Utility of the 70-Gene MammaPrint Assay for Prediction of Benefit From Extended Letrozole Therapy in the NRG Oncology/NSABP B-42 Trial.

PURPOSE: MammaPrint (MP) determines distant metastatic risk and may improve patient selection for extended endocrine therapy (EET). This study examined MP in predicting extended letrozole therapy (ELT) benefit in patients with early-stage breast cancer (BC) from the NSABP B-42 trial. PATIENTS AND METHODS: MP was tested in 1,866 patients randomly assigned to receive ELT or placebo. The primary end point was distant recurrence (DR). Secondary end points were disease-free survival (DFS) and BC-free interval (BCFI). Tumors were classified as MP high risk (MP-HR) or low risk (MP-LR). MP-LR tumors were further classified as ultralow risk (MP-UL) or low non-ultralow risk (MP-LNUL). RESULTS: There was no statistically significant difference in ELT benefit on DR between MP-HR and MP-LR (interaction P = .38). MP-LR tumors (n = 1,160) exhibited a statistically significant 10-year benefit of 3.7% for DR (hazard ratio [HR], 0.43 [95% CI, 0.25 to 0.74]; P = .002), whereas MP-HR tumors (n = 706) exhibited a nonsignificant 2.4% benefit (HR, 0.65 [95% CI, 0.34 to 1.24]; P = .19). The 10-year ELT benefit was significant for DFS (7.8%) and BCFI (7.0%) for MP-LR tumors, whereas MP-HR tumors did not significantly benefit (interaction DFS: P = .015, BCFI: P = .006). In exploratory analysis, the 10-year ELT benefit was significant and more pronounced in MP-LNUL (n = 908) tumors: 4.0% for DR, 9.5% for DFS, and 7.9% for BCFI; the benefit in MP-UL (n = 252) tumors was not significant: 3% for DR, 1.8% for DFS, and 4.1% for BCFI. CONCLUSION: The primary hypothesis of predictive ability of MP on DR was not confirmed. However, the secondary outcomes demonstrated MP was predictive of ELT response and identified a subset of patients with early-stage hormone receptor-positive BC (MP-LR) with improved outcomes from ELT. These data could have important clinical implications in patient selection beyond clinical risk assessment for EET.

Panel stacking is a threat to consensus statement validity.

Consensus statements can be very influential in medicine and public health. Some of these statements use systematic evidence synthesis but others fail on this front. Many consensus statements use panels of experts to deduce perceived consensus through Delphi processes. We argue that stacking of panel members toward one particular position or narrative is a major threat, especially in absence of systematic evidence review. Stacking may involve financial conflicts of interest, but nonfinancial conflicts of strong advocacy can also cause major bias. Given their emerging importance, we describe here how such consensus statements may be misleading, by analyzing in depth a recent high-impact Delphi consensus statement on COVID-19 recommendations as a case example. We demonstrate that many of the selected panel members and at least 35% of the core panel members had advocated toward COVID-19 elimination (Zero-COVID) during the pandemic and were leading members of aggressive advocacy groups. These advocacy conflicts were not declared in the Delphi consensus publication, with rare exceptions. Therefore, we propose that consensus statements should always require rigorous evidence synthesis and maximal transparency on potential biases toward advocacy or lobbyist groups to be valid. While advocacy can have many important functions, its biased impact on consensus panels should be carefully avoided.

Association of early menarche with breast tumor molecular features and recurrence.

BACKGROUND: Early menarche is an established risk factor for breast cancer but its molecular contribution to tumor biology and prognosis remains unclear. METHODS: We profiled transcriptome-wide gene expression in breast tumors (N = 846) and tumor-adjacent normal tissues (N = 666) from women in the Nurses' Health Studies (NHS) to investigate whether early menarche (age < 12) is associated with tumor molecular and prognostic features in women with breast cancer. Multivariable linear regression and pathway analyses using competitive gene set enrichment analysis were conducted in both tumor and adjacent-normal tissue and externally validated in TCGA (N = 116). Subgroup analyses stratified on ER-status based on the tumor were also performed. PAM50 signatures were used for tumor molecular subtyping and to generate proliferation and risk of recurrence scores. We created a gene expression score using LASSO regression to capture early menarche based on 28 genes from FDR-significant pathways in breast tumor tissue in NHS and tested its association with 10-year disease-free survival in both NHS (N = 836) and METABRIC (N = 952). RESULTS: Early menarche was significantly associated with 369 individual genes in adjacent-normal tissues implicated in extracellular matrix, cell adhesion, and invasion (FDR ≤ 0.1). Early menarche was associated with upregulation of cancer hallmark pathways (18 significant pathways in tumor, 23 in tumor-adjacent normal, FDR ≤ 0.1) related to proliferation (e.g. Myc, PI3K/AKT/mTOR, cell cycle), oxidative stress (e.g. oxidative phosphorylation, unfolded protein response), and inflammation (e.g. pro-inflammatory cytokines IFN α and IFN γ ). Replication in TCGA confirmed these trends. Early menarche was associated with significantly higher PAM50 proliferation scores (ß = 0.082 [0.02-0.14]), odds of aggressive molecular tumor subtypes (basal-like, OR = 1.84 [1.18-2.85] and HER2-enriched, OR = 2.32 [1.46-3.69]), and PAM50 risk of recurrence score (ß = 4.81 [1.71-7.92]). Our NHS-derived early menarche gene expression signature was significantly associated with worse 10-year disease-free survival in METABRIC (N = 952, HR = 1.58 [1.10-2.25]). CONCLUSIONS: Early menarche is associated with more aggressive molecular tumor characteristics and its gene expression signature within tumors is associated with worse 10-year disease-free survival among women with breast cancer. As the age of onset of menarche continues to decline, understanding its relationship to breast tumor characteristics and prognosis may lead to novel secondary prevention strategies.

Identifying drivers of first-line HR+/HER2- metastatic breast cancer treatment choices.

Aim: Assess factors associated with first-line (1L) treatment for HR+/HER2- metastatic breast cancer. Materials & methods: A cross-sectional survey of 250 US oncologists was conducted. Correlations were calculated between treatment class and demographics, treatment perceptions and other clinical/nonclinical characteristics. Results: Efficacy and safety/tolerability were critical in oncologists' 1L decision-making. CDK4/6i use positively correlated with proportion of Medicare and postmenopausal patients (r = 0.54-0.67). Chemotherapy use demonstrated positive correlations with perimenopausal and premenopausal patients and symptom burden (r = 0.31-0.42). Aromatase inhibitor (AI) monotherapy correlated positively with anticipated treatment compliance (r = 0.42). Conclusion: Efficacy and safety/tolerability were most important to 1L decision-making. Clinical characteristics corresponded with CDK4/6i and chemotherapy use. Anticipated compliance was associated with AI monotherapy use.

Patients in the USA with a certain type of metastatic breast cancer (mBC, i.e., HR+/HER2−) might get chemotherapy or hormone therapy alone instead of new and potentially better medicines called cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) as their first treatment.Researchers wanted to understand how US cancer specialists decided the first treatment for this type of mBC. In a survey of 250 cancer specialists, researchers looked at different factors that might influence decision-making, including patient characteristics, doctors' opinions about the treatments and other medical and non-medical features. This study also examined the connections between these factors and the cancer specialists' choice of first treatment.Researchers found that cancer specialists care most about how well a treatment works and how safe it is when choosing the first treatment for HR+/HER2− mBC. They are more likely to use CDK4/6i if their patients have Medicare coverage or are older (i.e., women who have been through menopause). Chemotherapy is chosen if their patients are younger (i.e., women who are near and before menopause) or have more symptoms. Cancer specialists tend to choose first treatment with hormone therapy alone if they think their patients have a hard time following their treatment plan. The results showed that patient characteristics, doctors' opinions of treatments and other medical and non-medical factors play a role in choosing treatment for HR+/HER2− mBC. By understanding these factors, researchers can work toward improving treatment choices for patients with this type of mBC.

Effects of aerobic exercise on neurocognitive function in postmenopausal women receiving endocrine therapy for breast cancer: The Exercise Program in Cancer and Cognition randomized controlled trial.

Objective: The Exercise Program in Cancer and Cognition (EPICC) Study was a randomized controlled trial (RCT) designed to determine whether six months of moderate-intensity aerobic exercise improves neurocognitive function in women with breast cancer (BC) receiving endocrine therapy (ET). Methods: Postmenopausal women with hormone receptor+, early-stage BC, within two years post-primary therapy were randomized to the exercise intervention (six months, ≥150 minutes of moderate-intensity aerobic exercise/week) or usual care control condition. Outcomes were assessed at pre-randomization and after intervention completion. Groups were compared using linear mixed-effects modeling. Results: Participants (N=153) were X ¯ = 62.09 ± 8.27 years old, with stage I BC (64.1%) and a median of 4.7 months post-diagnosis. We found a group-by-time interaction (p=0.041) and a trend for the main effect of time (p=0.11) for processing speed with improved performance in the exercise group and no change in the controls. Similar main effects of time were observed for learning and memory (p=0.024) and working memory (p=0.01). Better intervention adherence was associated with improved processing speed (p=0.017). Conclusions: Six months of moderate-intensity aerobic exercise improves processing speed in postmenopausal women with BC receiving ET who initiate exercise within two years of completing primary therapy (surgery +/- chemotherapy). This is the first large-scale study to examine the effects of aerobic exercise on neurocognitive function in women with BC. Additional research is needed to address the long-term effects of aerobic exercise on cognitive function.

CDK4/6 inhibitors: The Devil is in the Detail.

PURPOSE OF REVIEW: Update on the most recent clinical evidence on CDK4/6 inhibitors (CDK4/6i) in the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor (HER)2-negative breast cancer. RECENT FINDINGS: Over the past decade, CDK4/6i have become part of the standard of care treatment of patients with both metastatic and high-risk early HR + /HER2- breast cancers. The three available CDK4/6i (palbociclib, ribociclib and abemaciclib) have been extensively studied in combination with endocrine therapy (ET) in metastatic breast cancer (mBC) with consistent prolongation of progression free survival; however, ribociclib has emerged as the preferred first line agent in mBC given overall survival benefit over endocrine monotherapy. In early BC, abemaciclib is the only currently approved agent while ribociclib has early positive clinical trial data. Toxicities and financial burden limit the use of CDK4/6i in all patients and resource-poor settings, and optimal timing of their use in mBC remains unclear. There is considerable evidence for the use of CDK4/6i in metastatic and early HR + /HER2- breast cancer, but knowledge gaps remain, and further research is necessary to better define their optimal use.

Organizational Breast Cancer Data Mart: A Solution for Assessing Outcomes of Imaging and Treatment.

PURPOSE: In the United States, a comprehensive national breast cancer registry (CR) does not exist. Thus, care and coverage decisions are based on data from population subsets, other countries, or models. We report a prototype real-world research data mart to assess mortality, morbidity, and costs for breast cancer diagnosis and treatment. METHODS: With institutional review board approval and Health Insurance Portability and Accountability Act (HIPPA) compliance, a multidisciplinary clinical and research data warehouse (RDW) expert group curated demographic, risk, imaging, pathology, treatment, and outcome data from the electronic health records (EHR), radiology (RIS), and CR for patients having breast imaging and/or a diagnosis of breast cancer in our institution from January 1, 2004, to December 31, 2020. Domains were defined by prebuilt views to extract data denormalized according to requirements from the existing RDW using an export, transform, load pattern. Data dictionaries were included. Structured query language was used for data cleaning. RESULTS: Five-hundred eighty-nine elements (EHR 311, RIS 211, and CR 67) were mapped to 27 domains; all, except one containing CR elements, had cancer and noncancer cohort views, resulting in a total of 53 views (average 12 elements/view; range, 4-67). EHR and RIS queries returned 497,218 patients with 2,967,364 imaging examinations and associated visit details. Cancer biology, treatment, and outcome details for 15,619 breast cancer cases were imported from the CR of our primary breast care facility for this prototype mart. CONCLUSION: Institutional real-world data marts enable comprehensive understanding of care outcomes within an organization. As clinical data sources become increasingly structured, such marts may be an important source for future interinstitution analysis and potentially an opportunity to create robust real-world results that could be used to support evidence-based national policy and care decisions for breast cancer.

Treatment outcomes in older patients with metastatic breast cancer receiving palbociclib plus an aromatase inhibitor: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This summary describes an article published in the medical journal Frontiers in Oncology in September 2023. The article reports results from a study that looked at breast cancer treatments for older patients aged 75 years or older. The study focused on a type of cancer called HR+/HER2- metastatic breast cancer. HR+/HER2- stands for hormone receptorpositive/human epidermal growth factor receptor 2-negative. This study evaluated whether older patients with this type of cancer benefited from the combination of two medicines - palbociclib and an aromatase inhibitor - compared with taking an aromatase inhibitor alone. HOW WAS THE STUDY IN THIS SUMMARY CARRIED OUT?: The Flatiron database contains medical records for people with cancer in the US. This study used deidentified health care information from this database. 'Deidentified' means that all information that could identify an individual was removed to protect individuals' privacy. People in this study received treatment in routine care and not in a clinical trial. WHAT DO THE RESULTS MEAN?: Older patients who took palbociclib plus an aromatase inhibitor lived longer than those who took an aromatase inhibitor alone. Older patients who took palbociclib plus an aromatase inhibitor also lived longer without their cancer getting worse and started chemotherapy later than those who took an aromatase inhibitor alone. These results support using palbociclib plus an aromatase inhibitor as the first treatment for patients aged 75 years or older with HR+/HER2- metastatic breast cancer.

This study evaluated outcomes in elderly patients with metastatic breast cancer treated in routine care. Overall, patients who took palbociclib plus an aromatase inhibitor (AI) lived longer, and lived longer without their cancer getting worse, than those who took an AI alone.

Prolonging the lives of African-Americans with metastatic breast cancer by adding palbociclib to an aromatase inhibitor in routine clinical practice: a plain language summary of a real-world database study.

WHAT IS THIS SUMMARY ABOUT?: This summary is about a study that was published in the medical journal The Oncologist in July 2023. The combination of palbociclib with an aromatase inhibitor (AI) was approved by the FDA in 2015 as a treatment for people with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC). However, the effectiveness of palbociclib in African-Americans with MBC is not well studied. The goal of this study was to find out whether adding palbociclib to an AI helped African-Americans with HR+/HER2- MBC live longer. WHAT ARE THE KEY TAKEAWAYS?: This study used de-identified medical information from the Flatiron Database. This database contains healthcare information on people with cancer treated by doctors in the United States but personal information is removed to maintain privacy. Medical information for people who received certain treatments in routine clinical practice or real-world setting was included in the study.This study showed that in the real-world setting, African-Americans with HR+/HER2- MBC lived longer when receiving palbociclib with an AI than with an AI alone. Also, the study showed that African-Americans treated with palbociclib plus an AI lived longer without their cancer getting worse than those treated with an AI alone. WHAT WAS THE MAIN CONCLUSION REPORTED BY THE RESEARCHERS?: These results support the use of palbociclib with an AI as a first treatment for African-Americans with HR+/HER2- MBC.Clinical Trial Registration: NCT05361655 (ClinicalTrials.gov).

Effectiveness of palbociclib plus an aromatase inhibitor in African Americans with metastatic breast cancer in routine clinical practice: a plain language summary.

Health-related quality of life over chemotherapy course among individuals with early-stage breast cancer: the association of social determinants of health and neighborhood socioeconomic disadvantage.

PURPOSE: This study aimed to examine relationships between health-related quality of life (HRQOL), social determinants of health, and neighborhood socioeconomic disadvantage in individuals with early-stage breast cancer (ESBC) during chemotherapy. METHODS: This is a longitudinal study that recruited Black and White women with ESBC receiving chemotherapy. Participants completed questionnaires recording their sociodemographic information at baseline and the Functional Assessment of Cancer Therapy-General (FACT-G) to report their HRQOL before each chemotherapy cycle. Linear mixed modeling was employed to examine the associations between FACT-G scores, self-reported race, and area deprivation index (ADI) before and at the last chemotherapy cycle, with the duration of chemotherapy treatment as a covariate. RESULTS: A total of 84 Black and 146 White women with ESBC completed the surveys. Linear mixed modeling results suggested that women with ESBC who reported being Black experienced significantly worse physical well-being than those who reported being White throughout chemotherapy, with a 0.22-point lower average (p = 0.02). Both Black and White women with ESBC experienced decreased functional well-being over the chemotherapy, and Black women consistently reported lower scores than White women, with the change in functional well-being over time differing between racial groups (p = 0.03). Participants' ADI national percentiles were not significantly associated with their HRQOL throughout chemotherapy. CONCLUSIONS: These findings underscore possible racial differences in some dimensions of HRQOL during chemotherapy among women with ESBC. Future research should consider further assessing life stressors and past experiences of discrimination and racism that may contribute to these disparities and guide proactive interventions.

Long-Term Follow-Up of the Anthracyclines in Early Breast Cancer Trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 [NRG Oncology]).

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 co-primary 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.The primary joint efficacy analysis of the Anthracyclines in Early Breast Cancer (ABC) trials reported in 2017 failed to demonstrate nonanthracycline adjuvant therapy was noninferior to anthracycline-based regimens in high-risk, early breast cancer. Full analyses of the studies had proceeded when the prespecified futility boundary was crossed at a planned futility analysis for the ability to demonstrate noninferiority of a nonanthracycline regimen with continued follow-up. These results were presented with 3.3 years of median follow-up. This manuscript reports results of the final analyses of the study efficacy end points conducted with 6.9 years of median follow-up. Long-term analysis of invasive disease-free survival (IDFS), the primary end point of the ABC trials, remains consistent with the original results, as noninferiority of the nonanthracycline regimens could not be declared on the basis of the original criteria. The secondary end point of recurrence-free interval, which excluded deaths not due to breast cancer as events, favored anthracycline-based regimens, and tests for heterogeneity were significant for hormone receptor status (P = .02) favoring anthracycline regimens for the hormone receptor-negative cohorts. There was no difference in overall survival, and review of the type of IDFS events in the groups suggested reductions in cancer recurrences achieved with anthracycline regimens were offset by late leukemias and deaths unrelated to breast cancer.

Activity and safety of enobosarm, a novel, oral, selective androgen receptor modulator, in androgen receptor-positive, oestrogen receptor-positive, and HER2-negative advanced breast cancer (Study G200802): a randomised, open-label, multicentre, multinational, parallel design, phase 2 trial.

BACKGROUND: The androgen receptor is a tumour suppressor in oestrogen receptor-positive breast cancer. The activity and safety of enobosarm, an oral selective androgen receptor modulator, was evaluated in women with oestrogen receptor (ER)-positive, HER2-negative, and androgen receptor (AR)-positive disease. METHODS: Women who were postmenopausal (aged ≥18 years) with previously treated ER-positive, HER2-negative, locally advanced or metastatic breast cancer with an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled in a randomised, open-label, multicentre, multinational, parallel design, phase 2 trial done at 35 cancer treatment centres in nine countries. Participants were stratified on the setting of immediately preceding endocrine therapy and the presence of bone-only metastasis and randomly assigned (1:1) to 9 mg or 18 mg oral enobosarm daily using an interactive web response system. The primary endpoint was clinical benefit rate at 24 weeks in those with centrally confirmed AR-positive disease (ie, the evaluable population). This trial is registered with ClinicalTrials.gov (NCT02463032). FINDINGS: Between Sept 10, 2015, and Nov 28, 2017, 136 (79%) of 172 patients deemed eligible were randomly assigned to 9 mg (n=72) or 18 mg (n=64) oral enobosarm daily. Of these 136 patients, 102 (75%) patients formed the evaluable population (9 mg, n=50; 18 mg, n=52). The median age was 60·5 years (IQR 52·3-69·3) in the 9 mg group and 62·5 years (54·0-69·3) in the 18 mg group. The median follow-up was 7·5 months (IQR 2·9-14·1). At 24 weeks, 16 (32%, 95% CI 20-47) of 50 in the 9 mg group and 15 (29%, 17-43) of 52 in the 18 mg group had clinical benefit. Six (8%) of 75 patients who received 9 mg and ten (16%) of 61 patients who received 18 mg had grade 3 or grade 4 drug-related adverse events, most frequently increased hepatic transaminases (three [4%] of 75 in the 9 mg group and two [3%] of 61 in the 18 mg group), hypercalcaemia (two [3%] and two [3%]), and fatigue (one [1%] and two [3%]). Four deaths (one in the 9 mg group and three in the 18 mg group) were deemed unrelated to the study drug. INTERPRETATION: Enobosarm has anti-tumour activity in patients with ER-positive, HER2-negative advanced breast cancer, showing that AR activation can result in clinical benefit, supporting further clinical investigation of selective AR activation strategies for the treatment of AR-positive, ER-positive, HER2-negative advanced breast cancer. FUNDING: GTx.

Entinostat, nivolumab and ipilimumab for women with advanced HER2-negative breast cancer: a phase Ib trial.

We report the results of 24 women, 50% (N = 12) with hormone receptor-positive breast cancer and 50% (N = 12) with advanced triple-negative breast cancer, treated with entinostat + nivolumab + ipilimumab from the dose escalation (N = 6) and expansion cohort (N = 18) of ETCTN-9844 ( NCT02453620 ). The primary endpoint was safety. Secondary endpoints were overall response rate, clinical benefit rate, progression-free survival and change in tumor CD8:FoxP3 ratio. There were no dose-limiting toxicities. Among evaluable participants (N = 20), the overall response rate was 25% (N = 5), with 40% (N = 4) in triple-negative breast cancer and 10% (N = 1) in hormone receptor-positive breast cancer. The clinical benefit rate was 40% (N = 8), and progression-free survival at 6 months was 50%. Exploratory analyses revealed that changes in myeloid cells may contribute to responses; however, no correlation was noted between changes in CD8:FoxP3 ratio, PD-L1 status and tumor mutational burden and response. These findings support further investigation of this treatment in a phase II trial.

Final Results From the Randomized Phase III ASCENT Clinical Trial in Metastatic Triple-Negative Breast Cancer and Association of Outcomes by Human Epidermal Growth Factor Receptor 2 and Trophoblast Cell Surface Antigen 2 Expression.

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 co-primary 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.Sacituzumab govitecan (SG), a first-in-class anti-trophoblast cell surface antigen 2 (Trop-2) antibody-drug conjugate, demonstrated superior efficacy over single-agent chemotherapy (treatment of physician's choice [TPC]) in patients with metastatic triple-negative breast cancer (mTNBC) in the international, multicenter, phase III ASCENT study.Patients were randomly assigned 1:1 to receive SG or TPC until unacceptable toxicity/progression. Final efficacy secondary end point analyses and post hoc analyses of outcomes stratified by Trop-2 expression and human epidermal growth factor receptor 2 status are reported. Updated safety analyses are provided.In this final analysis, SG (n = 267) improved median progression-free survival (PFS; 4.8 v 1.7 months; hazard ratio (HR), 0.41 [95% CI, 0.33 to 0.52]) and median overall survival (OS; 11.8 v 6.9 months; HR, 0.51 [95% CI, 0.42 to 0.63]) over TPC (n = 262). SG improved PFS over TPC in each Trop-2 expression quartile (n = 168); a trend was observed for improved OS across quartiles. Overall, SG had a manageable safety profile, with ≤5% of treatment-related discontinuations because of adverse events and no treatment-related deaths. The safety profile was consistent across all subgroups.These data confirm the clinical benefit of SG over chemotherapy, reinforcing SG as an effective treatment option in patients with mTNBC in the second line or later.

Breast Cancer Index and Prediction of Extended Aromatase Inhibitor Therapy Benefit in Hormone Receptor-Positive Breast Cancer from the NRG Oncology/NSABP B-42 Trial.

PURPOSE: BCI (H/I) has been shown to predict extended endocrine therapy (EET) benefit. We examined BCI (H/I) for EET benefit prediction in NSABP B-42, which evaluated extended letrozole therapy (ELT) in patients with hormone receptor-positive breast cancer after 5 years of ET. EXPERIMENTAL DESIGN: A stratified Cox model was used to analyze RFI as the primary endpoint, with DR, BCFI, and DFS as secondary endpoints. Because of a nonproportional effect of ELT on DR, time-dependent analyses were performed. RESULTS: The translational cohort included 2,178 patients (45% BCI (H/I)-High, 55% BCI (H/I)-Low). ELT showed an absolute 10-year RFI benefit of 1.6% (P = 0.10), resulting in an underpowered primary analysis (50% power). ELT benefit and BCI (H/I) did not show a significant interaction for RFI (BCI (H/I)-Low: 10 years absolute benefit 1.1% [HR, 0.70; 95% confidence interval (CI), 0.43-1.12; P = 0.13]; BCI (H/I)-High: 2.4% [HR, 0.83; 95% CI, 0.55-1.26; P = 0.38]; Pinteraction = 0.56). Time-dependent DR analysis showed that after 4 years, BCI (H/I)-High patients had significant ELT benefit (HR = 0.29; 95% CI, 0.12-0.69; P < 0.01), whereas BCI (H/I)-Low patients were less likely to benefit (HR, 0.68; 95% CI, 0.33-1.39; P = 0.29; Pinteraction = 0.14). Prediction of ELT benefit by BCI (H/I) was more apparent in the HER2- subset after 4 years (ELT-by-BCI (H/I) Pinteraction = 0.04). CONCLUSIONS: BCI (H/I)-High versus BCI (H/I)-Low did not show a statistically significant difference in ELT benefit for the primary endpoint (RFI). However, in time-dependent DR analysis, BCI (H/I)-High patients experienced statistically significant benefit from ELT after 4 years, whereas (H/I)-Low patients did not. Because BCI (H/I) has been validated as a predictive marker of EET benefit in other trials, additional follow-up may enable further characterization of BCI's predictive ability.

Poziotinib treatment in patients with HER2-positive advanced breast cancer who have received prior anti-HER2 regimens.

PURPOSE: Poziotinib is an irreversible pan-inhibitor of the human epidermal growth factor receptor (HER) that has shown acceptable tolerability and antitumor activity in phase I and II trials in patients with advanced solid tumors. In the present open-label, multicenter phase II study, we demonstrate safety, tolerability, and preliminary efficacy data from two different dosing schedules in patients with HER2-positive advanced breast cancer. PATIENTS AND METHODS: Patients who had received at least two prior HER2-directed therapy lines for advanced disease, received 24 mg poziotinib on an intermittent dosing schedule (cohort 1) or 16 mg poziotinib once daily on a continuous dosing schedule (cohort 2). The primary endpoint was overall response rate (ORR). Secondary endpoints were progression-free survival (PFS), disease control rate (DCR), and time to progression (TTP). Secondary endpoints additionally included safety and pharmacokinetics. RESULTS: A total of 67 patients were enrolled. The ORR was 30% in both groups (p = 0.98). DCR was 60% vs 78% (p = 0.15) and median PFS and TTP were 4.1 vs 4.9 months (both p = 0.30) for cohorts 1 and 2, respectively. The most common treatment related adverse events (AEs) of any grade included diarrhea (88% vs 85%, p = 0.76), rash (88% vs 88%, p = 0.96), and stomatitis (64% vs 56%, p = 0.52), with grade 3-4 diarrhea occurring in 33% vs 32% of patients (p = 0.93) and grade 3-4 rash in 27% vs 35% of patients (p = 0.48) in cohort 1 vs cohort 2, respectively. CONCLUSION: Poziotinib demonstrated evidence of clinical activity in patients with pre-treated HER2-positive advanced breast cancer, although high levels of toxicity may preclude further studies at this time.

Real-world treatment patterns for palbociclib plus an aromatase inhibitor, or an aromatase inhibitor alone, for patients with metastatic breast cancer in the Flatiron Database.

There are limited real-world comparative effectiveness data for palbociclib plus an aromatase inhibitor (AI) as a first-line (1L) treatment examining endpoints that require long term follow-up and post 1L progression. The Flatiron Health Analytic Database was used to characterize treatment and dosing patterns in patients with hormone receptor-positive/human epidermal growth factor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) receiving palbociclib plus an AI vs an AI alone in routine US clinical practice. In addition, time to chemotherapy (TTC) and real-world progression-free survival (rwPFS) when combining 1L and second-line of therapy (rwPFS2) were assessed. Of 1324 patients who received palbociclib plus an AI between February 3, 2015 and March 31, 2020, 1110 (83.8%) started palbociclib at the recommended 125 mg/day dose. After stabilized inverse probability treatment-weighting (sIPTW), median TTC in patients treated with palbociclib plus an AI and AI alone was 37.4 months (95% confidence interval [CI], 33.7-40.7) and 29.2 months (95% CI, 26.8-33.5), respectively (hazard ratio [HR] = 0.77 [95% CI, 0.69-0.86], P < .0001); median rwPFS2 was 32.6 months (95% CI, 29.4-35.2) and 20.7 months (95% CI, 18.9-22.6), respectively (HR = 0.62 [95% CI, 0.54-0.70], P < .0001). Sensitivity analyses with propensity score matching showed similar results to sIPTW analyses. Results from this large real-world study examining additional effectiveness outcomes beyond 1L rwPFS and overall survival support the use of palbociclib plus an AI as a 1L treatment for patients with HR+/HER2- mBC.

The Effect of Race and Area Deprivation on Symptom Profiles over the Course of Early-Stage Breast Cancer.

Purpose: This study compared common symptoms (fatigue, pain), overall physical functioning and changes over time between Black and White women receiving early-stage breast cancer (ESBC) chemotherapy. Methods: A longitudinal, repeated measures comparative design was employed. Time points of symptom measurement (PROMIS domains) at baseline, mid and end point were adjusted as per patient chemotherapy schedule. Analyses: Linear mixed models were applied. Results: There were 147 patients, 36% Black 64% White (54±12 years) recommended to receive early-stage breast cancer chemotherapy with adequate data for symptom analysis. Pain: Main effect of race was significant (F(1, 390) = 29.43, p<.001) for pain with Black patients experiencing significantly higher pain scores compared to White patients at pretherapy (Mean Difference; MD=3.7, p=.034), midpoint (MD=5.8, p=.002), and endpoint (MD=7.8, p<.001). Fatigue: Fatigue significantly increased (deteriorated) at endpoint (MDT1-T3= 8.7, p<.001) for Black patients. Among White patients, fatigue significantly increased at midpoint (MDT1-T2= 5.7) and at endpoint (MDT1-T3=10.1, p<.001; MDT2-T3=4.3, p= .017). Physical function: Black patients had significantly lower physical function scores compared to White patients at midpoint (MD=4.0, p=.027). Physical function decreased by endpoint in Black (MDT1-T3=7.8, p<.001), and White patients (MDT1-T3=7.7, p<.001). Conclusion: Symptom burden significantly increased over the course of chemotherapy for all patients. Scores for pain and physical function were higher overall for Black patients and deteriorated at a greater rate for Black vs. White women over the course of chemotherapy. This assessment holds implication for proactive assessment and mitigation strategies.

Phase Ib study of HSP90 inhibitor, onalespib (AT13387), in combination with paclitaxel in patients with advanced triple-negative breast cancer.

Background: Heat shock protein 90 (HSP90) is a molecular chaperone required for stabilization of client proteins over-activated in triple-negative breast cancer (TNBC). Over-expression of HSP90 client proteins has been implicated in paclitaxel resistance. Onalespib (AT13387) is a potent inhibitor of HSP90 that could improve paclitaxel efficacy when administered in combination. Design: This phase Ib trial administered onalespib with paclitaxel in patients with advanced TNBC to assess safety and establish a recommended phase II dose (RP2D). Objectives: The primary objectives were determining the dose-limiting toxicities and maximum tolerated dose of combination therapy. Secondary objectives included pharmacokinetic (PK) analysis and determination of overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Methods: Patients with advanced TNBC were treated with standard dose intravenous paclitaxel in combination with intravenous onalespib at doses ranging from 120 to 260 mg/m2 administered on days 1, 8, and 15 of a 28-day cycle using a standard 3 + 3 design. A total of 15 patients were enrolled to dose expansion cohort at RP2D to confirm safety profile. Results: Thirty-one patients were enrolled in the study, of which over 90% had received prior taxane therapy. Paclitaxel was given for metastatic disease in 23% of patients. Adverse events (AEs) included anemia (grade 3: 20%), lymphopenia (grade 3: 17%), and neutropenia (grade 3: 33%, grade 4: 4%). The most frequent grade ⩾3 non-hematologic AE was diarrhea (7%). The established RP2D was 260 mg/m2 onalespib when given with paclitaxel at 80 mg/m2. PK analysis revealed a modest drug interaction profile for onalespib in the combination regimen. ORR was 20%. Three patients achieved complete responses, all of whom had received prior taxane therapy. Median DOR was 5.6 months; median PFS was 2.9 months. Conclusion: Combination treatment with onalespib and paclitaxel had an acceptable toxicity profile and RP2D was determined to be 260 mg/m2 of onalespib. Combination therapy showed antitumor activity in patients with advanced TNBC. Trial registration: Onalespib and paclitaxel in treating patients with advanced TNBC https://clinicaltrials.gov/ct2/show/NCT02474173.

Phase 1b study of HSP90 inhibitor called onalespib in combination with paclitaxel in patients with advanced triple-negative breast cancer This Phase 1b study demonstrated that treatment with a combination of onalespib and paclitaxel was reasonably well tolerated by most patients. Onalespib at 260 mg/m² given intravenously on days 1, 8 and 15 on 28-day cycles in combination with standard dose and schedule of paclitaxel was established as the recommended phase 2 dose for further clinical development. Despite minor drug-drug interactions between these 2 agents, onalespib did not alter paclitaxel exposure and paclitaxel did not affect exposure to onalespib. While onalespib with paclitaxel combination therapy did not yield durable objective responses or prolonged progression-free survival, there were several patients with long-lasting benefit from this combination including patients who previously experienced progression on taxane therapy.