Lin, Nancy U.

Abstract Background: There is an increasing recognition that many young women with breast cancer will have favorable outcomes without chemotherapy. We sought to characterize decision-making surrounding adjuvant chemotherapy treatment (CT) in this population for whom chemotherapy has historically been a standard of care. Methods: As part of an ongoing, multi-center, prospective cohort of young women diagnosed with breast cancer at age 40 and younger, we identified 657 women with Stage I-III breast cancer. Participants were asked to complete surveys by mail that included questions about socio-demographics, decision-making, and treatment history within the first year following diagnosis. Tumor characteristics were ascertained via pathology and medical record review. We used Chi-square tests to compare: decisional involvement (patient-driven vs. shared vs. physician-driven), degree of confidence, and feeling informed about the CT decision (the latter two measured on a 0-10 scale, categorized as follows: 0-5=low; moderate=6-8; 9-10=high) between women who did and did not receive CT. To explore clinical appropriateness of the CT decision, we used logistic regression to assess the relationship between tumor characteristics and non-receipt of CT among women with Stage I/II disease. Results: Among women with Stage I (n=250), II (n=312), and III (n=95), disease, 66%, 95%, and 100%, received CT, respectively. A greater proportion of women who had CT were highly confident with their decision compared with women who did not have CT (80% vs. 60%, p<0.0001); women who did not have CT were more likely to report a low level of feeling informed about the CT decision compared to women who received CT (20% vs. 5%, p<0.0001). Women who did not have CT were also more likely to report the final CT decision as made by their doctor (49% vs. 28%) and less likely to report a shared decision (33% vs. 59%, p<0.0001). Non-receipt of CT in women with Stage I/II disease (n=546) was associated within having node negative disease, T1 (vs. T2 or larger), Her2- negative, and hormone receptor positive tumors. Conclusion: Although non-receipt of CT would be expected to be viewed favorably by patients and doctors, we found that women who received CT felt more confident and better informed than those who received no CT. Given that women who did not have CT were also less likely to perceive the CT decision as shared, improved communication together with better decisional support may be beneficial, especially for women who do not receive adjuvant chemotherapy. Citation Format: Shoshana M Rosenberg, Karen Sepucha, Kathryn J Ruddy, Lidia Schapira, Steven Come, Virginia Borges, Evan Morgan, Nancy U Lin, Shari Gelber, Rulla M Tamimi, Ann H Partridge. Decision-making surrounding adjuvant chemotherapy in young women with early stage breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-10-03.

Abstract Purpose: Tigatuzumab (TIG), an agonistic anti-DR5 antibody, triggers apoptosis in DR5+ human tumor cells without crosslinking. TIG has strong in vitro/in vivo activity against basal-like breast cancer cells enhanced by chemotherapy agents. This study evaluates activity of TIG and chemotherapy in patients with metastatic triple-negative breast cancer (TNBC). Experimental Design: Randomized 2:1 phase II trial of albumin-bound paclitaxel (nab-PAC) ± TIG in patients with TNBC stratified by prior chemotherapy. Patients received nab-PAC weekly × 3 ± TIG every other week, every 28 days. Primary objective was within-arm objective response rate (ORR). Secondary objectives were safety, progression-free survival (PFS), clinical benefit, and TIG immunogenicity. Metastatic research biopsies were required. Results: Among 64 patients (60 treated; TIG/nab-PAC n = 39 and nab-PAC n = 21), there were 3 complete remissions (CR), 8 partial remissions (PR; 1 almost CR), 11 stable diseases (SD), and 17 progressive diseases (PD) in the TIG/nab-PAC arm (ORR, 28%), and no CRs, 8 PRs, 4 SDs, and 9 PDs in the nab-PAC arm (ORR, 38%). There was a numerical increase in CRs and several patients had prolonged PFS (1,025+, 781, 672, 460, 334) in the TIG/nab-PAC arm. Grade 3 toxicities were 28% and 29%, respectively, with no grade 4–5. Exploratory analysis suggests an association of ROCK1 gene pathway activation with efficacy in the TIG/nab-PAC arm. Conclusions: ORR and PFS were similar in both. Preclinical activity of TIG in basal-like breast cancer and prolonged PFS in few patients in the combination arm support further investigation of anti-DR5 agents. ROCK pathway activation merits further evaluation. Clin Cancer Res; 21(12); 2722–9. ©2015 AACR. See related article by Paoletti et al., p. 2771

Abstract Background: 1/3 of women with metastatic HER2+ breast cancer will develop central nervous system (CNS) metastases yet evidence-based treatments for women with progressive CNS disease are limited. Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4 which has promising activity in HER2+ breast cancer. Preclinical evidence suggests it may cross the blood brain barrier. Trial Design: This is a multicenter, phase II, open-label study of neratinib for patients with HER2+ breast cancer and brain metastases. Neratinib is administered at 240 mg orally daily during a 28 day cycle. Two cohorts will be enrolled: Cohort 1 will enroll 40 patients with progressive CNS disease; cohort 2 will enroll ≤5 patients who are candidates for surgical excision of intracranial disease. Surgical candidates receive neratinib 7–21 days preoperatively and resume postoperatively. All patients are re-staged every 2 cycles. Those who develop non-CNS progression have an option to extend therapy with trastuzumab+neratinib. Circulating tumor cells (CTC) are collected at baseline and progression; neurocognitive testing, HADS and EORTC QLQ30/BN20 measures are administered at baseline, cycle 2, cycle 3, and progression (cohort 1). Intracranial tumor, cerebrospinal fluid (CSF), and plasma are collected at surgery (cohort 2). Specific Aims: The primary endpoint is CNS objective response rate (ORR) by composite criteria. Additional endpoints include: non-CNS ORR, progression-free survival, overall survival (OS), site of 1st progression, and toxicity. Correlative and exploratory endpoints include association of CTC count and OS and longitudinal neurocognitive function and quality of life. In an exploratory analysis (cohort 2), we will quantify neratinib concentrations in CSF, intracranial tissue, and plasma and examine associations with response. Eligibility: Patients must have confirmed HER2+ metastatic disease with ≥1 parenchymal brain lesion measuring ≥10 mm that is new or progressed after completing ≥1 line of standard CNS-directed treatment (cohort 1) or CNS disease that is amenable for surgery, including those without prior CNS treatments (cohort 2). Additional eligibility criteria (cohorts 1,2) include: adequate performance status and end organ/marrow function, and ejection fraction ≥50%. Any number of prior lines of therapy is allowed, including prior lapatinib. Statistical Methods: Cohort 1 has a 2-stage design with up to 40 patients. CNS ORR is defined as ≥50% reduction in sum volume of CNS target lesions, without evidence of new lesions, progression of non-target CNS lesions, non-CNS disease progression, worsening neurological symptoms, or increase in corticosteroids. CNS lesion measurements are performed centrally by the Harvard Tumor Imaging Metrics Core. If 1/18 patients have a CNS response in the 1st stage, another 22 patients will enroll. With this design, if ≥5 of 40 patients achieve a CNS response, the drug will be deemed worthy of future study. This 2-stage design has 92% power to distinguish between a true CNS ORR of 20% and a null of 6% (one-sided type I error rate=9%). Accrual: Accrual has begun. Target=45 (cohort 1=40, cohort 2=5) Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-11.

Purpose To provide formal expert consensus–based recommendations to practicing oncologists and others on the management of brain metastases for patients with human epidermal growth factor receptor 2 (HER2) –positive advanced breast cancer. Methods The American Society of Clinical Oncology (ASCO) convened a panel of medical oncology, radiation oncology, guideline implementation, and advocacy experts and conducted a systematic review of the literature. When that failed to yield sufficiently strong quality evidence, the Expert Panel undertook a formal expert consensus–based process to produce these recommendations. ASCO used a modified Delphi process. The panel members drafted recommendations, and a group of other experts joined them for two rounds of formal ratings of the recommendations. Results No studies or existing guidelines met the systematic review criteria; therefore, ASCO conducted a formal expert consensus–based process. Recommendations Patients with brain metastases should receive appropriate local therapy and systemic therapy, if indicated. Local therapies include surgery, whole-brain radiotherapy, and stereotactic radiosurgery. Treatments depend on factors such as patient prognosis, presence of symptoms, resectability, number and size of metastases, prior therapy, and whether metastases are diffuse. Other options include systemic therapy, best supportive care, enrollment onto a clinical trial, and/or palliative care. Clinicians should not perform routine magnetic resonance imaging (MRI) to screen for brain metastases, but rather should have a low threshold for MRI of the brain because of the high incidence of brain metastases among patients with HER2-positive advanced breast cancer.