Metastatic Breast Cancer or Multiple Myeloma? Camouflage by Lytic Lesions

We report a case of a female with stage I infiltrating ductal carcinoma who received adjuvant therapy including trastuzumab. One year later she developed lytic lesions and was retreated with trastuzumab that was held after she developed symptomatic heart failure. Lytic lesions were attributed to relapse of breast cancer, and cardiac failure attributed to prior trastuzumab therapy. After complications necessitated multiple hospitalizations, a further workup revealed that the lytic lesions were not metastatic breast cancer but multiple myeloma. Her advanced multiple myeloma was associated with systemic amyloidosis involving gut and heart, which ultimately led to her demise. This report addresses the pitfalls of overlapping symptoms and the question of which patients with suspected metastatic disease should undergo a biopsy

Racial disparities in treatment patterns and clinical outcomes in patients with HER2-positive metastatic breast cancer.

Data characterizing demographics, treatment patterns, and clinical outcomes in black patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) are limited. registHER is a large, observational cohort study of patients (n = 1,001) with HER2-positive MBC diagnosed ≤6 months of enrollment and followed until death, disenrollment, or June 2009 (median follow-up of 27 months). Demographics, treatment patterns, and clinical outcomes were described for black (n = 126) and white patients (n = 793). Progression-free survival (PFS) following first-line therapy and overall survival (OS) were examined. Multivariate analyses adjusted for baseline and treatment factors. Black patients were more likely than white patients to be obese (body mass index ≥30), to have diabetes, and to have a history of cardiovascular disease; they were also less likely to have estrogen receptor or progesterone receptor positive disease. In patients treated with trastuzumab, the incidence of cardiac safety events (grade ≥3) was higher in black patients (10.9 %) than in white patients (7.9 %). Unadjusted median OS and PFS (months) were significantly lower in black patients than in white patients (OS: black: 27.1, 95 % confidence interval [CI] 21.3-32.1; white: 37.3, 95 % CI 34.6-41.1; PFS: black: 7.0, 95 % CI 5.7-8.2; white: 10.2, 95 % CI 9.3-11.2). The adjusted OS hazard ratio (HR) for black patients compared with white patients was 1.29 (95 % CI 1.00-1.65); adjusted PFS HR was 1.29 (95 % CI 1.05-1.59). This real-world evaluation of a large cohort of patients with HER2-positive MBC shows poorer prognostic factors and independently worse clinical outcomes in black versus white patients. Further research is needed to identify potential biologic differences that could have predictive impact for black patients or that could explain these differences

Treatment patterns and clinical outcomes in elderly patients with HER2-positive metastatic breast cancer from the registHER observational study.

Limited data exist regarding treatment patterns and outcomes in elderly patients with HER2-positive metastatic breast cancer (MBC). registHER is an observational study of patients (N = 1,001) with HER2-positive MBC diagnosed within 6 months of enrollment and followed until death, disenrollment, or June 2009 (median follow-up 27 months). Outcomes were analyzed by age at MBC diagnosis: younger (<65 years), older (65-74 years), elderly (≥75 years). For progression-free survival (PFS) and overall survival (OS) analyses of first-line trastuzumab versus nontrastuzumab, older and elderly patients were combined. Cox regression analyses were adjusted for baseline characteristics and treatments. Estrogen receptor/progesterone receptor status was similar across age groups. Underlying cardiovascular disease was most common in elderly patients. In patients receiving trastuzumab-based first-line treatment, elderly patients were less likely to receive chemotherapy. In trastuzumab-treated patients, incidence of left ventricular dysfunction (LVD) and congestive heart failure (CHF) (grades ≥ 3) were highest in elderly patients (LVD: elderly 4.8 %, younger 2.8 %, older 1.5 %; CHF: elderly 3.2 %, younger 1.9 %, older 1.5 %). Unadjusted median PFS (months) was significantly higher in patients treated with first-line trastuzumab than those who were not (<65 years: 11.0 vs. 3.4, respectively; ≥65 years: 11.7 vs. 4.8, respectively). In patients <65 years, unadjusted median OS (months) was significantly higher in trastuzumab-treated patients; in patients ≥65 years, median OS was similar (<65 years: 40.4 vs. 25.9; ≥65 years: 31.2 vs. 28.5). In multivariate analyses, first-line trastuzumab use was associated with significant improvement in PFS across age. For OS, significant improvement was observed for patients <65 years and nonsignificant improvement for patients ≥65 years. Elderly patients with HER2-positive MBC had higher rates of underlying cardiovascular disease than their younger counterparts and received less aggressive treatment, including less first-line trastuzumab. These real-world data suggest improved PFS across all age groups and similar trends for OS

SARS‐CoV‐2 research using human pluripotent stem cells and organoids

Experimental cell models are indispensable for clarifying the pathophysiology of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and for developing therapeutic agents. To recapitulate the symptoms and drug response of COVID-19 patients in vitro, SARS-CoV-2 studies using physiologically relevant human embryonic stem (ES)/induced pluripotent stem (iPS) cell-derived somatic cells and organoids are ongoing. These cells and organoids have been used to show that SARS-CoV-2 can infect and damage various organs including the lung, heart, brain, intestinal tract, kidney, and pancreas. They are also being used to develop COVID-19 therapeutic agents, including evaluation of their antiviral efficacy and safety. The relationship between COVID-19 aggravation and human genetic backgrounds has been investigated using genetically modified ES/iPS cells and patient-derived iPS cells. This review summarizes the latest results and issues of SARS-CoV-2 research using human ES/iPS cell-derived somatic cells and organoids

Neratinib + capecitabine sustains health-related quality of life in patients with HER2-positive metastatic breast cancer and ≥ 2 prior HER2-directed regimens

Health-related quality of life; Metastatic breast cancer; NeratinibCalidad de vida relacionada con la salud; Cáncer de mama metastásico; NeratinibQualitat de vida relacionada amb la salut; Càncer de mama metastàtic; NeratinibPurpose To characterize health-related quality of life (HRQoL) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) from the NALA phase 3 study. Methods In NALA (NCT01808573), patients were randomized 1:1 to neratinib + capecitabine (N + C) or lapatinib + capecitabine (L + C). HRQoL was assessed using seven prespecified scores from the European Organisation for Research and Treatment of Cancer Quality Of Life Questionnaire core module (QLQ-C30) and breast cancer-specific questionnaire (QLQ-BR23) at baseline and every 6 weeks. Descriptive statistics summarized scores over time, mixed models evaluated differences between treatment arms, and Kaplan–Meier methods were used to assess time to deterioration in HRQoL scores of ≥ 10 points. Results Of the 621 patients randomized in NALA, patients were included in the HRQoL analysis if they completed baseline and at least one follow-up questionnaire. The summary, global health status, physical functioning, fatigue, constipation, and systemic therapy side effects scores were stable over time with no persistent differences between treatment groups. There were no differences in time to deterioration (TTD) for the QLQ-C30 summary score between treatment arms; the hazard ratio (HR) for N + C vs. L + C was 0.94 (95% CI 0.63–1.40). Only the diarrhea score worsened significantly more in the N + C arm as compared to the L + C arm, and this remained over time (HR for TTD for N + C vs. L + C was 1.71 [95% CI 1.32–2.23]). Conclusion In NALA, patients treated with N + C maintained their global HRQoL over time, despite a worsening of the diarrhea-related scores. These results may help guide optimal treatment selection for HER2-positive MBC.This work was supported by Puma Biotechnology Inc., Los Angeles, CA, USA [no grant number is applicable]. Puma Biotechnology Inc. funded the provision of editorial support provided by CMD Consulting and Miller Medical Communications

Approaching Neoadjuvant Therapy in the Management of Early-Stage Breast Cancer.

Neoadjuvant therapy is integral to the treatment of early-stage breast cancer. Goals of treatment include surgical downstaging of the tumor, rendering inoperable tumors resectable, and de-escalating axillary surgery in those with clinically positive nodes. Additionally, response to treatment provides important prognostic information regarding risk of recurrence and guides future adjuvant treatment. Although chemotherapy serves as the backbone of neoadjuvant treatment, an increased understanding of the tumor\u27s clinical course as well as its molecular and genetic make-up aids in individualizing treatment and developing novel agents. This review summarizes current clinical approaches and the future direction to the management of breast cancer patients in the neoadjuvant setting

Real-world treatment patterns and effectiveness of palbociclib plus an aromatase inhibitor in patients with metastatic breast cancer aged 75 years or older

BackgroundElderly patients are generally underrepresented in oncology clinical trials; therefore, real-world data are needed to inform clinical management of elderly patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) metastatic breast cancer (mBC). This subanalysis of the P-REALITY X study (NCT05361655) evaluated palbociclib treatment patterns and comparative effectiveness of palbociclib plus an aromatase inhibitor (AI) versus an AI alone among patients with HR+/HER2− mBC aged ≥ 75 years treated in routine clinical practice in the United States.MethodsThis retrospective observational cohort study used electronic health records from the Flatiron Health Analytic Database. Palbociclib treatment patterns, overall survival (OS), real-world progression-free survival (rwPFS), and time to chemotherapy (TTC) were evaluated. Three methods were used for comparative analyses: (1) an unadjusted analysis, (2) stabilized inverse probability treatment weighting (sIPTW; primary analysis), and (3) propensity score matching (PSM; sensitivity analysis).ResultsA total of 961 patients aged ≥ 75 years with HR+/HER2− mBC were identified who started palbociclib plus an AI (n = 313) or an AI alone (n = 648) as first-line (1L) therapy between February 2015 and March 2020 (data cut-off: September 30, 2020). Among patients in the palbociclib plus an AI group with a documented palbociclib starting dose (n = 306), approximately 75% started palbociclib at 125 mg/day, and approximately 40% experienced dose adjustment. After sIPTW, patients treated with palbociclib plus an AI versus an AI alone had significantly improved OS (median of 43.0 vs. 32.4 months; hazard ratio [HR], 0.66 [95% confidence interval (CI), 0.51–0.84]; P = 0.0007), rwPFS (median of 20.0 vs. 15.0 months; HR, 0.72 (0.59–0.89); P = 0.0021), and TTC (median of 40.2 vs. 27.4 months; HR, 0.69 [0.55–0.87]; P = 0.0014). These significant improvements in OS, rwPFS, and TTC remained consistent in the unadjusted analysis and after PSM.ConclusionThis real-world comparative analysis demonstrated that 1L palbociclib plus an AI is associated with improved effectiveness compared with an AI alone among patients with HR+/HER2− mBC aged ≥ 75 years. These findings support palbociclib plus an AI as a standard-of-care 1L treatment for elderly patients with HR+/HER2− mBC

Targeted Mutation Detection in Advanced Breast Cancer Using MammaSeq Identifies RET as a Potential Contributor to Breast Cancer Metastasis

The lack of any reported breast cancer specific diagnostic NGS tests inspired the development of MammaSeq, an amplicon based NGS panel built specifically for use in advanced breast cancer. In a pilot study to define the clinical utility of the panel, 46 solid tumor samples, plus an additional 14 samples of circulating-free DNA (cfDNA) from patients with advanced breast cancer were sequenced and analyzed using the OncoKB precision oncology database. We identified 26 clinically actionable variants (levels 1-3) annotated by the OncoKB precision oncology database, distributed across 20 out of 46 solid tumor cases (40%), and 4 clinically actionable mutations distributed across 4 samples in the 14 cfDNA sample cohort (29%). The mutation allele (MAF) frequencies of ESR1-D538G and FOXA1-Y175C mutations correlated with CA.27.29 levels in patient-matched blood, indicating that MAF may be a reliable marker for disease burden. Interestingly, 4 of the mutations found in metastatic samples occurred in the gene RET, an oncogenic receptor tyrosine kinase. In an orthogonal study, the lab has recently identified RET as one of the most recurrently upregulated genes in breast cancer brain metastases. Interestingly, the ligand for RET is the family of glial-cell derived neurotrophic factors (GDNF), a growth factor secreted by glial cells of the central nervous system. This lead to the hypothesis that RET overexpression facilitates breast cancer brain metastasis in response to the high levels of GDNF, while RET activating point mutations increase metastatic capacity without specific organ tropism. While the effect of GDNF treatment on proliferation in 2D was limited, in ultra-low attachment (ULA) plates we saw a significant increase in anchorage independent growth of MCF-7 cells. To determine if GDNF acts as a chemoattractant for RET positive BrCa cells, we utilized a transwell migration assay, with GDNF as the sole chemoattractant. When RET was overexpressed, there was a visual increase in cell migration. Together, these studies demonstrate the clinical feasibility of using MammaSeq to detect clinically actionable mutations in breast cancer patients, and provides provisional data supporting the investigation of RET signaling as a potentially targetable mediator of breast cancer brain metastasis