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Purpose: Cisplatin is synergistic with vinorelbine and the PARP inhibitor veliparib, and has antineoplastic activity in triple-negative breast cancer (TNBC) and BRCA mutation–associated breast cancer. This phase I study assessed veliparib with cisplatin and vinorelbine.Experimental Design: A 3+3 dose-escalation design evaluated veliparib administered twice daily for 14 days with cisplatin (75 mg/m2 day 1) and vinorelbine (25 mg/m2 days 1, 8) every 21 days, for 6 to 10 cycles, followed by veliparib monotherapy. Pharmacokinetics, measurement of poly(ADP-ribose) in peripheral blood mononuclear cells, and preliminary efficacy were assessed. IHC and gene-expression profiling were evaluated as potential predictors of response.Results: Forty-five patients enrolled in nine dose cohorts plus five in an expansion cohort at the highest dose level and recommended phase II dose, 300 mg twice daily. The MTD of veliparib was not reached. Neutropenia (36%), anemia (30%), and thrombocytopenia (12%) were the most common grade 3/4 adverse events. Best overall response for 48 patients was radiologic response with 9-week confirmation for 17 (35%; 2 complete, 15 partial), and stable disease for 21 (44%). Germline BRCA mutation presence versus absence was associated with 6-month progression-free survival [PFS; 10 of 14 (71%) vs. 8 of 27 (30%), mid-P = 0.01]. Median PFS for all 50 patients was 5.5 months (95% confidence interval, 4.1–6.7).Conclusions: Veliparib at 300 mg twice daily combined with cisplatin and vinorelbine is well tolerated with encouraging response rates. A phase II randomized trial is planned to assess veliparib's contribution to cisplatin chemotherapy in metastatic TNBC and BRCA mutation–associated breast cancer. Clin Cancer Res; 22(12); 2855–64. ©2016 AACR.

Table S1: Schedule of pharmacokinetic analysis; Table S2: Overview of study dose levels (N=50); Table S3. Adverse events reported at any time during study therapy: grade 3-4 adverse events; Table S4: Veliparib pharmacokinetic (PK) parameters by cohort; Table S5: Total and ultrafilterable platinum pharmacokinetic parameters by cohort; Table S6: Immunohistochemistry results for 28 pre-therapy samples; Figure S1: Veliparib Cmax (ng/mL, panel A) and veliparib AUC0-6 (hr*ng/mL, panel B) by dose Cohort; Figure S2: Veliparib pharmacokinetic parameters (A) Cmax and (B) AUC0-6 at cycles 1 and 4 by cohort; Figure S3: Ultrafilterable platinum pharmacokinetic parameters Cmax and AUC0-24 at cycles 1 and 4 by cohort; Figure S4: Consort 2010 flow diagram for exploratory efficacy analysis comparing germline BRCA mutation positive to wild type; Figure S5: PAR assay results (pg/mL) for 14 patients in dose cohorts 6-8 (120-200 mg)

Supplementary Table 1 from Functional Phosphodiesterase 11A Mutations May Modify the Risk of Familial and Bilateral Testicular Germ Cell Tumors

Inactivating germline mutations in phosphodiesterase 11A (PDE11A) have been implicated in adrenal tumor susceptibility. PDE11A is highly expressed in endocrine steroidogenic tissues, especially the testis, and mice with inactivated Pde11a exhibit male infertility, a known testicular germ cell tumor (TGCT) risk factor. We sequenced the PDE11A gene-coding region in 95 patients with TGCT from 64 unrelated kindreds. We identified 8 nonsynonymous substitutions in 20 patients from 15 families: four (R52T, F258Y, G291R, and V820M) were newly recognized, three (R804H, R867G, and M878V) were functional variants previously implicated in adrenal tumor predisposition, and one (Y727C) was a known polymorphism. We compared the frequency of these variants in our patients to unrelated controls that had been screened and found negative for any endocrine diseases: only the two previously reported variants, R804H and R867G, known to be frequent in general population, were detected in these controls. The frequency of all PDE11A-gene variants (combined) was significantly higher among patients with TGCT (P = 0.0002), present in 19% of the families of our cohort. Most variants were detected in the general population, but functional studies showed that all these mutations reduced PDE activity, and that PDE11A protein expression was decreased (or absent) in TGCT samples from carriers. This is the first demonstration of the involvement of a PDE gene in TGCT, although the cyclic AMP signaling pathway has been investigated extensively in reproductive organ function and their diseases. In conclusion, we report that PDE11A-inactivating sequence variants may modify the risk of familial and bilateral TGCT. [Cancer Res 2009;69(13):5301–6]

Supplementary Table 2 from Functional Phosphodiesterase 11A Mutations May Modify the Risk of Familial and Bilateral Testicular Germ Cell Tumors

Patients with small node-negative HER2-positive breast cancer are commonly treated with paclitaxel and 1 year of adjuvant trastuzumab. We performed a sub-analysis of the ALTTO trial to explore the long-term outcomes of patients with small node-negative tumours.The ALTTO trial randomised 8381 patients with early HER2-positive BC treated with adjuvant chemotherapy (anthracycline/taxane- or taxane/carboplatin-based), to trastuzumab (T), lapatinib (L), their sequence (T → L) or their combination (L + T). Patients with tumours ≤3 cm and node-negative were included in this sub-analysis.A total of 2821 patients were analysed (median follow-up of 7 years). The median age was 52 years, and most patients had tumours ≤2 cm (64.3%). The 7-year disease-free survival (DFS) was 88.1% (95% CI: 86.7-89.3%). DFS was similar for arms T, T + L and T⟶L and significantly lower for arm L (stratified log-rank P = 0.031). The 7-year overall survival rate was 95.9% (95% CI: [95.0-96.6%) and the 7-year time-to-distant recurrence was 93.4% (95% CI: 92.3-94.4%).With most patients treated with anthracycline-based regimens, ALTTO shows that patients with small tumours treated with trastuzumab and concomitant chemotherapy have excellent long-term outcomes, similar to those of the APT trial.Clinicaltrials.gov identifier NCT00490139.

Limited data exist on the safety of using anti-human epidermal growth factor receptor 2 (HER2) targeted agents during pregnancy. To date, only retrospective studies have assessed the prognosis of patients with a pregnancy after prior early breast cancer, with no data in HER2-positive patients.The Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO) trial and the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) trial were randomized phase 3 trials for patients with HER2-positive early breast cancer. In both trials, pregnancy information was prospectively collected. Pregnancy outcomes were compared between patients unintentionally exposed to trastuzumab and/or lapatinib during gestation (the exposed group) and those who became pregnant after trastuzumab and/or lapatinib completion (the unexposed group). In the ALTTO trial, disease-free survival (DFS) was compared between pregnant patients and those aged 40 years or younger without a subsequent pregnancy via an extended Cox model with time-varying covariates to account for a guarantee-time bias.Ninety-two patients (12 in the exposed group and 80 in the unexposed group) had a pregnancy: 7 in the NeoALTTO trial and 85 in the ALTTO trial. Seven patients (58.3%) in the exposed group and 10 patients (12.5%) in the unexposed group opted for an induced abortion; in the unexposed group, 10 patients (12.5%) had a spontaneous abortion. No pregnancy/delivery complications were reported for the remaining cases, who successfully completed their pregnancy, with the exception of 1 fetus with trisomy 21 (Down syndrome). No significant difference in DFS (adjusted hazard ratio, 1.12; 95% confidence interval, 0.52-2.42) was observed between young patients with a pregnancy (n = 85) and young patients without a pregnancy (n = 1307).For patients with HER2-positive early breast cancer, having a pregnancy after treatment completion appears to be safe without compromising fetal outcome or maternal prognosis.

A growing number of young breast cancer survivors consider reproductive health issues, including subsequent fertility and pregnancy, of great importance, but many questions regarding safety remain unanswered. We conducted a comprehensive literature search and review of published articles, control-matched, population-based, and co-operative group reports that addressed various aspects of pregnancy after breast cancer (patients’ expectations, fertility damage, assessment and preservation, maternal and fetal outcome, breast feeding). Overall, available data support pregnancy and breast feeding after breast cancer as safe and feasible for women at low risk of recurrence. This retrospective and population-based evidence is, however, frequently incomplete; usually not representative of the entire population, it can be biased by patients’ related effects or underpowered and is often not controlled for biological factors and risk determinants in the statistical model used. Before making any definitive assumption on this delicate and fundamental aspect of a woman’s life after breast cancer, we should demonstrate without any reasonable doubt that the scattered information available today is scientifically sound. The Breast International Group and North American Breast Cancer Group are planning a global prospective study in young women with endocrine responsive, early breast cancer who desire pregnancy, to assess both patients’ and pregnancy outcomes. The trial will include an observational phase investigating the feasibility and impact of a temporary treatment interruption to allow conception and an experimental phase investigating the optimal duration of the subsequent endocrine treatment after delivery or the last failed attempt to get pregnant.

B126 Background Soy foods are a dietary staple in Asian countries and may play a role in this region’s historically low rates of breast cancer incidence. Isoflavones found in soy have structural similarities to estrogens and could exert protective effects by interacting with estrogen receptors, binding proteins, or metabolic enzymes. In a sample of Asian-American women we test whether soy is associated with urinary concentrations of estrogens and estrogen metabolites (EM). Methods This analysis was conducted among controls from a population-based case-control study of breast cancer among women of Chinese, Japanese and Filipino ancestry, aged 20-55 years, and living in San Francisco-Oakland (CA), Los Angeles (CA) and Oahu (HI). Of 966 controls, we included the 571 (59%) women who donated a 12-hour urine and had not been pregnant or lactating or used exogenous hormones in the last 6 months. At urine collection, 168 women were postmenopausal, 233 were pre-menopausal in mid-luteal phase, and 170 were in other categories. Fifteen EM were measured simultaneously with a highly sensitive and reproducible liquid chromatography-tandem mass spectrometry method. Participants had been queried about their usual adult frequency of intake of tofu and other selected soy foods. Robust regression was used to model the associations of soy intake (in tertiles) with EM measures. Models were adjusted for age, ethnicity, body mass index (BMI), and birthplace (Asia/West). Results No statistically significant associations were seen between soy intake and urinary concentrations of estrone, estradiol, estriol, or total EM in postmenopausal women or premenopausal women. In postmenopausal but not premenopausal women, we found significant trends across tertiles of soy intake for EM grouped by metabolic pathways. The 2- and 4-hydroxylated EM and the methylated catechols, each expressed as a percent of total EM, increased with soy intake, while relative levels of EM in the 16-hydroxylation pathway decreased. Models adjusted for age and ethnicity were similar. Factor analysis was used to confirm EM groupings. Among postmenopausal women, factor analysis identified four independent EM patterns, termed ‘catechols’, ‘methylated catechols’, ‘16-hydroxylation pathway EM’, and ‘parent estrogens’ based on the predominant EM. Factors for premenopausal women were similar. Discussion Our findings do not support the hypothesis that soy intake influences endogenous production of estrogens but they do suggest that soy intake can modify estrogen metabolism in postmenopausal women. Increased ratios of 2-hydroxyestrone to 16α-hydroxyestrone have been associated with lower breast cancer risk in some epidemiologic studies. Methylation of catechol estrogens results in deactivation of these metabolites and prevents conversion into genotoxic quinones. Thus, the trends by soy intake represent variations in EM metabolism that could reduce breast cancer risk. Citation Information: Cancer Prev Res 2008;1(7 Suppl):B126.