Davidson, Nancy E.

579 Background: N9831 and other clinical trials have demonstrated the additive survival benefit of trastuzumab (H) therapy with chemotherapy for patients with resected HER-2 positive breast cancer. Cardiac toxicity (CTox) is increased by this strategy. Prediction of or early detection of CTox is important. Methods: 95 patients provided informed consent. Brain natriuretic peptide (BNP), C-reactive protein (CRP), troponin T (TnT) and I (TnI), TNF-alpha, IL-1b, and IL-6 were to be drawn at baseline, after initiation of doxorubicin/cyclophosphamide (AC), after initiation of paclitaxel (T), and after the initiation of H (may have been given concurrently with T). 67 patients with at least a baseline sample, a post-treatment sample, and a baseline and subsequent evaluation of LVEF were studied. No patient in this group had a grade 3 decline in LVEF. Only 3 of these patients did not receive H. Values above the 99th percentile were considered abnormal for troponin. 40 ng/ml was considered elevated for BNP. Results: Values of CRP, TNF-alpha, IL- 6 and IL1b changed in very few patients and without a discernible pattern. For further evaluation of BNP, TnI, and TnT, 2 definitions of CTox were tested: 1. a >10% drop in LVEF from baseline (n=27) and 2. a drop in LVEF of 10–15% to less than the institutional lower limit of normal (LLN) OR a >15% decline in LVEF (n=14). No pre-treatment marker appeared to predict a > 10% decline in LVEF (definition 1). For patients fulfilling definition 2, pre-treatment BNP > 40 was seen in 21% of patients vs 8% of normals (nls) (p= 0.18) and an abnormal TnI (>0.04) was seen in 21% vs 6% of nls (p=0.10). Only doubling of BNP appeared promising as a serial marker of CTox using definition 2 (27% vs 7% for nls (p = 0.09). Conclusions: Baseline BNP and TnI and serial measures of BNP may be promising for further investigation for the prediction and detection of treatment-related CTox. Due to limitations of the study including the small numbers of patients analyzed, the difficulty in defining CTox, and the variation in the timing of sample procurement and assessment, these data are considered exploratory. Supported by CA-25224, CA-2115, CA 38926, CA31946. No significant financial relationships to disclose.

512 Background: The joint efficacy analysis of NCCTG N9831 and NSABP B-31 demonstrated improved outcomes with the addition of trastuzumab (H) to doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) in women with surgically removed HER2- positive breast cancer (NEJM 2005). Following this report, patients randomized to AC→T and less than 6 months from completion of chemotherapy were eligible to receive H. We have updated the initial combined results of these two trials. Methods: Primary and secondary efficacy endpoint were disease free survival (DFS) and overall survival (OS). Cox modeling was performed. Hazard ratios are adjusted for nodal status, tumor size, T schedule, hormone receptor status, and trial (also age for OS). Results: Among the 3,969 women enrolled (ages: 22 to 80yrs), there have been 619 events (H group: 222, non-H: 397). First events were: recurrence (511), contralateral breast disease (18), other second primary cancers (48), and death without recurrence or second primary cancers (42). The median follow-up among the 3,711 women still alive is 2.9 years (range up to 6,4 years). The 4 yr DFS rate and 4 yr OS rate respectively were: 85.9% (95%CI: 84.0–87.8%) and 92.6% (95%CI: 91.2–94.2%) in H group and 73.1% (95%CI: 70.6–75.8%) and 89.4% (95%CI: 87.6–91.2%) in non- H group. Hazard ratio for adjuvant (H/non-H) was 0.49 (P<0.0001; 95%CI: 0.41–0.58) for DFS and 0.63 (P=0.0004; 95%CI: 0.49–0.81) for OS.The rates of a first event per 1,000 women/year during yrs 1–4 were: 26.7, 52.9, 49.6 and 23.2 for H and 42.3, 102.3, 107.6 and 61.5 for non-H. The impact of crossover on clinical outcome will be explored. Conclusions: With an increase in the median follow-up of 11 months and with 225 additional events, the demonstration of substantial improvement in outcomes with the addition of trastuzumab to chemotherapy persist. This improvement continues in spite of some degree of cross-over occurring after the initial results were reported.Updated data regarding crossover outcomes and H duration (as they relate to disease free survival) will be presented. [Table: see text]

PURPOSE To update the ASCO guideline on pharmacologic interventions for breast cancer risk reduction and provide guidance on clinical issues that arise when deciding to use endocrine therapy for breast cancer risk reduction. METHODS An Expert Panel conducted targeted systematic literature reviews to identify new studies. RESULTS A randomized clinical trial that evaluated the use of anastrozole for reduction of estrogen receptor–positive breast cancers in postmenopausal women at increased risk of developing breast cancer provided the predominant basis for the update. UPDATED RECOMMENDATIONS In postmenopausal women at increased risk, the choice of endocrine therapy now includes anastrozole (1 mg/day) in addition to exemestane (25 mg/day), raloxifene (60 mg/day), or tamoxifen (20 mg/day). The decision regarding choice of endocrine therapy should take into consideration age, baseline comorbidities, and adverse effect profiles. Clinicians should not prescribe anastrozole, exemestane, or raloxifene for breast cancer risk reduction to premenopausal women. Tamoxifen 20 mg/day for 5 years is still considered standard of care for risk reduction in premenopausal women who are at least 35 years old and have completed childbearing. Data on low-dose tamoxifen as an alternative to the standard dose for both pre- and postmenopausal women with intraepithelial neoplasia are discussed in the Clinical Considerations section of this article. Additional information is available at www.asco.org/breast-cancer-guidelines .

Abstract The recent pace, extent, and impact of paradigm-changing cancer prevention science has been remarkable. The American Association for Cancer Research (AACR) convened a 3-day summit, aligned with five research priorities: (i) Precancer Atlas (PCA). (ii) Cancer interception. (iii) Obesity-cancer linkage, a global epidemic of chronic low-grade inflammation. (iv) Implementation science. (v) Cancer disparities. Aligned with these priorities, AACR co-led the Lancet Commission to formally endorse and accelerate the NCI Cancer Moonshot program, facilitating new global collaborative efforts in cancer control. The expanding scope of creative impact is perhaps most startling—from NCI-funded built environments to AACR Team Science Awarded studies of Asian cancer genomes informing global primary prevention policies; cell-free epigenetic marks identifying incipient neoplastic site; practice-changing genomic subclasses in myeloproliferative neoplasia (including germline variant tightly linked to JAK2 V617F haplotype); universal germline genetic testing for pancreatic cancer; and repurposing drugs targeting immune- and stem-cell signals (e.g., IL-1β, PD-1, RANK-L) to cancer interception. Microbiota-driven IL-17 can induce stemness and transformation in pancreatic precursors (identifying another repurposing opportunity). Notable progress also includes hosting an obesity special conference (connecting epidemiologic and molecular perspectives to inform cancer research and prevention strategies), co-leading concerted national implementation efforts in HPV vaccination, and charting the future elimination of cancer disparities by integrating new science tools, discoveries and perspectives into community-engaged research, including targeted counter attacks on e-cigarette ad exploitation of children, Hispanics and Blacks. Following this summit, two unprecedented funding initiatives were catalyzed to drive cancer prevention research: the NCI Cancer Moonshot (e.g., PCA and disparities); and the AACR-Stand Up To Cancer bold “Cancer Interception” initiative.

For the hundreds of thousands of premenopausal women who are diagnosed annually with endocrine-sensitive breast cancer, treatment strategies are complex. For many, chemotherapy may not be necessary, and endocrine therapy decision making is paramount. Options for adjuvant endocrine regimens include tamoxifen for 5 years, tamoxifen for 10 years, ovarian function suppression (OFS) plus tamoxifen for 5 years, and OFS plus an aromatase inhibitor for 5 years. There are modest differences in efficacy between these regimens, with a benefit from OFS most obvious among patients with higher-risk disease; therefore, choosing which should be used for a given patient requires consideration of expected toxicities and patient preferences. An aromatase inhibitor cannot be safely prescribed without OFS in this setting. Additional research is needed to determine whether genomic tests such as Prosigna and Endopredict can help with decision making about optimal duration of endocrine therapy for premenopausal patients. Endocrine therapy side effects can include hot flashes, sexual dysfunction, osteoporosis, and infertility, all of which may impair quality of life and can encourage nonadherence with treatment. Ovarian function suppression worsens menopausal side effects. Hot flashes tend to be worse with tamoxifen/OFS, whereas sexual dysfunction and osteoporosis tend to be worse with aromatase inhibitors/OFS. Pregnancy is safe after endocrine therapy, and some survivors can conceive naturally. Still, embryo or oocyte cryopreservation should be considered at the time of diagnosis for patients with endocrine-sensitive disease who desire future childbearing, particularly if they will undergo chemotherapy.

270 Background: Neuropathy is a common and potentially enduring and disabling complication of adjuvant taxane therapy. Recent studies have identified candidate host single nucleotide polymorphisms (SNPs) associated with taxane-induced neuropathy (Schneider et al. ASCO 2011, abstr. 1000). We therefore sought to determine whether neuropathy was associated with breast cancer recurrence. Methods: This study included 4,950 eligible women with axillary lymph node positive or high-risk node-negative breast cancer who received up to 4 cycles of AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) every 3 weeks, followed by either: (1) paclitaxel 175 mg/m2 every 3 weeks x 4 (P3), (2) paclitaxel 80 mg/m2 weekly x 12 (P1), (3) docetaxel 100 mg/m2 every 3 weeks x 4 (D3), or (4) docetaxel 35 mg/m2 weekly x 12 (D1). Chemotherapy doses were based on actual body weight. Cox proportional hazards model were used to determine the relationship between neuropathy and disease free survival (DFS) and overall survival (OS) treating neuropathy status as a time dependent covariate and using a landmark analysis. Results: Of 4,702 patients who received at least 1 taxane dose, grade 2-4 neuropathy developed in 20%, 27%, 16%, and 16% in the P3, P1, D3, and D1 arms, respectively. In a model including age, tumor size, nodal status, treatment arm, neuropathy, and the neuropathy- treatment interaction, there was no relationship between neuropathy and DFS and OS in the entire population, for any of the individual treatment arms, or for any breast cancer subtypes, whether analyzed as a time-dependent covariate or using a landmark analysis. Baseline covariates associated with an increase rate of neuropathy included black race (25% vs. 19% grade 2-4, p=0.02) and obesity (21% vs. 19%, p=0.04), but not age. Conclusions: There was no association between taxane-induced neuropathy and DFS or OS in patients treated with contemporary AC-taxane therapy, including weekly paclitaxel. These findings show that taxane-induced neuropathy is not associated with outcome, thus suggesting that validation of SNPs predictive of neuropathy may be useful in identifying patients at higher risk for neuropathy but not taxane benefit and thereby improve therapeutic individualization.