Citations

Abstract Purpose: Based on promising preclinical data, we conducted a single-arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) ≥24 weeks, in HER2mut nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2mut detection. Experimental Design: Tumor tissue positive for HER2mut was required for eligibility. Neratinib was administered 240 mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2mut). Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2mut (lobular 7.8% vs. ductal 1.6%; P = 0.026). Thirteen additional HER2mut cases were identified locally. Twenty-one of these 22 HER2mut cases were estrogen receptor positive. Sixteen patients [median age 58 (31–74) years and three (2–10) prior metastatic regimens] received neratinib. The CBR was 31% [90% confidence interval (CI), 13%–55%], including one CR, one PR, and three SD ≥24 weeks. Median PFS was 16 (90% CI, 8–31) weeks. Diarrhea (grade 2, 44%; grade 3, 25%) was the most common adverse event. Baseline ctDNA sequencing identified the same HER2mut in 11 of 14 tumor-positive cases (sensitivity, 79%; 90% CI, 53%–94%) and correctly assigned 32 of 32 informative negative cases (specificity, 100%; 90% CI, 91%–100%). In addition, ctDNA HER2mut variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression. Conclusions: Neratinib is active in HER2mut, nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2mut cancers for clinical trial participation. Clin Cancer Res; 23(19); 5687–95. ©2017 AACR.

Serum response factor (SRF) was found to be involved in the phenotypic transition and fibrosis of the peritoneal membrane during treatment with peritoneal dialysis (PD), but the exact mechanism remains unclear. SRF regulates microRNAs (miRNAs) that contain the SRF-binding consensus (CArG) element in the promoter region. Therefore, we investigated whether the miR-199a/214 gene cluster, which contains a CArG element in its promoter, is directly regulated by SRF. High-glucose (HG) treatment significantly unregulated the expression of the miR-199a-5p/214–3p gene cluster in human peritoneal mesothelial cells (HPMCs). By chromatin immunoprecipitation and reporter assays, we found that SRF binds to the miR-199a-5p/214–3p gene cluster promoter after HG stimulation. In vitro , in HPMCs, silencing of miR-199a-5p or miR-214–3p inhibited the HG-induced phenotypic transition and cell migration but enhanced cell adhesion, whereas ectopic expression of mimic oligonucleotides had the opposite effects. Both miR-199a-5p and miR-214–3p targeted claudin-2 and E-cadherin mRNAs. In a PD rat model, treatment with an SRF inhibitor silenced miR-199a-5p and miR-214–3p and alleviated HG-PD fluid–induced damage and fibrosis. Overall, this study reveals a novel SRF–miR-199a/miR-214–E-cadherin/claudin-2 axis that mediates damage and fibrosis in PD.

3 Background: There is a clear need to develop a clinically relevant molecular subtyping approach for prostate cancer. We hypothesized that prostate cancer can be subtyped based on luminal versus basal lineage. Methods: We applied the PAM50 classifier, which is used clinically to identify luminal and basal cancers in breast cancer, to subtype a total of 3,782 prostate cancer samples using a high-density microarray platform run in a CLIA-certified laboratory. We examined the associations of these subtypes and clinical outcomes. Results: We demonstrate that PAM50 segregates prostate cancer into three reproducible subtypes in both retrospective cohorts and on prospective validation: luminal A (33.3%-34.3%), luminal B (28.5%-32.6%), and basal (34.1%-37.1%). Luminal B prostate cancers exhibited the worst clinical prognoses, followed by basal and luminal A subtypes (10-year biochemical recurrence-free survival: 29/39/41%; distant metastasis-free survival: 53/73/73%; prostate cancer-specific survival: 78/86/89%; overall survival: 69/80/82% respectively) on both univariable and multivariable analyses accounting for standard clinicopathologic prognostic factors. Known luminal lineage markers, such as NKX3.1 and KRT18, and the basal lineage CD49f signature, were enriched in luminal- and basal-like cancers respectively, demonstrating the connection between these subtypes and established prostate cancer biology. While both luminal-like subtypes were associated with increased AR expression and signaling, only luminal B prostate cancers were significantly associated with post-operative response to androgen deprivation therapy (ADT) in a subset analysis matching patients based on clinicopathologic variables (interaction p = 0.006, luminal B 10-year metastasis: 33% (treated) vs. 55% (untreated), non-luminal B: 37% (treated) vs. 21% (untreated)). Conclusions: These findings contribute novel insight into the biology of prostate cancer, and provide translatable clinical tools for personalizing post-operative ADT for patients with prostate cancer. Similar to breast cancer, these findings suggest that luminal/basal subtyping may be useful in treatment selection in prostate cancer.

133 Background: The genomic classifier, Decipher, has been validated to predict risk of metastasis after radical prostatectomy (RP). However, the cohort size and event rate in the previous studies did not allow for a thorough investigation into performance within individual clinicopathologic or treatment subgroups. In this study, we present the first meta-analysis of the performance of the 22-marker genomic classifier in men with prostate cancer (PCa) post-RP. Methods: MEDLINE, EMBASE, and the Decipher genomic resource information database were searched for published reports of men with PCa treated by RP between 2010 and 2016 where the benefit of the Decipher genomic classifier test was assessed. The primary end point was the ability of Decipher to independently improve prognostication of regional or distant metastasis over routine clinicopathologic factors. Meta-analysis was performed with random-effects modeling, and extent of heterogeneity between studies was determined with the I2 test. Results: Five studies (975 total patients, and 855 with individual patient genomic and clinicopathologic data) were eligible for analysis. The median follow-up was 8 years. All patients had clinical high-risk disease, yet 60.9%, 22.6%, and 16.5% of patients were classified as low, intermediate, and high-risk, respectively by Decipher and had 10-year cumulative incidence rates of metastases of 5.5%, 15.0% and 26.7% (p < 0.001), respectively. Adjusting for standard clinicopathologic variables, on multivariable analysis Decipher remained a statistically significant predictor of metastasis (hazard ratio [HR] 1.30 per 0.1 unit, 95% confidence interval [CI] 1.14-1.47, p < 0.001), and the summary HR for metastasis of Decipher across the 5 studies was 1.52 (95% CI 1.39-1.67) per 0.1 unit. Conclusions: The genomic classifier test, Decipher, has the ability to independently improve prognostication of men post-RP, as well as within nearly all clinicopathologic and treatment subgroups. Strong consideration should be given to incorporating the use of genomic testing in clinical decision making and clinical trials to better individualize treatment.

Abstract Purpose: Cyclin-dependent kinase (CDK) 4/6 drives cell proliferation in estrogen receptor–positive (ER+) breast cancer. This single-arm phase II neoadjuvant trial (NeoPalAna) assessed the antiproliferative activity of the CDK4/6 inhibitor palbociclib in primary breast cancer as a prelude to adjuvant studies. Experimental Design: Eligible patients with clinical stage II/III ER+/HER2− breast cancer received anastrozole 1 mg daily for 4 weeks (cycle 0; with goserelin if premenopausal), followed by adding palbociclib (125 mg daily on days 1–21) on cycle 1 day 1 (C1D1) for four 28-day cycles unless C1D15 Ki67 &gt; 10%, in which case patients went off study due to inadequate response. Anastrozole was continued until surgery, which occurred 3 to 5 weeks after palbociclib exposure. Later patients received additional 10 to 12 days of palbociclib (Cycle 5) immediately before surgery. Serial biopsies at baseline, C1D1, C1D15, and surgery were analyzed for Ki67, gene expression, and mutation profiles. The primary endpoint was complete cell cycle arrest (CCCA: central Ki67 ≤ 2.7%). Results: Fifty patients enrolled. The CCCA rate was significantly higher after adding palbociclib to anastrozole (C1D15 87% vs. C1D1 26%, P &lt; 0.001). Palbociclib enhanced cell-cycle control over anastrozole monotherapy regardless of luminal subtype (A vs. B) and PIK3CA status with activity observed across a broad range of clinicopathologic and mutation profiles. Ki67 recovery at surgery following palbociclib washout was suppressed by cycle 5 palbociclib. Resistance was associated with nonluminal subtypes and persistent E2F-target gene expression. Conclusions: Palbociclib is an active antiproliferative agent for early-stage breast cancer resistant to anastrozole; however, prolonged administration may be necessary to maintain its effect. Clin Cancer Res; 23(15); 4055–65. ©2017 AACR.

Abstract Background: The utility of alpha-fetoprotein (AFP) for hepatocellular carcinoma (HCC) surveillance is controversial. We aimed to identify factors associated with elevated AFP and define the patients for whom AFP is effective for surveillance. Methods: Data from the NCI Early Detection Research Network phase II HCC biomarker study (233 early-stage HCC and 412 cirrhotic patients) were analyzed. We analyzed 110 early-stage HCC and 362 cirrhotic hepatitis C virus (HCV) patients for external validation. Sensitivity, specificity, and area under the ROC curve (AUC) for HCC were calculated. Results: HCV etiology, non-White race, and serum alanine transaminase (ALT) predicted elevated AFP in cirrhotics. Non-White race and ALT predicted elevated AFP in HCC patients. Higher AUC of AFP for HCC was noted in patients with HBV (0.85) and alcohol (0.84), whereas it was lower in patients with hepatitis C virus (HCV; 0.80) and nonviral/alcohol etiology (0.76). The AUC was higher in HCV patients with serum ALT ≤40 U/L than patients with serum ALT &gt;40 U/L (0.91 vs. 0.75, P &lt; 0.01). At 90% specificity, the sensitivity of AFP increased from 44% to 74% in Whites with HCV and from 50% to 85% in non-Whites with HCV. There was a trend toward higher AUC in HCV patients with serum ALT ≤40 U/L than those with serum ALT &gt;40 U/L (0.79 vs. 0.69, P = 0.10) in the validation cohort. Conclusions: The satisfactory performance of AFP in HCV patients with normal ALT should be further validated. Impact: The AFP may serve as a valuable surveillance test in HCV patients with normal ALT. Cancer Epidemiol Biomarkers Prev; 26(7); 1085–92. ©2017 AACR.