N083E (Alliance): long-term outcomes of patients treated in a pilot phase II study of docetaxel, carboplatin, trastuzumab, and lapatinib as adjuvant therapy for early-stage HER2-positive breast cancer.

BACKGROUND: The addition of lapatinib (L) to trastuzumab (T) was previously found to be synergistic in preclinical models and in the neoadjuvant setting. Prior to the results of the ALTTO trial, this study assessed the safety and feasibility of adding L to the standard adjuvant docetaxel, carboplatin, and trastuzumab (TCH) regimen in early-stage HER2-positive breast cancer (HER2+ BC). METHODS: In this single-arm, 2-stage, phase II study, patients with stages I-III HER2+ BC received TCH plus L at 1000 mg daily for a total of 12 months. The primary endpoint was the safety and tolerability, including the rate of diarrhea. Secondary endpoints included adverse event (AE) profile using the NCI CTCAE v3.0 and cardiac safety. RESULTS: Thirty eligible patients were enrolled. Median follow-up is 5.3 years. Diarrhea was the most common AE with 50% Grade (G)1/2 and 43% G3 diarrhea. However, it was responsive to dose reduction of L (750 mg) and institution of anti-diarrheal medications. Cardiovascular AE were infrequent and no patients experienced congestive heart failure while on treatment. CONCLUSION: TCHL was a tolerable regimen at a starting L dose of 750 mg PO daily when given concurrently with chemotherapy.

Development of a multigenerational digital lifestyle intervention for women cancer survivors and their families.

OBJECTIVES: This paper presents the results of a study developed to inform the design of a multigenerational digital lifestyle intervention for overweight/obese women cancer survivors and their families. We followed the first six phases of the Integrate, Design, Assess, and Share (IDEAS) framework. METHODS: Grandmothers with breast, endometrial, or ovarian cancers (n = 46; 66.1 ± 0.9 years old; 34% Hispanic, 33% non-Hispanic black, 33% non-Hispanic white) self-reported their lifestyle behaviors, family structure, mobile device use, and interest in a family-based lifestyle intervention. A randomly selected subset of 21 participants subsequently completed qualitative interviews to understand their family relationships, weight-related challenges, and feedback on intervention prototypes. RESULTS: Participants reported low fruit intake (0.9 ± 0.1 servings/day), moderate vegetable intake (3.0 ± 0.2 servings/day), and high levels of moderate physical activity (990 ± 234 MET-minutes/week). The majority owned a smartphone (93%) and expressed interest in family-based programs (80%) that focused on weight management (91%). Qualitative data were collapsed into seven intervention considerations, including: capitalizing on existing familial support, involving local family who need lifestyle change, tapping into survivors' internal strengths, validating prior weight loss, overcoming barriers to sustained lifestyle change, providing information on cancer risk, and motivating families through reinforcing activities. CONCLUSIONS: Following the IDEAS framework, our next steps are to develop a fully-functioning prototype and conduct a randomized pilot trial to test the feasibility and effects of a digital intervention that empowers racially/ethnically diverse overweight/obese women cancer survivors to improve their physical activity and dietary intake and to lose weight by encouraging healthy lifestyle behaviors in their children and grandchildren.

Correlative Analysis of Genetic Alterations and Everolimus Benefit in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From BOLERO-2.

PURPOSE: To explore the genetic landscape of tumors from patients enrolled on the BOLERO-2 trial to identify potential correlations between genetic alterations and efficacy of everolimus treatment. The BOLERO-2 trial has previously demonstrated that the addition of everolimus to exemestane prolonged progression-free survival by more than twofold in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer previously treated with nonsteroidal aromatase inhibitors. PATIENTS AND METHODS: Next-generation sequencing was used to analyze genetic status of cancer-related genes in 302 archival tumor specimens from patients representative of the BOLERO-2 study population. Correlations between the most common somatic alterations and degree of chromosomal instability, and treatment effect of everolimus were investigated. RESULTS: Progression-free survival benefit with everolimus was maintained regardless of alteration status of PIK3CA, FGFR1, and CCND1 or the pathways of which they are components. However, quantitative differences in everolimus benefit were observed between patient subgroups defined by the exon-specific mutations in PIK3CA (exon 20 v 9) or by different degrees of chromosomal instability in the tumor tissues. CONCLUSION: The data from this exploratory analysis suggest that the efficacy of everolimus was largely independent of the most commonly altered genes or pathways in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. The potential impact of chromosomal instabilities and low-frequency genetic alterations on everolimus efficacy warrants further investigation.

A phase 1B dose escalation trial of Scutellaria barbata (BZL101) for patients with metastatic breast cancer.

The purpose of this study was to determine the safety and maximum tolerated dose (MTD) of BZL101 (FDA IND# 59,521), an orally delivered aqueous extract from the herb Scutellaria barbata, in women with metastatic breast cancer (MBC). The trial was an open-label, phase 1B, multicenter, dose escalation study. Eligible patients had histologically confirmed breast cancer and measurable stage IV disease. The standard phase 1 "3 + 3" study design was used to determine the MTD. Primary endpoints were toxicity and MTD of BZL101. Secondary outcomes included efficacy based on RECIST criteria. A total of 27 women with a median of 2 prior chemotherapy treatments for metastatic disease were treated in four different dose cohorts. Grade 3 and 4 adverse events (AEs) were uncommon. Dose-limiting toxicities included the following: grade 4 AST elevation, grade 3 diarrhea, grade 3 fatigue, and grade 3 rib pain. Fourteen patients were evaluable according to Response Evaluation Criteria in Solid Tumors. Investigator assessment classified three patients with stable disease for >120 days (21%). One patient was on BZL101 for 449 days and remains stable for 700 + days. Independent radiology review identified three patients with objective tumor regression (>0% and <30%). The MTD was not reached, thus per protocol, the MTD was defined as the maximum administered dose of BZL101 40 g/day. In conclusion, oral administration of BZL101 was safe, well tolerated, and showed promising clinical evidence of anticancer activity in this heavily pretreated population of women with MBC.

Pegylated liposomal doxorubicin (Doxil) for metastatic breast cancer: the Cancer Research Network, Inc., experience.

Pegylated liposomal doxorubicin (Doxil) was formulated to improve the safety profile of doxorubicin. The major toxicities, mucositis and palmar-plantar erythrodysesthesia, are dose and schedule dependent, respectively. Anecdotal experience suggests that a dosage of 40 mg/m2 every 4 weeks is well tolerated. To evaluate the safety and efficacy of this regimen in women with metastatic breast cancer, we performed a retrospective chart review at a private practice. Forty women received a median initial dose of 42.5 mg/m2 usually every 4 weeks and a median cumulative dose of 135 mg/m2 (range: 40-595 mg/m2). There were 10 partial responses and seven patients with stable disease for more than 6 months resulting in a clinical benefit rate of 43% in the intent-to-treat analysis. The median time to progression was 4 months in all patients, 6.5 months in patients who had partial responses, and 10 months in patients who had stable disease for more than 6 months. There was no grade 4 toxicity. The only grade 3 toxicities were leukopenia in seven (18%) patients, mucositis in one (3%), and palmar-plantar erythrodysesthesia in one (3%). More studies are warranted to confirm our findings, which suggest that pegylated liposomal doxorubicin at a dosage of 40-45 mg/m2 every 4 weeks is clinically active in, and well tolerated by, women with metastatic breast cancer.