Robert, Nicholas J.

This prospective phase II clinical trial (Side Out 2) explored the clinical benefits of treatment selection informed by multi‐omic molecular profiling (MoMP) in refractory metastatic breast cancers (MBCs). Core needle biopsies were collected from 32 patients with MBC at trial enrollment. Patients had received an average of 3.94 previous lines of treatment in the metastatic setting before enrollment in this study. Samples underwent MoMP, including exome sequencing, RNA sequencing (RNA‐Seq), immunohistochemistry, and quantitative protein pathway activation mapping by Reverse Phase Protein Microarray (RPPA). Clinical benefit was assessed using the previously published growth modulation index (GMI) under the hypothesis that MoMP‐selected therapy would warrant further investigation for GMI ≥ 1.3 in ≥ 35% of the patients. Of the 32 patients enrolled, 29 received treatment based on their MoMP and 25 met the follow‐up criteria established by the trial protocol. Molecular information was delivered to the tumor board in a median time frame of 14 days (11–22 days), and targetable alterations for commercially available agents were found in 23/25 patients (92%). Of the 25 patients, 14 (56%) reached GMI ≥ 1.3. A high level of DNA topoisomerase I (TOPO1) led to the selection of irinotecan‐based treatments in 48% (12/25) of the patients. A pooled analysis suggested clinical benefit in patients with high TOPO1 expression receiving irinotecan‐based regimens (GMI ≥ 1.3 in 66.7% of cases). These results confirmed previous observations that MoMP increases the frequency of identifiable actionable alterations (92% of patients). The MoMP proposed allows the identification of biomarkers that are frequently expressed in MBCs and the evaluation of their role as predictors of response to commercially available agents. Lastly, this study confirmed the role of MoMP for informing treatment selection in refractory MBC patients: more than half of the enrolled patients reached a GMI ≥ 1.3 even after multiple lines of previous therapies for metastatic disease.

1005 Background: B in combination with weekly paclitaxel or docetaxel (D) as 1st-line therapy for MBC has improved progression-free survival (PFS) compared with the respective taxane alone in two large Phase III trials. This study investigated the addition of B to standard 1st-line chemotherapy regimens for MBC. Methods: Patients were randomized in 2:1 ratio to receive B + chemotherapy or placebo (pl) + chemotherapy. Prior to randomization, investigators chose capecitabine (Cap) (2000 mg/m2 x 14d), taxane (T) (nab-paclitaxel [260 mg/m2] or D [75 or 100 mg/m2], q3wk), or anthracycline (Ant)-based chemotherapy (q3wk). B or pl was administered at 15 mg/kg q3wk. Key eligibility criteria included MBC or locally-recurrent disease, no prior cytotoxic treatment, ECOG PS 0 or 1, HER2-negative disease and no CNS metastases. The primary endpoint was investigator-assessed PFS. Secondary endpoints included overall survival (OS), objective response rate (ORR), independent review of PFS, and safety. At progression, all patients were eligible for B with 2nd line chemotherapy. The Cap cohort and the pooled T or Ant (T + Ant) cohort were independently powered and analyzed in parallel using two-sided stratified log-rank test (Cap: 80% power to detect HR=0.75; T + Ant: 90% power to detect HR=0.7). Results: RIBBON-1 enrolled 1237 patients (Cap, 615; T, 307; Ant, 315) from 12/05 to 8/07 in 22 countries with a median follow-up of 15.6 months in the Cap cohort and 19.2 months in the T + Ant cohort. The results are summarized below. OS data are limited with only 33% of events. Safety was consistent with results of prior B trials. Conclusions: The addition of B to Cap, T; or Ant-based chemotherapy regimens used in 1st-line treatment of MBC resulted in statistically-significant improvement in PFS with a safety profile comparable to prior Phase III studies. [Table: see text] [Table: see text]

550 Background: 5187 postmenopausal women were originally randomized to NCIC CTG MA.17 to receive letrozole (LET) or placebo (PLAC) after 5 years of tamoxifen. The hazard ratio (HR) for disease-free survival (DFS) was 0.58 (0.450.76, p=0.00004) after a median follow-up of 30 months (mo). The trial was unblinded in October 2003 after the first interim analysis. Women randomized to PLAC were offered LET at the time of unblinding. The goal of this analysis was to determine whether women switching from PLAC to LET benefit in terms of disease outcome and to evaluate treatment related toxicities. Methods: LET and PLAC-LET have been compared to PLAC, based on the hazard ratio and adjusting for baseline patient and disease variables including, among others, tumor size, nodal status and prior adjuvant chemotherapy. Results: Information about their follow-up treatment after unblinding was available on 2268 women originally assigned to PLAC and who were free of recurrence and alive at the time of unblinding. Among them, 1655 crossed over from PLAC to LET while 613 elected no treatment. With 54 mo f/up the HR for DFS was 0.31 (0.18, 0.55: p<0.0001) favoring patients who crossed over to LET compared to those who stayed on no treatment. The treatment switch was well tolerated with no significant difference in bone fractures or cardiovascular events. An updated analysis of DFS, DDFS and OS by nodal and tumor receptor status, prior chemotherapy, menopausal status at the start of tamoxifen, and duration of prior tamoxifen therapy will be presented at the meeting. Conclusion: Women with hormone dependent breast cancer prescribed LET after a prolonged delay from completing tamoxifen experienced a significant improvement in outcome (DFS, DDFS, OS) and should be considered for this therapy. [Table: see text]

299 Background: In 2011, ASCO launched a forum for the oncology research community to facilitate and promote the implementation of quality clinical research. The ASCO Research Community Forum (RCF) was created to provide a solution-oriented venue for research sites to address common challenges with conducting clinical trials. It offers in-person and virtual forums and resources to learn and share best practices with peers on a variety of topics, including site quality assessment and improvement, research site operations, and clinical trial access and accrual. Methods: An assessment was performed to measure the ASCO RCF output and to gather information on its potential impact on the cancer community. Results: The ASCO RCF has provided an in-person venue for physicians and research administrators with a steady increase in attendance, from 52 attendees in 2012 to 159 in 2018. Multi-stakeholder meetings and manuscripts have promoted best practices and solutions to address challenges with implementing quality clinical trials. Tools and resources to facilitate best practices and quality improvement at trial sites have been accessed by a range of types of research sites from across the U.S. and internationally. Its web-based library of resources was accessed over 27,000 times in 2018, alone. An online forum was launched in 2019 to provide a new opportunity to connect and impact the research community. Conclusions: The ASCO RCF is a productive and esteemed resource for the cancer research community. In-person and virtual forums, along with practical tools, promote access and accrual to clinical trials by facilitating networking, developing solutions, and providing education and resources. The ASCO RCF impact has extended from community-based oncology practices to larger research networks and academic centers across the U.S. and internationally. Its efforts to promote and facilitate access to quality clinical trials align with the vision and mission of ASCO to conquer cancer through research, education, and promotion of the highest quality patient care.

Abstract Background: Although the efficacy of different immunotherapeutic agents varies greatly across tumor types, little is known about the role of different metastatic tumor microenvironments in modulating the expression of immune-checkpoints like PD-L1. Using metastatic breast cancer as a model, this work explored whether metastatic lesions derived from different patients, but colonizing the same host target organ, showed organ-specific immune signatures. Methods: Snap frozen metastatic lesions collected from 30 breast cancer patients enrolled in a prospective phase II multi-omic precision medicine clinical trial (“Side-Out II”) were used for this analysis. Sites of metastasis were: liver (LI) (n=10), skin/chest wall (SC) (n=10), and other lesions (OL) (n=10) [including lymph nodes (LN) (n=4), lung (LU) (n=3), and intra-abdominal lesions (IA) (n=3)]. Pure tumor epithelia were isolated from each specimen via Laser Capture Microdissection (LCM). PD-L1 expression (Antibody Clone E1L3N) was quantitatively measured using the Reverse Phase Protein Microarray (RPPA), a high-throughput, multiplex immunoassay that provides operator-independent quantitative data starting from a small amount of biological material. Proportion of patients with PD-L1 expression above the median and the 75th percentile of the population was compared across metastatic sites. Results: PD-L1 expression had a &gt;5 fold dynamic range across breast cancer-derived metastatic lesions with different distribution across metastatic sites. Specifically, PD-L1 expression of 6/10 LIs, 5/10 OLs (including 2 LU and 3 LN positive lesions), and 4/10 SC metastases was greater than the population median of all metastases combined. LI metastases were the most represented group above the 75th percentile of the population (4/10), followed by OS (2/10) (including 1 LU and 1 LN positive lesions), and SC (1/10). Of the 15 lesions above the population median, 6 were LI (40%), 5 were OS (33%), and 4 were SC (27%); of the 7 metastases above the 75th percentile, 4 were LI (57%), 2 were OS (29%), and 1 was SC (14%). Conclusions: The LCM-RPPA workflow can capture PD-L1 protein expression on a continuous quantitative scale and provide a broader understanding of the dynamic range of expression. Our data suggest that organ specific microenvironments in which metastatic lesions develop may strongly influence overall PD-L1 tumor cell expression. If different metastatic host organs can modulate PD-L1 expression, location of the metastatic lesion should be kept in consideration when selecting patients that are candidates for immunotherapy. Such hypotheses should be further validated in prospective clinical trial where quantitative PD-L1 expression of different metastatic lesions is evaluated along with response to targeted immuno-oncology compounds. Citation Format: Mariaelena Pierobon, K Alex Hodge, Elisa Baldelli, Steven Anthony, Nicholas J. Robert, Donald W. Northfelt, Mohammad J. Jahanzeb, Linda Vocila, Lance A. Liotta, Bryant Dunetz, Emanuel F. Petricoin. PD-L1 expression differs across cancer metastatic sites from breast tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3129.

Abstract Background: The efficacy of immunotherapy, including therapeutic strategies capable of modulating innate/adaptive immune resistance, varies greatly across tumor types. As the number of available immunotherapies accelerates, the study of predictive markers by IHC (e.g. PDL1 expression) is under intense investigation. However, staining protocol inconsistency, variation across scoring systems, and subjective interpretation of the immunostaining have produced conflicting results thus far. This work explored the role of Laser Capture Microdissection (LCM) coupled with Reverse Phase Protein Microarray (RPPA) as an alternative high throughput, quantitative, operator independent platform for measuring PDL1 expression across tumor types. Material and Methods: Pure epithelial cells were isolated via LCM from 178 samples including: 72 ovarian cancers (OC), 57 lung adenocarcinomas (LC), 30 metastatic breast cancers (MBC), and 19 pancreatic cancers (PC). PDL1 expression was measured on a continuous scale using quantitative RPPA based analysis. Each tumor type was processed and arrayed independently. Experimental samples and reference standards used for inter-assay normalization were printed in triplicates. Results: PDL1 expression varied greatly across tumor types. LC were characterized by the greatest intra-tumor fold dynamic range (&gt; 35-fold), followed by OC (&lt; 13-fold), MBC (&lt; 4-fold), and PC (&lt; 2-fold). PDL1 expression of 46/57 (80.7%) LC, 17/30 (56.7%) MBC, 6/19 (31.5%) PC, and 20/72 (27.8%) OC was greater than the population median of all tumors combined. Within the LC samples with PDL1 expression equal to the top quartile of the population, 10 (71.4%) were KRAS mutant lesions and 4 (28.6%) were WT tumors. Finally, amongst LC and PC harboring a KRAS mutation, PC showed an overall lower expression of PDL1 with only 2/19 (10.5%) cases been above the population median and none within the top quartile of the population. Conclusions: The LCM-RPPA workflow has the unique ability to capture immune checkpoint expression on a continuous quantitative scale as well as capture its broad dynamic range. Because RPPA is unconstrained by antigen retrieval issues as well as subjectivity of IHC interpretation, this approach may generate more accurate cut-point of therapeutic response prediction. Overall the dynamic range of PDL1 was broader in LC compared to other solid tumors, and LC had a much higher proportion of patients with tumors expressing high levels of PDL1. These quantitative differences may explain therapeutic efficacy of PDL1 inhibition across tumor types. Such speculative hypothesis should be further validated in prospective clinical trials. Finally, these preliminary data suggest that organ specific microenvironments more than specific driving mutations (e.g. KRAS) may strongly influence PDL1 expression in malignant lesions. Citation Format: Elisa Baldelli, Valerie Calvert, K. Alex Hodge, Maria Isabella Sereni, Guido Gambara, Eric B. Haura, Lucio Crino', Bryant Dunetz, Sergio Pecorelli, David J. Perry, Stephen P. Anthony, Nicholas Robert, Donald W. Northfelt, Mohammad Jahanzeb, Emanuel F. Petricoin, Mariaelena Pierobon. Quantitative measurement of PDL1 expression across tumor types using laser capture microdissection and reverse phase protein microarray [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5656. doi:10.1158/1538-7445.AM2017-5656

LBA506 Background: MA.17R is a Canadian Cancer Trials Group (CCTG) led phase III randomized controlled trial comparing letrozole to placebo after 5 years of aromatase inhibitor (AI) as adjuvant therapy for hormone-receptor positive breast cancer. The primary endpoint was disease-free survival. Quality of life (QOL) was a secondary endpoint. Methods: QOL was measured with the SF-36 (2 summary scores and 8 domains) and menopause-specific QOL (MENQOL) (4 symptom domains) at baseline and every 12 months (mo) up to 60 mo. QOL assessment was mandatory for CCTG centres but optional to centres in other groups. Mean change scores from baseline were calculated at 12 and 36 mo. Between-arm differences were assessed with the Wilcoxon test. Results: 1918 patients were randomized and 1428 patients completed the baseline QOL assessment. Compliance with QOL measures was over 85%. Baseline summary scores for SF-36 physical (PCS, 47.5 for letrozole and 47.9 for placebo) and mental (MCS, 55.5 for letrozole and 54.8 for placebo) were close to population norms (50). No differences were seen between groups in mean change scores for the SF-36 PCS and MCS and the other 8 QOL domains. Patients randomized to letrozole reported worse vasomotor symptoms (12 mo p = 0.02, 36 mo p = 0.03) and worse sexual functioning (12 mo p = 0.01, 36 mo p = 0.01). Further analyses with follow up to 60 months will be presented. Conclusions: No differences were seen in overall QOL measured by the SF 36 summary measures between letrozole and placebo groups. Differences existed for vasomotor symptoms and sexual functioning which were worse in the letrozole group and attributed to improvements in mean scores seen for women randomized to placebo. The data indicate that continuation of AI therapy after 5 years prior treatment is not associated with a deterioration of overall QOL. Treatment related vasomotor and sexual functioning alterations occur with ongoing treatment. Clinical trial information: NCT00754845.