvant setting. Therefore, ESR1m should be considered a mechanism of acquired endocrine resistance in the context of advanced disease. Further research should be conducted to identify factors associated with intrinsic resistance to ET.

Incidence and Management of Diarrhea With Adjuvant Pertuzumab and Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.

BACKGROUND: The APHINITY (BIG 4-11) study showed that pertuzumab significantly improved the rates of invasive disease-free survival among patients with human epidermal growth factor receptor 2 (HER2)-positive, operable breast cancer when added to adjuvant trastuzumab and chemotherapy. Because diarrhea was a common adverse event that could compromise treatment administration, we evaluated the incidence and management of diarrhea in the APHINITY study. PATIENTS AND METHODS: The APHINITY trial is a prospective, randomized, multicenter, multinational, double-blind, placebo-controlled trial. The eligible patients were randomly assigned to receive standard adjuvant chemotherapy and 1 year of trastuzumab combined with pertuzumab or placebo. The diarrhea incidence, severity (National Cancer Institute common terminology criteria for adverse events, version 4.0), onset, and management were analyzed. RESULTS: A total of 4805 patients were randomized. Diarrhea of any grade was the most common adverse event and occurred in 71% of patients in the pertuzumab arm versus 45% in the placebo arm. Diarrhea grade 3 to 4 was observed in 10% and 4% in the pertuzumab and placebo arms, respectively. The greatest incidence of diarrhea was reported during the concomitant administration of HER2-targeted therapy and taxane (61% vs. 34% of patients experienced an event with pertuzumab vs. placebo, respectively). A marked decrease was observed on chemotherapy cessation. Antidiarrheal agents were commonly used, and diarrhea rarely caused treatment dose modifications or discontinuation. CONCLUSION: Diarrhea was a common adverse event in the APHINITY study. Most episodes were low grade and were generally manageable with common antidiarrheal agents. The incidence of diarrhea was greater with the combination of a taxane and HER2-targeted treatment and decreased once chemotherapy was stopped.

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).

PURPOSE: Operable triple-negative breast cancers (TNBCs) have a higher risk of relapse than non-TNBCs with standard therapy. The GEICAM/2003-11_CIBOMA/2004-01 trial explored extended adjuvant capecitabine after completion of standard chemotherapy in patients with early TNBC. PATIENTS AND METHODS: Eligible patients were those with operable, node-positive-or node negative with tumor 1 cm or greater-TNBC, with prior anthracycline- and/or taxane-containing chemotherapy. After central confirmation of TNBC status by immunohistochemistry, patients were randomly assigned to either capecitabine or observation. Stratification factors included institution, prior taxane-based therapy, involved axillary lymph nodes, and centrally determined phenotype (basal v nonbasal, according to cytokeratins 5/6 and/or epidermal growth factor receptor positivity by immunohistochemistry). The primary objective was to compare disease-free survival (DFS) between both arms. RESULTS: Eight hundred seventy-six patients were randomly assigned to capecitabine (n = 448) or observation (n = 428). Median age was 49 years, 55.9% were lymph node negative, 73.9% had a basal phenotype, and 67.5% received previous anthracyclines plus taxanes. Median length of follow-up was 7.3 years. DFS was not significantly prolonged with capecitabine versus observation [hazard ratio (HR), 0.82; 95% CI, 0.63 to 1.06; P = .136]. In a preplanned subgroup analysis, nonbasal patients seemed to derive benefit from the addition of capecitabine with a DFS HR of 0.53 versus 0.94 in those with basal phenotype (interaction test P = .0694) and an HR for overall survival of 0.42 versus 1.23 in basal phenotype (interaction test P = .0052). Tolerance of capecitabine was as expected, with 75.2% of patients completing the planned 8 cycles. CONCLUSION: This study failed to show a statistically significant increase in DFS by adding extended capecitabine to standard chemotherapy in patients with early TNBC. In a preplanned subset analysis, patients with nonbasal phenotype seemed to obtain benefit with capecitabine, although this will require additional validation.