Background: Hyperactivation of the PI3K-AKT-mTOR pathway is a postulated mechanism of resistance to anti-HER2 therapies and has also been described in triple-negative breast tumors. In HER2−amplified (HER2+) laboratory models, inhibition of this pathway induces activation of upstream receptor tyrosine kinases such as HER3. In triple-negative breast cancer (TN), HER1 overexpression has been identified and models show sensitivity to combined HER1 and mTOR inhibition. We hypothesize that dual inhibition of the PI3K pathway, HER1/2, and induced HER3 may be highly effective in patients with HER2+ or TN breast cancer (BC). This phase I/II trial is designed to determine the tolerability and possible efficacy of the mTOR inhibitor temsirolimus (T) plus the HER1/2 inhibitor neratinib (N) in patients with trastuzumab-refractory, HER2+ or TN BC. We will also explore mutational activation of the PI3K pathway in trastuzumab-refractory tumors as it relates to response to the T-N combination. Methods: The phase I dose-escalation study evaluated T (flat dose IV weekly) plus N (240 mg oral daily) in patients with metastatic HER2+ or TN BC. Cycle length was 4 weeks. Phase I end points included definition of maximum tolerated dose (MTD) and response rate (RR) per RECIST. The phase II study has a Simon two-stage design and evaluates the HER2+ and TN patients separately. Phase II endpoints include progression free survival and duration of response. Response was evaluated radiographically every 8 weeks, toxicity assessed every 2 weeks. All patients underwent biopsy of metastatic disease for biomarker assessment. Activating mutations in PIK3CA were assayed using the Sequenom MassARRAY system. Expression of PTEN was assessed by immunohistochemistry utilizing a published scoring system. Results: The phase I study enrolled 8 HER2+ patients who received a median of 5 (1-13) cycles of therapy. All patients had received trastuzumab and a median of 5.5 (2-12) prior lines of therapy. Frequent treatment-related grade 2 events were: hyperglycemia (4/8), elevated CPK (3/8), diarrhea (2/8), and rash (2/8). Grade 3 diarrhea was the dose-limiting toxicity. Other grade 3 toxicity was hyperglycemia (1/8); hematologic toxicities were not observed. The MTD of temsirolimus with neratinib is 8 mg IV weekly. Six patients treated at MTD were evaluable for response; 4 patients had PR, 1 had SD for a RR of 67%. PI3K pathway activation, through PIK3CA mutational activation or PTEN loss, was identified in 4/6 tumors analyzed and did not preclude response to temsirolimus and neratinib. Updated results reflecting the phase II patients will be reported. Conclusions: Temsirolimus plus neratinib is active in trastuzumab-refractory HER2+ patients. The phase II study is ongoing and additional efficacy and safety data in both HER2−amplified and triple-negative breast cancer patients will be presented. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD09-08.
Background: Germline mutations in the BRCA1 and BRCA2 genes lead to hereditary breast cancers that are defective in homologous recombination (HR) repair and sensitive to DNA damaging agents. HR deficiency (HRD) also occurs in sporadic breast cancers, but its incidence and etiology are unclear. Genomic signatures of HRD recently were employed as biomarkers in clinical trials with modest success. We posited that sporadic breast cancers displaying functional HR deficiency would harbor genetic alterations affecting HR DNA repair genes. To test this hypothesis, we applied a functional assay to define lack of competent HR DNA repair and sequenced the exomes of consecutive sporadic breast cancers. Methods: We developed an assay to assess the ability of cancer cells to localize RAD51 into sub nuclear foci in response to ex-vivo irradiation (IR) in fresh sporadic breast cancer tissue specimens from 60 patients. RAD51 focus formation was compared between mock and IR conditions to determine relative fold induction. Twenty-nine tumors with sufficient DNA underwent whole-exome sequencing. Structural genomic signatures of HRD (i.e. large state transitions (LST), telomeric imbalance (NtAI), loss-of-heterozygositiy (LOH)) and a previously reported mutational signature related to BRCA1/2 hereditary breast cancers were assessed. HR deficient tumors were defined as those with both RAD51 foci defects and a genomic signature of HR deficiency (LST>15 or presence of a BRCA mutational signature). Somatic, germ-line, and copy number changes in HR genes were investigated. BRCA1 methylation status was determined. Results: Seventeen of 60 (28%) tumors displayed defective RAD51 recruitment following ex-vivo IR (RAD51-DEF). RAD51-DEF was seen in all breast cancer subtypes , including 7 of 33 (21%) ER+/HER2-, 4 of 14 (29%) HER2+, and 6 of 13 (48%) triple-negative cases. Of the 29 sequenced tumors, 13 (45%) were RAD51-DEF and 16 (55%) were competent for inducing RAD51 foci. LST was elevated in 10 tumors (LST >15) and associated with RAD51-DEF (p=0.02), whereas NtAI (p=0.10) and LOH (p=0.052) did not show a significant association with RAD51-DEF. The BRCA1/2 mutational signature was evident in 4 tumors, all were RAD51-DEF (p=0.03) and 2 were BRCA2 mutated. Nine of 29 (31%) sequenced tumors were determined to have HRD by the RAD51 assay and presence of a genomic scar. Eight of these 9 (88%) cases with HRD had a genetic alteration of both alleles of a bona fide HR gene due to a pathogenic mutation (somatic or germline) coupled with loss of heterozygosity or a homozygous deletion compared to 1 (5%) tumor without HRD (p<0.001). Both alleles of a gene were affected for BRCA2 (n=4), FAAP100 (n=2), CHEK2 (n=1), TP53BP1 (n=1) and BRCA1 (n=1). BRCA1 gene promoter methylation was found not to be significantly associated with HRD. Conclusion: Combined functional and genomic analyses of breast tumors demonstrated that genetic loss of an HR gene may underpin HRD in sporadic breast cancers. Our findings warrant further comprehensive genetic assessment (somatic, germline, and copy number) of HR genes as potential biomarker for HR-directed therapies. Citation Format: Powell SN, Riaz N, Mutter RW, Ng CKY, Delsite R, Piscuoglio S, King TA, Martelotto L, Sakr R, Brogi E, Edelweiss M, Lim R, Higginson D, Weigelt B, Lee W, Reis-Filho JS. A functional assay for homologous recombination (HR) DNA repair and whole exome sequencing reveal that HR-defective sporadic breast cancers are enriched for genetic alterations in DNA repair genes. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S4-03.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.