Ruddy, Kathryn J.

Abstract Introduction. Male breast cancer (male BC) is a rare disease for which disease management is extrapolated from females. IMBC, an international consortium, which previously reported on clinico-pathological aspects, now reports on molecular subgroups revealed by RNA sequencing and their relation to patient outcome. Methods. Tumor samples from the retrospective MALE BC registry diagnosed between 1990-2010 and with pathology and outcome data (relapse-free- (RFS) and overall survival (OS)) were included (n=699). To allow the discovery of prognostic features, we selected, stratified for known risk factors (TN stage, grade, age at diagnose and adjuvant endocrine treatment), from the cohort 152 cases with poor (RFS <= 4 yrs) and good outcome (RFS > 7yrs) evenly distributed. Here, we report RNA sequencing results of the first 73 cases, 38 with poor and 35 with good outcome. RNA sequencing reads were used to generate gene expression values and to report transcripts carrying driver mutations. Unsupervised clustering identified subgroups and within subgroups differentially expressed genes were identified. The reported prognostic male BC subgroups M1 and M2 (Johansson BCR 2012(14):R31) were also annotated. All identified subgroups were related to outcome using logistic regression (p-value using Wald test). Results. Unsupervised clustering revealed 2 main subgroups of which group 1 was enriched for expression of ER target genes, WNT3 and genes from amplicons known for female BC, e.g. 19p13 (CCNE1), 8q24 (MYC), and 11q13 (CCND1). The biology of the smaller group 2 was less defined but TGFβ2 expression was high as were various kallikreins (KLK) including interestingly KLK3 (prostate specific antigen). Other known amplified regions [(8p11 (FGFR1), 20q13 (ZNF217) and 12q15 (MDM2)] and mutated transcripts [PIK3CA (H1047R/L/Q; E542K, E545K, N345K; 16% of cases), TP53 and SF3B1 (K700E) (2% of cases)] were identified. Profound tumor infiltrate gene expression was present in 5% of cases and one third of cases expressed proliferation markers. Except for TP53, none of these latter characteristics were unevenly distributed among the 2 main subgroups. ER and AR were highly correlated, particularly in group 1. The two main groups could be further subdivided. Group 1 comprised 3 subgroups of which subgroup 1a expressed TFF1/3 and NAT1, well-known ER targets, while subgroups 1b and 1c expressed other ER targets,respectively BEX1 and PITX1. HOXC cluster expression differentiated subgroup 1b from 1a and 1c. None of these intrinsic subgroups were, however, related to RFS. The previously reported M2 subgroup, which largely segregated with subclusters 1a and 1b, was associated with a better RFS than the M1 subgroup (OR=2.9; 95%CI 1.1-7.5; p-value=0.03). Conclusions. 1) Intrinsic subtypes of male BC were revealed and their subgrouping is defined by ER associated subsets of genes. 2) The association of the reported M2 subgroup of male BC with longer RFS was validated; 3) Currently identified biological characteristics of male BC may improve future treatments. The full report on 152 cases including a comparison to female BC will be presented at the conference. This research was funded by Breast Cancer Research Foundation Citation Format: Martens JWM, Sieuwerts A, Ponchet C, Smid M, de Weerd V, Slaets L, Piper T, van Deurzen CHM, Schroder CP, Stangle C, Kloosterman W, van Leeuwen-Stok E, Nilsson C, Vermeij J, Peeters S, Goulioti T, Nowaczyk M, Aebi S, Rubio IT, Kelly C, Bayani J, Porter P, Murray M, Hudis C, Middleton L, Korde L, Ruddy K, Winer E, Bogler O, van den Weyngaert D, dal Lago L, Fraser J, Benstead K, van Asperen C, Linderholm B, Hedenfalk I, Tryfonidis K, Giordano S, Bartlett J, Cardoso F. Molecular subtyping of male breast cancer by the International male breast cancer program (IMBC): EORTC 10085/TBCRC 0-29/BIG 2-07/NABCG/BOOG 2009-04 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD7-12.

Abstract Breast cancer is the most common cancer among women in the United States, with up to 30% of those diagnosed displaying a family history of breast cancer. To date, 18% of the familial risk of breast cancer can be explained by SNPs. This review summarizes the discovery of risk-associated SNPs using candidate gene and genome-wide association studies (GWAS), including discovery and replication in large collaborative efforts such as The Collaborative Oncologic Gene-environment Study and OncoArray. We discuss the evolution of GWAS studies, efforts to discover additional SNPs, and methods for identifying causal variants. We summarize findings associated with overall breast cancer, pathologic subtypes, and mutation carriers (BRCA1, BRCA2, and CHEK2). In addition, we summarize the development of polygenic risk scores (PRS) using the risk-associated SNPs and show how PRS can contribute to estimation of individual risks for developing breast cancer. Cancer Epidemiol Biomarkers Prev; 27(4); 380–94. ©2018 AACR. See all articles in this CEBP Focus section, “Genome-Wide Association Studies in Cancer.”

Purpose of review Due to medical advances and an aging population, the number of cancer survivors continues to rise. Survivors often experience late and long-term sequelae of cancer and its treatment (e.g., fatigue, pain, fear of recurrence, and stress). As a result, some patients have utilized or expressed interest in integrative medicine (IM) modalities for prevention of recurrence, optimizing health, enhancing quality of life, and managing symptoms. The purpose of this review is to focus on research published during the past year that informs our understanding of the utility of IM for cancer survivors. Recent findings Physical activity, diet, dietary supplements, mind–body modalities, acupuncture, and massage therapy all may play a role in the management of the physical (e.g., fatigue and pain) and emotional (e.g., anxiety and fear) issues faced by cancer survivors. Summary IM therapies are appealing to and utilized by many cancer survivors and may reduce symptom burden. Clinicians who provide cancer survivorship care may improve patient care by understanding the evidence for and against their use.

184 Background: While evidence of the challenges of cancer caregiving has been growing, scant research addresses the experience of partners of young adults with cancer. These individuals and their relationships may be particularly vulnerable to stress, especially when managing the complexity of cancer care and survivorship with their partner. We sought to evaluate psychosocial concerns and mental health in the partners of young survivors of early stage breast cancer (BC). Methods: We invited partners of young women w/BC diagnosed at age ≤ 40 yrs enrolled in a prospective cohort study to participate in a one-time survey evaluating psychosocial concerns including quality of life, coping, social support, financial insecurity, partnership concerns, parenting concerns, anxiety and depression. Logistic regression was used to explore predictors of anxiety (score > 8 on Hospital Anxiety and Depression Scale (HADS)). Results: Most respondents (284/289) were male, with median age 43 yrs (range 27-65). The median time of survey completion was 62 months (range 16 -114) after their partner’s dx. Respondents were mostly white (93%), working full time (94%), and college educated (78%); 29% reported some financial stress, 74% were parenting children < 18 yrs, and 32% reported at least a fair amount of relationship concern. 42% (106/250) had anxiety (39/289 respondents (13%) had incomplete/missing HADS). In univariable analyses, lower education, working full time, parenting concerns, insufficient social support and maladaptive coping were associated (p < .05) with anxiety. In the multivariable model, only maladaptive coping remained significantly associated with anxiety (p < .01, OR = 2.32 (95% CI: 1.22, 4.39)). Conclusions: Partners of young BC survivors who used less constructive/more maladaptive coping strategies experience negative mental health outcomes after tx has ended. Caregivers’ anxiety may have implications for both their own and survivors’ health and QOL. Future interventions might focus on the development of constructive coping strategies to enhance adjustment and role effectiveness in dealing with the impact of cancer.

220 Background: Paclitaxel is associated with both an acute pain syndrome (P-APS) and chronic chemotherapy-induced peripheral neuropathy (CIPN). Preliminary animal data suggest that minocycline may be effective for the prevention of chemotherapy-induced neurotoxicity. The purpose of this pilot study was to investigate the efficacy of minocycline for the prevention of CIPN and P-APS. Methods: Patients with breast cancer were enrolled prior to initiating neoadjuvant or adjuvant weekly paclitaxel for 12 weeks. They were randomized to receive minocycline 200mg on day 1 followed by 100mg twice daily or a placebo, with the same dosing schedule. Patients completed (1) an acute pain syndrome questionnaire daily during chemotherapy, and (2) the EORTC QLQ-CIPN20 questionnaire at baseline, prior to each dose of paclitaxel, and monthly for 6 months post treatment. The primary goal was to obtain pilot data regarding the possible effect of minocycline on the prevention of paclitaxel-induced CIPN and P-APS, to determine if conducting a larger phase III placebo-controlled trial was indicated. Scores obtained from patient questionnaires were converted to a 0-100 scale, where higher scores = better quality of life. Results: Forty-seven patients were randomized, 45 of which were evaluable, with a mean age of 55. There were no remarkable differences noted between the two groups for the overall sensory score of the EORTC-CIPN 20 or its individual sub-questions, which evaluated tingling, numbness, or shooting burning pain in hands and feet. However, there was a significant difference in the daily average AUC pain score attributed to P-APS, favoring minocycline (median 96.0 vs 84.3; p = 0.02). Correspondingly, patients receiving minocycline used less opioid pain medications for control of P-APS (0% vs 23%, P = 0.05). Not only were no increased toxicities reported with minocycline, but there was an apparent improvement in fatigue (median AUC 76.7 vs 59.0; P = 0.02). Conclusions: Based on the results of this pilot study, minocycline did not appear to be beneficial for the prevention of CIPN, but did look promising for reducing P-APS. Further study of this effect may be warranted. Clinical trial information: NCT02297412.

176 Background: The purpose of the study was to determine the effectiveness of olanzapine (OLN) for the prevention of nausea and vomiting in patients receiving highly emetogenic chemotherapy (HEC). Methods: A randomized, double-blind, phase III trial was performed in chemotherapy-naïve patients receiving cisplatin, > 70 mg/m2, or cyclophosphamide-anthracycline-based chemotherapy, comparing OLN to placebo in combination with aprepitant (APR), a 5-HT3 receptor antagonist (5-HT3), and dexamethasone (DEX). The OLN regimen was 10 mg of oral OLN, 125 mg APR, a 5-HT3, and oral DEX 12 mg pre-chemotherapy, day 1, and 10 mg/day of oral OLN and 8 mg DEX on days 2-4 post-chemotherapy plus 80 mg APR on days 2, 3 post-chemotherapy. The placebo (PLA) regimen was oral placebo, pre-chemotherapy, day 1, and on days 2-4 post-chemotherapy; the APR, 5-HT3, and DEX pre- and post-chemotherapy were identical to that used in the OLN regimen. Fosaprepitant (150 mg IV), day 1 was allowed for substitution for the oral aprepitant. Palonosetron, ondansetron, or granisetron were the permitted 5-HT3 options. Nausea was measured on a 0-10 visual analogue scale, with 0 being “no nausea at all” and 10 being “nausea as bad as it can be”. No nausea was the primary endpoint and, complete response (no emesis and no use of rescue medications) was a secondary endpoint. Results: 401 patients (202 OLN, 199 PLA) were enrolled in the study. The proportion of patients who had no nausea was significantly greater for the OLN regimen compared to the PLA regimen for the acute period (24h post-chemotherapy) (74% vs. 45%, p < 0.0006), for the delayed period ( 24-120 h post-chemotherapy) (43% vs. 26%, p < 0.0006), and for the overall period (0-120 h) (39% vs. 22%, p < 0.0006). Complete response was significantly improved for the OLN patients compared to PLA patients for the acute (85% vs. 65%, p < 0.0001), the delayed (67% vs. 53%, p < 0.0078), and the overall periods (64% vs. 41%, p < 0.0001). There were no grade 3 or 4 toxicities. Conclusions: No nausea, the primary endpoint, and complete response, a secondary endpoint, were significantly improved with OLN, compared to PLA. Clinical trial information: NCT02116530.

202 Background: Posttraumatic stress disorder (PTSD) is associated with morbidity and mortality in affected populations. Cancer survivors experience PTSD at a rate higher than the general population, with young age and female gender identified as risk factors. While young women with breast cancer experience greater psychosocial distress in general following diagnosis (dx), little is known about PTSD in this population. Methods: Women dx’d with Stage I-III breast cancer at age ≤ 40 were surveyed as a part of a multi-site cohort study. Demographic, treatment, psychosocial characteristics (including self-reported psychiatric conditions and use of psychiatric medications prior to dx), anxiety and depression (Hospital Anxiety and Depression Scale), fear of recurrence (Lasry Scale), and social support (Medical Outcomes Study) were assessed within 1 year after dx. PTSD was measured at 30 months post-dx using the PTSD Checklist – Civilian Version; a score ≥ 50 was considered positive for PTSD. Univariable and stepwise multivariable logistic regression were used to evaluate factors associated with PTSD. Results: 572 women were eligible for this analysis; median age at dx was 37 (range: 17-40); 87% had Stage I or II cancer. 37/572 women (6.5%) met criteria for PTSD at 30 months. Lower educational attainment, less financial comfort, less social support, stage 2 (vs. 1) disease, receipt of chemotherapy, fear of recurrence, anxiety and depression, and psychiatric comorbidities were associated (p ≤ 0.05) with PTSD in univariable analyses. Chemotherapy (OR = 3.48, 95% CI = 1.09-11.06), anxiety by HADS (OR = 20.29, 95% CI = 7.83-52.53), and psychiatric comorbidities (OR = 4.22, 95% CI = 1.40-12.74) were associated with increased likelihood of PTSD, whereas college education (OR = 0.25, 95% CI = 0.10-0.59) and greater social support (OR = 0.41, 95% CI = 0.17-0.99) appeared to be protective in multivariable analyses. Conclusions: PTSD affects a minority of young breast cancer survivors, with the prevalence in our cohort similar to that seen in other breast cancer populations. Early identification of those at risk for developing PTSD is essential for the adequate treatment of affected women and for the improvement of health outcomes and quality of life in cancer survivors.