Background Oncology research increasingly involves biospecimen collection and data sharing. Ethical challenges emerge when researchers seek to use archived biospecimens for purposes that were not well defined in the original informed consent document (ICD). We sought to inform ongoing policy debates by assessing patient views on these issues. Materials and Methods We administered a cross‐sectional self‐administered survey to patients with cancer at an academic medical center. Survey questions addressed attitudes toward cancer research, willingness to donate biospecimens, expectations regarding use of biospecimens, and preferences regarding specific ethical dilemmas. Results Among 240 participants (response rate 69%), virtually all (94%) indicated willingness to donate tissue for research. Most participants (86%) expected that donated tissue would be used for any research deemed scientifically important, and virtually all (94%) expected that the privacy of their health information would be protected. Broad use of stored biospecimens and data sharing with other researchers increased willingness to donate tissue. For three scenarios in which specific consent for proposed biobank research was unclear within the ICD, a majority of patient's favored allowing the research to proceed: 76% to study a different cancer, 88% to study both inherited (germline) and tumor specific (somatic) mutations, and 70% to permit data sharing. A substantial minority believed that research using stored biospecimens should only proceed with specific consent. Conclusion When debates arise over appropriate use of archived biospecimens, the interests of the research participants in seeing productive use of their blood or tissue should be considered, in addition to addressing concerns about potential risks and lack of specific consent. Implications for Practice This survey evaluated views of patients with cancer regarding the permissible use of stored biospecimens from cancer trials when modern scientific methods are not well described in the original informed consent document. The vast majority of patients support translational research and expect that any biospecimens they donate will be used to advance knowledge. When researchers, policy makers, and those charged with research oversight debate use of stored biospecimens, it is important to recognize that research participants have an interest in productive use of their blood, tissue, or data, in addition to considerations of risks and the adequacy of documented consent.

Running head: Mechanisms of resistance to PARP inhibitors/platinum in metastatic breast cancer Keywords: BRCA1, BRCA2, breast cancer, PARP inhibitor, platinum Key message: We analyzed mechanisms of resistance to PARP inhibitor or platinum chemotherapy in 8 patients with BRCA1/2-mutant metastatic breast cancer. Four patients acquired resistance by genomic reversion to a functional BRCA1/2 protein; two patients acquired resistance by upregulating DNA end resection. RAD51 foci by immunohistochemistry correlated with clinical response to PARP inhibitor/platinum. Abstract Background:Little is known about mechanisms of resistance to PARP inhibitors and platinum chemotherapy in patients with metastatic breast cancer and BRCA1/2 mutations. Further investigation of resistance in clinical cohorts may point to strategies to prevent or overcome treatment failure. Patients and Methods:We obtained tumor biopsies from metastatic breast cancer patients with BRCA1/2 deficiency before and after acquired resistance to PARP inhibitor or platinum chemotherapy. Whole exome sequencing was performed on each tumor, germline DNA, and circulating tumor DNA. Tumors underwent RNA sequencing, and immunohistochemical staining for RAD51 foci on tumor sections was performed for functional assessment of intact homologous recombination. Results:Pre-and post-resistance tumor samples were sequenced from 8 patients (4 with BRCA1 and 4 with BRCA2 mutation; 4 treated with PARP inhibitor and 4 with platinum). Following disease progression on DNA-damaging therapy, four patients (50%) acquired at least one somatic reversion alteration likely to result in functional BRCA1/2 protein detected by tumor or circulating tumor DNA sequencing. Two patients with germline BRCA1 deficiency acquired genomic alterations anticipated to restore homologous recombination through increased DNA end resection: loss of TP53BP1 in one patient and amplification of MRE11A in another. RAD51 foci were acquired post-resistance in all patients with genomic reversion, consistent with reconstitution of homologous recombination. All patients whose tumors demonstrated RAD51 foci post-resistance were intrinsically resistant to subsequent lines of DNA-damaging therapy.Conclusions: Genomic reversion in BRCA1/2 was the most commonly observed mechanism of resistance, occurring in 4 of 8 patients. Novel sequence alterations leading to increased DNA end resection were seen in two patients, and may be targetable for therapeutic benefit. The presence of RAD51 foci by immunohistochemistry was consistent with BRCA1/2 protein functional status from genomic data and predicted response to later DNA-damaging therapy, supporting RAD51 focus formation as a clinically useful biomarker.

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Background: The HER3 protein is expressed in multiple solid tumor types, including breast cancer, and high expression of HER3 is associated with poor prognosis. U3-1402 is a novel HER3-targeted antibody-drug conjugate designed with a peptide-based cleavable linker and a topoisomerase I inhibitor payload. U3-1402 has a high drug-to-antibody ratio (~ 8:1), and the stable linker is selectively cleaved by lysosomal enzymes upregulated in tumor cells. In addition, high cell membrane cross-penetration allows for potential payload activity against neighboring tumor cells with antigen heterogeneity. This ongoing phase 1/2, multicenter, open-label, first-in-human study was initiated in Japan and expanded to the United States to evaluate the safety and efficacy of U3-1402 in HER2-negative (including hormone receptor [HR]-positive disease and TNBC), HER3-expressing advanced/unresectable or metastatic breast cancer (NCT02980341/JapicCTI-163401). The study comprises 3 parts: dose escalation, dose finding, and dose expansion. Preliminary results from the phase 1 dose-escalation and dose-finding parts demonstrated the recommended dose for expansion, with antitumor activity of U3-1402 in this heavily pretreated patient population (Masuda, et al. SABCS 2018). Methods: In the ongoing, phase 2, dose-expansion part of this trial, U3-1402 is administered via intravenous infusion every 3 weeks to patients with HER3-expressing advanced/unresectable or metastatic breast cancer. Approximately 110 patients will be treated in the dose-expansion part within cohorts based on breast cancer molecular subtype and HER3 protein expression: patients with HER3-high, HER2-negative, HR-positive disease will receive 4.8 or 6.4 mg/kg U3-1402; patients with HER3-low, HER2-negative, HR-positive disease will receive 6.4 mg/kg U3-1402; and patients with HER3-high, TNBC will receive 6.4 mg/kg U3-1402. Eligible patients for dose expansion are aged ≥ 18 years in the United States (≥ 20 years in Japan); have documented HER3-positive disease, as measured by immunohistochemistry; must undergo fresh tumor biopsy prior to starting treatment, if a sample has not already been submitted for assessment of HER3 expression. For all cohorts except TNBC, patients must have received ≥ 2 and ≤ 6 prior chemotherapy regimens, including ≥ 2 regimens for advanced/unresectable or metastatic disease. For the TNBC cohort, patients must have progressed after receiving 1 to 2 prior chemotherapy regimens in the advanced setting. Patients with previously treated or asymptomatic untreated brain metastases are eligible. Treatment will continue until progression, unacceptable toxicity, death, withdrawal of consent, or termination of the study. The primary objective of dose expansion is to evaluate the safety and efficacy of U3-1402; the secondary objectives are to evaluate the relationship between the efficacy of U3-1402 and HER3 expression and to assess pharmacokinetics and antidrug antibodies. Efficacy assessments include investigator-assessed objective response rate per RECIST v1.1, response duration, time to response, clinical benefit rate, progression-free survival, overall survival, and percent change in target lesion(s). Patients receiving at least 1 dose of U3-1402 with pretreatment and posttreatment tumor assessments will be evaluated for efficacy. Citation Format: Ian Krop, Norikazu Masuda, Takahiro Kogawa, Shunji Takahashi, Kan Yonemori, Kenichi Inoue, Takahiro Nakayama, Yutaka Yamamoto, Ricardo Alvarez, Tatsuya Toyama, Akihiko Osaki, Masato Takahashi, Joyce O'Shaughnessy, Yasuaki Sagara, Shigehira Saji, Virginia Kaklamani, Sun Young Oh, William Gradishar, Barbara Haley, Tsutomu Iwasa, Tiffany Traina, Naoto Ueno, Steve Isakoff, Shoichi Ohwada, Yoshimi Tanaka, Sabeen Mekan, Hiroshi Onuma, Om Sharma, Hiroji Iwata. Phase 1/2 first-in-human study of U3-1402, an anti-human epidermal growth factor receptor 3 (HER3) antibody-drug conjugate, in HER3-expressing advanced/unresectable or metastatic breast cancer, including those with triple negative breast cancer (TNBC) or HER3-low disease [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-07-06.