Research Biopsies Research Articles

Prexasertib, a cell cycle checkpoint kinase 1 inhibitor, in BRCA mutant recurrent high-grade serous ovarian cancer (HGSOC): A proof-of-concept single arm phase II study.

6038 Background: Preclinical data suggest cell cycle checkpoint inhibition induces greater cell death in BRCA mutant HGSOC by causing replication stress and dysregulation of DNA damage responses. We hypothesized that prexasertib, a cell cycle checkpoint kinase 1 (CHK1) inhibitor, would be active in BRCA mutated HGSOC patients. Methods: We conducted a single center, two-stage phase II study of prexasertib (105mg/m2 IV every 2 weeks) in HGSOC patients with known germline or somatic BRCA mutations. The primary endpoint was RECIST response rate (RR). Progression-free survival (PFS) and safety (CTCAE v4) were secondary endpoints. Baseline research biopsies and blood samples were collected for exploratory biomarker endpoints. Results: Between February 2015 and July 2019, 22 heavily pretreated (median 5 prior systemic therapies [1-12]) women with BRCA mutant HGSOC (median age 58.7 [44-74.8]) received at least one dose of prexasertib. 13 (59%) patients were secondary platinum-resistant (median 8 [3-12] prior therapies) and 9 (41%) maintained platinum-sensitivity (median 4 [1-5] prior therapies). All but one received prior PARP inhibitor (PARPi) either in combination (10 [48%]) or as monotherapy (11 [52%]), with a median 5 month [mo; 1-29] PARPi-free interval prior to study entry. There was one complete response (41+mo, platinum-sensitive, no prior PARPi) and one partial response (9+mo, platinum-sensitive, 13.5mo PARPi-free interval) yielding an 11% RR (2/18 evaluable). No response was seen in platinum-resistant patients with prior PARPi. Median duration on study treatment was 4mo [1-9] among 21 patients with prior PARPi and 4mo [1.5-9] among 17 evaluable patients with prior PARPi. Common (>10%) grade 3/4 adverse events were neutropenia (82%), leukopenia (64%), and thrombocytopenia (14%); only one patient had grade 3 febrile neutropenia. 16 of 18 (89%) patients with grade 3/4 neutropenia received prophylactic growth factors for subsequent treatments. Conclusions: Prexasertib is tolerable and has modest activity in heavily pretreated BRCA mutant HGSOC patients. Further evaluation of predictive biomarkers for exceptional responders is ongoing. Clinical trial information: NCT02203513.

High intratumoral tryptophan metabolism is a poor predictor of response to pembrolizumab (pembro) in metastatic melanoma (MM): Results from a prospective trial using baseline C11-labeled alpha-methyl tryptophan (C11-AMT) PET imaging for response prediction.

3556 Background: Molecular imaging of metabolic pathways critical for effector T cell response other than glucose could predict response to PD1 inhibitors. We have previously shown that high expression of tryptophan metabolic pathway enzymes in stage III/IV melanoma correlates with reduced abundance of tumor-infiltrating lymphocytes (TILs, ASCO 2019, e21014). Here we investigated C11-AMT, a PET tracer that images tryptophan metabolism, as a predictor of response to pembro in patients (pts) with PD1 inhibitor-naïve MM. Methods: In this trial (NCT03089606) pts must have had measurable MM by RECIST, have undergone IV contrast CT, FDG-PET, and C11-AMT PET scan (30-40 min dynamic imaging), plus a mandatory tumor biopsy prior to pembro treatment. Results: 21 pts (16 males; 15 stage IV; median age 61) had all 3 baseline scans and evaluable research biopsies. 13 pts were non-progressors (CR = 4, PR = 6, and SD = 3). At a median f/u of 13.7 mons (2.8-25.1+), 6 pts are dead from MM, 11 are alive without MM and 4 are alive with MM. 46 tumor lesions were assessed by all 3 scans. Of the pts with tumor lesion, C11-AMT PET SUVmax < 7 and skewness < +0.3 of the tumor lesion with the highest C11-AMT SUVmax was associated with non-progression by RECIST (SUVmax < 7/skewness < +0.3 in progressors vs. non-progressors; Fisher’s 2-tail test p= 0.055). The corresponding association between baseline FDG-PET (SUVmax < 14 and skewness < +0.3) with treatment response was insignificant ( p= 0.08). There was a weak (Spearman ρ= 0.33) but significant correlation ( p= 0.001) in SUVmax between FDG-PET and C11-AMT among the 46 tumors analyzed. There was no significant correlation between melanoma-specific expression of the tryptophan- (TPH1, TPH2, IDO1, TDO2, LAT1) and glucose-metabolizing enzymes (GLUT1, HK1, HK3) by immunohistochemistry. Response to pembro trends to associate with present TILs (Fisher’s p= 0.087). Conclusions: Baseline C11-AMT PET imaging using simple radiomics measures (highest metabolic activity, SUVmax, and tumor heterogeneity, skewness) may better predict clinical benefit from pembro in MM than FDG PET. Variability in C11-AMT’s SUVmax cannot be solely explained by FDG-PET’s SUVmax, suggesting that these two imaging modalities may provide complementary information about intratumoral metabolic dysregulation that may relate with pembro response. Texture analysis using LifeX v4.0 will be presented at the meeting. Clinical trial information: NCT03089606 .

A phase II trial of nivolumab (NIVO) + palbociclib (PAL) + anastrozole (ANA) in postmenopausal women and men with estrogen receptor (ER)+/human epidermal growth factor 2 (HER2)- primary breast cancer (BC): CheckMate 7A8.

TPS1105 Background: Cyclin-dependent kinase 4/6 (CDK 4/6) inhibition coupled with ER signaling blockade is an efficient treatment approach for patients (pts) with metastatic hormone receptor-positive, HER2− BC. Preclinical data suggest synergistic activity of CDK 4/6 inhibition and PD-1 blockade; in a syngeneic mouse tumor model, improved efficacy and complete tumor regression were observed with phased administration of ABE + PD-L1 therapy. Methods: CheckMate 7A8 (NCT04075604) is a randomized, noncomparative, multicenter, phase 2 study evaluating PAL + ANA +/- NIVO in postmenopausal pts with ER+, HER2− primary BC. After determining safe doses for NIVO combination regimens in the safety run-in phase, pts will be randomized in a 4:4:3 ratio to 1 of 3 treatment arms (Table) stratified by PD-L1 expression, node status and tumor size. Following treatment, all pts will undergo surgery and safety follow-up. Eligible pts are postmenopausal women and men with newly diagnosed, untreated, histologically confirmed ER+, HER2− BC with primary tumor ≥ 2 cm; suitable for neoadjuvant endocrine monotherapy and surgery; ECOG PS of 0–1; have baseline tumor tissue available; willing to undergo on-treatment research biopsy and tissue collection at surgery. Primary endpoints are number of pts with occurrence of dose-limiting toxicity (safety run-in phase) and residual cancer burden 0–I rate by central assessment at time of definitive surgery (randomized phase). Secondary endpoints include safety and tolerability, pathologic complete response, objective response rate and breast-conserving surgery rate. Key exploratory endpoints include biomarkers indicative of pharmacodynamic changes and potentially predicting treatment sensitivity. Interim analyses are planned. The study is currently enrolling. Clinical trial information: NCT04075604 . [Table: see text]

Radioiodine (RAI) in combination with durvalumab for recurrent/metastatic thyroid cancers.

6587 Background: Immune checkpoint blockade (ICB) has limited efficacy for radioiodine-refractory thyroid cancer. The high incidence of autoimmune thyroid disease and ICB-induced hypothyroidism suggests that loss of T cell tolerance to thyroid protein epitopes is common and can be activated by ICB to induce immune responses. We hypothesize that RAI can enhance presentation of thyroid protein immunogens and putative neoantigens in thyroid cancers to amplify the effectiveness of ICB. We studied the safety and efficacy of RAI plus the anti-PD-L1 agent durvalumab (durva) in recurrent/metastatic (R/M) patients (pts). Methods: Pts. had at least one RAI-avid tumor on the most recent RAI scan or one tumor on FDG PET with an SUVmax < 10. RECIST measurable disease was required. Any number of prior therapies was allowed. Pts were treated with durva 1500 mg IV every 4 weeks with recombinant human TSH (rhTSH)-stimulated RAI (100 mCi) administered in Cycle 1. Treatment beyond progression was allowed. The primary objective was to assess safety. Durva related dose limiting toxicities (DLTs) were monitored for 6 weeks after the first dose. Since no durva DLTs were observed in the first 6 pts, per protocol rules the trial accrued 11 pts total. Secondary objectives were assessing best overall response (BOR) per RECIST and progression-free survival (PFS). Results: 11 pts (7 female) were enrolled. Eight had prior drug therapy. No DLTs or > Grade 3 durva related adverse events (AEs) were observed. The most common non-laboratory AEs (regardless of attribution) were cough (7), hypertension (7), pain (6), edema (5), and fatigue/nausea/diarrhea/arthralgia/dry skin/dyspnea/edema (4 each). As of 2/6/20, 2 had partial response, 7 stable disease, and 2 progression of disease as BOR. Six pts had tumor regression. Four pts received treatment for > 6 months. Six are still on treatment. Analyses of research biopsies (bxs) (8 had pre-treatment bxs, 6 had an additional on-treatment bx) will be presented. Conclusions: Durva plus RAI is safe and well tolerated. The preliminary efficacy signal in this small cohort is promising. Understanding how RAI plus PD-L1 targeting impacts the tumor immune microenvironment may guide how RAI should be evaluated in future ICB trials. Clinical trial information: NCT03215095 .

How COVID-19 Has Changed the Management of Glomerular Diseases.

A 26-year-old woman contacted our office asking for an urgent call back. She had a history of steroid-dependent and frequently relapsing minimal change disease, and calls like this usually meant her home dipsticks had turned positive. Instead, she reported that she had just tested positive for the

Abstract OT1-01-02: Neoadjuvant pembrolizumab + decitabine followed by standard neoadjuvant chemotherapy for locally advanced HER2-breast cancer

Abstract Background: Higher levels of tumor-infiltrating lymphocytes (TIL) in breast cancers are associated with increased likelihood of pathologic complete response (pCR) to chemotherapy and improved outcomes. DNA methyltransferase inhibitors (DNMTi) can augment immune responses to cancers by upregulating tumor antigen expression, increasing MHC Class I expression and antigen presentation, decreasing numbers and activity of myeloid derived suppressor cells (MDSC) and increasing responsiveness of T lymphocytes. We have shown that decitabine augments the effectiveness of immunotherapy against murine triple negative breast cancer (TNBC). Trial design: Patients with HER-2-negative breast cancer who are candidates for neoadjuvant chemotherapy will receive decitabine (15 mg/kg x 4 doses over 5 days) followed by 2 doses of pembrolizumab (200 mg, 2 weeks apart) prior to starting neoadjuvant chemotherapy. Two research biopsies are obtained - 1 prior to the window immunotherapy and 1 afterwards, prior to starting chemotherapy. Chemotherapy regimens: TNBC - ddAC X 4 followed by weekly Taxol + Carboplatin X 12; HR+ - ddAC X 4 followed by weekly Taxol X 12. After the safely lead-in, the sequence of regimens can be reversed, per treating physician preference. Safety Lead-In: During immunotherapy and dose-dense AC in the first 11 patients enrolled and who have received at least 3 doses of decitabine and at least 1 dose of pembrolizumab, clinically significant immune related adverse events (irAEs) will be reported in an expedited manner. Accrual was halted until the safety lead-in phase was completed. Brief Eligibility criteria: Primary breast cancer, candidates for neoadjuvant chemotherapy Cohort A: TNBC (ER<10%, PR<10%, Her-2 negative) cT2, N1 or N2 cT2, 3-5 cm, N0 Any T3 or T4 Cohort B: ER+ or PR+, Her-2 negative cT2, N1 or N2 Any T3 or T4ECOG status 0-1 No Active autoimmune diseases Absence of metastatic disease too extensive to consider surgery for the primary Specific aims: Primary endpoint: Changes in Lymphocyte infiltration - by 10-15% Tumor area Stromal area Secondary endpoints: Gene expression (Nanostring) Multiplex Cell Markers (DAPI/CD4/CD8/FOXP3/CK/PDL1/PDL2, and MDSCs) pCR Percentage of patients with lymphocyte-predominant breast cancer Correlation of PD-L1 expression with pCR MDSC in blood samples pre- and post- window portion Sample Size and Statistical methods: Cohort A (TNBC) is the primary target group in this trial. When Cohort A has achieved its required sample size of 28 evaluable patients, Cohort B (HR+) will be closed to accrual irrespective of accrual to that cohort. However, in the unlikely event that accrual to Cohort B occurs at a faster rate than in Cohort A, Cohort B will be capped at 18 patients. Therefore, the projected sample size for this study is 32-50 patients. A one-sided paired t-test will be used to compare baseline and post-treatment percentage of tumor and stromal areas with infiltrating lymphocytes. The paired t-test will be applied separately to Cohorts A and B. Present accrual and target accrual: 12 subjects have been accrued; 1 withdrew prior to any protocol therapy. The 11 patient safety lead-in has been completed. As described above, the projected total sample size is 32-50 patients. Citation Format: Harry Douglas Bear, Michael O. Idowu, Andrew Poklepovic, Adam Sima, Maciej Kmieciak. Neoadjuvant pembrolizumab + decitabine followed by standard neoadjuvant chemotherapy for locally advanced HER2-breast cancer [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 OT1-01-02.

Abstract P5-11-04: A phase I/IIb study of palbociclib (PALBO) plus everolimus (EVE) and exemestane (EXE) in hormone-receptor positive (HR+)/HER2- metastatic breast cancer (MBC) after progression on a CDK4/6 inhibitor (CDK4/6i): Results of the phase II study

Abstract Background: For patients (pts) with HR+ /HER2- MBC, the optimal regimen following disease progression on the combination of a CDK4/6i plus endocrine therapy (ET) is unknown, and there is a need to evaluate whether continued CDK 4/6 blockade is beneficial in subsequent lines of therapy. Methods: We developed an investigator initiated Phase I/II, open-label trial (NCT02871791) of triplet therapy: palbociclib (PALBO; CDK4/6i) + everolimus (EVE; mTOR inhibitor) + exemestane (EXE; ET) in men or postmenopausal women with measurable HR+ /HER2− MBC who had progressed on prior CDK4/6i and a non-steroidal aromatase inhibitor (NSAI). Pts may have received any number of prior lines of ET, and 0-1 prior line of chemotherapy. Exclusion criteria included prior use of mTORi or EXE. The primary objective was to estimate efficacy of the combination, defined as the clinical benefit rate (CR+PR+SD>6mo). With a one-sided alpha of 0.1, the study had 90% power to detect an improvement in CBR from 40% to 65%. The phase I determined RP2D to be PALBO 100 mg/day (21 of 28 days) + EVE 5mg/day + EXE 25mg/day (previously presented). For pts who entered into the phase IIa part of the study, a research biopsy at baseline and serial research blood collection for circulating tumor DNA (ctDNA) analysis were mandatory. The tumor tissue underwent whole exome sequencing and RNA sequencing and the ctDNA underwent whole exome sequencing. Here we present the first results of the phase 2 study of this triplet regimen. Results: As of June 29, 2019, after a median follow up of 3.8 (2.8-6.2) months, 32 patients were evaluable in the phase II portion of the study. The triplet combination was associated with a clinical benefit rate of 12.5% (n=4), which did not meet the predefined primary endpoint threshold (65%). There were no objective responses achieved. The median PFS was 3.8 (95%CI: 2.0-8.4) months and the 1-year PFS was 16.1% (95%CI: 3.1%-38.0%). The most common AEs were mucositis (all grades, 87.5%; grade 3/4, 15.6%), neutropenia (all grades 84.4%; grade 3/4, 71.9%), and fatigue (all grades 53.1%; grade 3/4, 0%). Data regarding genomic alterations and its association with outcomes will be presented. Conclusions: Among patients with metastatic HR+/HER2- MBC who had previous progression on a NSAI and a CDK 4/6i, there did not appear to be benefit from the addition of PALBO to EXE and EVE, but there were added toxicities. These findings suggest further evaluation of this triplet combination in patients with CDK 4/6i resistance is not warranted. Genomic data from baseline biopsies and circulating tumor DNA will be presented and may help us to explain why patients included in this study were intrinsically resistant to the triplet. Citation Format: Romualdo Barroso-Sousa, Tianyu Li, Lorenzo Trippa, Rebecca Rees, Chelsea Andrews, Arlindo R Ferreira, Karla Helvie, Ann H Partridge, Beth Overmoyer, Eric P Winer, Nikhil Wagle, Sara M Tolaney. A phase I/IIb study of palbociclib (PALBO) plus everolimus (EVE) and exemestane (EXE) in hormone-receptor positive (HR+)/HER2- metastatic breast cancer (MBC) after progression on a CDK4/6 inhibitor (CDK4/6i): Results of the phase II study [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 P5-11-04.

Abstract P2-16-03: Neoadjuvant treatment of triple negative breast cancer patients with docetaxel and carboplatin to assess anti-tumor activity

Abstract Background: Anthracycline- and taxane-based neoadjuvant chemotherapy (NAT) in triple negative breast cancer (TNBC) patients yields a pathological complete response (pCR) rate of approximately 45%. Anthracyclines can lead to long-term toxicities including congestive heart failure and leukemia. TNBC patients achieving pCR have excellent long-term outcomes irrespective of NAT regimen. This study was designed to evaluate the efficacy of a non-anthracycline NAT regimen with carboplatin and docetaxel in TNBC. Correlative studies include detecting and tracking plasma circulating tumor DNA (ctDNA) to determine if it will predict clinical outcomes, and whole exome sequencing (WES) on tissue samples to decipher the genomic architecture of those who achieve pCR versus those who do not. Methods: This is a joint analysis of two identical multicenter trials. Eligible patients with AJCC 7 clinical stages II and III TNBC received docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks X 6 cycles. Following NAT, all patients underwent definitive surgery. The primary endpoint is pCR (no invasive tumor in the breast and axilla). Secondary objectives include evaluating ctDNA as a prognostic biomarker that may be used in identifying TNBC patients at a high risk of disease relapse, and evaluating differences in the genomic architecture between pCR and non-pCR patients. Patients have a research biopsy at baseline, cycle 1 day 3 (optional), and at definitive surgery for those with residual disease. Plasma for ctDNA is collected at baseline, cycle 1 day 3, at definitive surgery, and every 6 months for 5 years. Results: Between 2014 and 2019, 103 patients have been registered. Median age is 53 years (range 25-74), 27.2%: African-American, 77.7%: clinical stage II. Ninety-nine have completed NAT and have had surgery. In the intent to treat population, the preliminary pCR rate is 46.5% (95% CI 36.9% - 56.2%). Nine (8.7%) have developed recurrent disease, and 7 (6.8%) have died. Preliminary ctDNA results from 6 patients (4 non-pCR, 2 pCR) show that ctDNA is detectable in 67%. We identified 627 somatic variants by exome analysis. Of these, 10 variants overlapped with the Swift panel (Accel-Amplicon™ 56G Oncology Panel v2) used for ctDNA sequencing and variant detection. TP53 variants were identified in all 6 patients’ tumor tissue samples. At least one TP53 variant was identified in 4 patients’ baseline pre-chemotherapy ctDNA. Both pCR patients had either no detectable ctDNA TP53 mutations, or clearance of ctDNA following chemotherapy. Three non-PCR patients had persistent TP53 mutations in ctDNA during the treatment course. WES and ctDNA analysis on all patients is currently ongoing. Conclusions: We report a very encouraging pCR rate of 46.5% in TNBC patients with carboplatin and docetaxel NAT. This rate is similar to observed rates with anthracycline- and taxane-based NAT and may represent an option for treatment for TNBC patients. Correlative genomic and ctDNA studies are ongoing. Clinical trial information: NCT02124902 & NCT02547987. Citation Format: FOLUSO O ADEMUYIWA, Mothaffar F Rimawi, Tracy Summa, Jingqin Luo, Tao Wang, Rama Suresh, Lindsay Peterson, Michael Naughton, Ashley Frith, Leonel Hernandez-Aya, Katherine Weilbaecher, Cynthia Ma, Aadel A Chaudhuri, Yang-Yang Feng, Zachary L Skidmore, Obi L Griffith, Malachi Griffith, Matthew Ellis. Neoadjuvant treatment of triple negative breast cancer patients with docetaxel and carboplatin to assess anti-tumor activity [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 P2-16-03.

Abstract P3-08-20: The normal breast Active transcriptome associated with future breast cancer risk is driven by a dysregulated adipocyte microenvironment

Abstract Background: Previous studies of breast samples from cosmetic surgeries, benign biopsies associated with abnormal mammograms or cancer-adjacent tissue have identified at least two different transcriptional phenotypes of “normal” human breast tissue (Troester, 2009; Haakensen, 2011), including an “Active” phenotype linked to increased risk of later breast cancer mortality (Roman-Perez, 2012; Troester, 2016). This study compares breast histology and transcriptional phenotypes from healthy parous women with no prior history of breast disease who donated breast core biopsies for research and supplied reproductive histories enabling breast cancer risk calculation. Since the Active transcriptome phenotype was recently associated with increased mammary adipocyte content, we focused on the possibility that adipocyte activation contributes to the Active transcriptome and drives breast cancer risk. Methods: RNA from paraffin-embedded tissue sections sufficient for RNAseq analysis (~100ng) was extracted from 151/200 core biopsies donated to the Komen Tissue Bank by healthy, parous white women (age range: 27-66, median = 45) with no history of breast cancer. Questionnaire data enabled breast cancer risk (Gail) score calculation; and digitized H&E images were used for histologic analyses. A previously validated classifying signature was used in unsupervised hierarchical clustering to identify samples with Active (78/151) vs. Inactive (73/151) transcriptome phenotypes for comparison with donor risk factors, breast tissue composition, and expression of candidate genes and gene signatures. Results: Mean (+/-SD) BMI and Gail score values were 29.60 (+/-7.92) and 1.27 (+/- 1.34), respectively; BMI scores were not significantly different by phenotype, but Gail scores were significantly higher for donors with an Active phenotype (1.46 vs. 1.18; p=0.007, Wilcoxon rank-sum). Active normal breast tissue samples possessed significantly more (%) adipocyte nuclei (p=3.9e-11) and greater adipocyte size (p<0.01), with fewer (%) stromal (p=4.3e-7) and (%) epithelial (p=1.2e-10) nuclei. Differentially expressed genes between the Active and Inactive phenotypes were significantly enriched for gene sets (GSEA) involved in fat differentiation and metabolism (14% at FDR q≤10%). Signature scores for cAMP-dependent lipolysis (known to drive breast cancer progression), as well as white adipose tissue “browning,” were significantly higher (Wilcoxon p<0.01) for the Active samples, as were specific genes reflecting adipocyte activation (leptin, adiponectin), remodeling (CAV1, BNIP3), adipokine growth factors (IGF-1, FGF2), and pro-inflammatory fat signaling (IKBKG, CCL13). Conclusion: In this cohort of predominantly non-obese women without breast disease, ~50% express an Active transcriptome phenotype previously linked to later-life breast cancer mortality. While >80% of this donor cohort would not qualify for breast cancer chemoprevention, those with Active transcriptomes had significantly higher Gail scores supporting their increased future risk for breast cancer development. The Active breast transcriptome is strongly associated with increased adipocyte content, size, and overexpression of signatures and genes (including those previously linked to breast cancer progression) indicating a differentially activated adipocyte population. This dysregulated mammary adipocyte microenvironment not only appears to underlie the Active transcriptome phenotype but also precedes and potentially predicts the future histologic development of breast cancer. Citation Format: Christopher C Benz, Taekyu Kang, Christina Yau, Chris Wong, Yulia Newton, Charlie Vaske, Stephen C Benz, Gregor Krings, Roman Camarda, Jill E Henry, Josh Stuart, Mark Powell. The normal breast Active transcriptome associated with future breast cancer risk is driven by a dysregulated adipocyte microenvironment [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 P3-08-20.

Abstract P2-21-01: Feasibility of a multidisciplinary diagnostic breast research biopsy project

Abstract Background: The comprehensive analysis of clinically annotated tissue specimens from those with either benign, high risk or malignant breast findings is critical to improve the understanding of breast cancer biology and treatment. Through a multidisciplinary team approach, we designed a protocol to allow a breast research biopsy to be collected with informed patient consent concurrent with the diagnostic biopsy at our institution. Here we describe the feasibility of the project. Methods: IRB approval was obtained for the prospective collection and storage of clinically-annotated specimens, including breast biopsy cores, excess surgical tissue from breast surgery, and optional blood collection. Potential participants are identified through the list of scheduled breast biopsies at the Massachusetts General Hospital breast imaging center. Eligible patients are those ≥ age 18 undergoing a clinical breast biopsy. Research consent is obtained in the procedure room immediately following the clinical consent process and prior to the clinical biopsy. Following completion of standard clinical biopsy workflow, two research core biopsy specimens are obtained with a core biopsy needle ranging from 9 to 18 gauge. The first research specimen is flash frozen and stored on dry ice to preserve high molecular weight DNA and RNA. The second sample is cryopreserved in DMSO or a related agent to allow viable cell recovery. All consented patients are entered into a prospective database in REDCap. Medical records of the participating patients are reviewed periodically to collect data on patient demographics, tumor characteristics, and long-term outcomes. Results: From 1/17/19 through 6/28/19, 144 patients were approached. 77.8% of patients consented, resulting in 96 lesions being biopsied for research. Of these, 45.8% were invasive carcinoma, 3.1% were DCIS, 6.1% were high risk lesions, and 44.8% were benign. Among the invasive breast cancers, 78.6% were hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-), 9.5% were HER2+, and 11.9% were triple negative. Conclusion: We demonstrated that an upfront breast research biopsy program in patients presenting for initial diagnostic breast biopsy is feasible, with high rates of patient participation. Overall, 77.8% of approached subjects agreed to a concurrent research breast biopsy at the time of diagnostic biopsy. This approach may provide a high yield mechanism to generate a rich tissue repository with low cost and marginal additional time commitment by patient and providers that can support novel, cross-disciplinary research. A number of collaborative research projects are planned. Citation Format: Kassidy Beyerlin, Christine Edmonds, Siang Boon Koh, Veerle Bossuyt, Annie Ma, Rachel Jimenez, Michelle Specht, Barbara L Smith, Brian Dontchos, Dennis Sgroi, Steven J Isakoff, Constance Lehman, Leif W Ellisen, Laura M Spring. Feasibility of a multidisciplinary diagnostic breast research biopsy project [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 P2-21-01.

Abstract OT2-04-02: CheckMate 7A8: A phase 2 trial of nivolumab + abemaciclib or palbociclib + anastrozole in postmenopausal women with ER+, HER2−primary breast cancer

Background: Programmed death-1 (PD-1) pathway inhibition has demonstrated clinical activity in breast cancer (BC), with modest response rate in advanced, heavily pretreated, hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−) BC. Cyclin-dependent kinase 4/6 (CDK 4/6) inhibition coupled with estrogen receptor (ER) signaling blockade is an efficient treatment approach for patients with metastatic HR+/HER2− BC, evaluated in the primary setting. Preclinical data suggest potential synergistic activity of CDK 4/6 inhibition coupled with PD-1 blockade through modulation of the tumor microenvironment by the former modality. In a syngeneic mouse tumor model, improved efficacy and complete tumor regression were observed with abemaciclib priming the immune response in phased administration of abemaciclib + anti-programmed death ligand 1 (PD-L1) therapy. Preliminary clinical data demonstrated activity of pembrolizumab + abemaciclib in a phase 1b study of pretreated patients with metastatic HR+, HER2− BC. Trial Design: CheckMate 7A8 is a randomized, noncomparative, multicenter, phase 2 study evaluating nivolumab + either abemaciclib or palbociclib + anastrozole in postmenopausal patients with ER+, HER2− primary BC. After determining safe doses for the nivolumab combination regimens in the safety run-in phase, patients will be randomized in a 4:4:3:4:4:3 ratio to 1 of 6 treatment arms (Table) stratified by PD-L1 expression (+ or −), node status (+ or −), and tumor size (> 3 cm or ≤ 3 cm). Following treatment, all patients will undergo surgery and safety follow-up. Eligible patients are postmenopausal women with newly diagnosed, untreated, histologically confirmed ER+, HER2− BC with primary tumor ≥ 2 cm; with measurable disease based on RECIST v1.1; suitable for neoadjuvant endocrine monotherapy and surgery; have an ECOG PS of 0 or 1; have tumor tissue available at baseline; and are willing to undergo on-treatment research biopsy and tissue collection at surgery. Women of childbearing potential or who are breastfeeding, have a history of ipsilateral invasive BC regardless of treatment or DCIS treated with radiotherapy, metastatic disease, inflammatory/inoperable, multicentric, or bilateral invasive BC, or those suitable for neoadjuvant chemotherapy are excluded. Primary study endpoints are: i) number of patients with occurrence of dose-limiting toxicity (safety run-in phase), and ii) residual cancer burden (RCB) 0-I rate by central assessment at time of definitive surgery (randomized phase). Secondary endpoints include safety and tolerability, pathologic complete response, and objective response rate. Key exploratory endpoints include biomarkers indicative of pharmacodynamic changes in the tumor microenvironment, biomarkers predicting treatment sensitivity, changes in Ki67 levels, ER status and preoperative endocrine prognostic index score, and efficacy by PD-L1 status. Sample size was calculated assuming a 22% target RCB rate; 40 treated patients will provide 81% power at 10% 2-sided type I error to reject the null hypothesis that the true RCB rate is 8%, below which is not clinically meaningful. For primary and secondary endpoints, estimates of response rates and corresponding 95% confidence intervals will be generated for each arm using the Clopper-Pearson method. No patients have yet been recruited. For information, please contact Xiaochun.Liu@bms.com. Citation Format: Sara Tolaney, Guy Jerusalem, Roberto Salgado, Xiaochun Liu, Tian Chen, Hongxia Zhang, Mustimbo Roberts, Dimitrios Zardavas, Aleix Prat. CheckMate 7A8: A phase 2 trial of nivolumab + abemaciclib or palbociclib + anastrozole in postmenopausal women with ER+, HER2−primary breast cancer [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 OT2-04-02.

Abstract OT1-08-01: A phase Ib trial of sequential combinations of BN-brachyury, entinostat, ado-trastuzumab emtansine (T-DM1) and bintrafusp alfa (M7824) in advanced stage breast cancer (BrEAsT)

Abstract Immune checkpoint blockade (ICB) monotherapy has produced limited benefit in breast cancer (BC) with response rates (RR) ranging from 5 to 23%. Combination ICB improved RR and progression free survival (PFS) resulting in atezolizumab + nab-paclitaxel receiving FDA accelerated approval for programmed cell death ligand 1 (PD-L1) positive, triple negative breast cancers (TNBC). BC has historically been considered immunologically quiet with most having a low mutational burden, low PD-L1 expression, defective antigen presentation machinery, and immuosuppressive signals in the tumor microenvironment (TME). An approach using a combination of immuno-oncology (IO) agents including ICB, immunomodulators and vaccines may shift the TME to allow for improved antigen presentation, the release of immunostimulatory cytokines, more immunogenic cell death and increased PD-L1 expression. The transcription factor brachyury plays an important role in breast tumor plasticity. High brachyury expression is associated with treatment resistance and a worse prognosis. Entinostat is a histone deacetylase inhibitor that has activity in multiple breast cancer subtypes. Preclinical data demonstrates entinostat upregulates MHC, enhances immune-mediated lysis and upregulates PD-L1 expression through epigenetic modification. Bintrafusp alfa is a bifunctional protein composed of the extracellular domain of the TGF-βRII receptor (TGF-β“trap”) fused to a human IgG1. Preclinical data shows bintrafusp alpha treatment increases T-cell trafficking, antigen-specific CD8+ T-cell lysis and NK cell activation. Monotherapy clinical studies with these agents have produced modest results in solid tumors, including BC. Preclinical data evaluating combinations of these agents shows a reduction in in tumor size, improved antigen-specific T-cell responses, reduced regulatory T cells, increased CD8+T-cells, and increased PD-L1 expression. We propose the stepwise addition of BN-Brachyury, Bintrafusp alfa, T-DM1 and Entinostat in advanced BC. This phase Ib study will assess efficacy and safety of the regimen and has three cohorts: Cohort 1(TNBC) will receive BN-Brachyury + Bintrafusp alfa. Cohort 2 (HER2+) will receive T-DM1 + BN-Brachyury + Bintrafusp alfa +/- entinostat. After safety is established in Cohort 2, patients in Cohort 3 (HER2+) will be assigned to receive T-DM1 + BN-Brachyury + Bintrafusp alfa +/- entinostat. Responses are evaluated every 2 cycles (6 weeks). Patients in Cohorts 2 and 3 will undergo research biopsies -baseline and after 2 cycles to evaluate changes within TME. Peripheral immune responses will be evaluated at selected time points. All patients must have measurable disease and HER2+ patients must have biopsiable disease. >1 prior treatment is required. Asymptomatic or brain metastases treated > 6 weeks are allowed. Well controlled HIV, HBV or treated HCV is allowed. Exclusion criteria include symptomatic brain metastases or clinically significant bleeding (<3 months from study entry). Co-primary objectives are RR and safety. Secondary objectives include PFS and changes in tumor infiltrating lymphocytes (Cohorts 2 and 3). Exploratory analyses include changes in immune cells and cytokines in the peripheral blood. Analyses performed will be descriptive, reporting the outcome measure for each treatment arm indicated along with two-tailed 80% and 95% confidence intervals. All cohorts employ a safety assessment in the initial 6 patients and a Simon minimax 2-stage design for clinical efficacy. We plan to recruit 51 patients: 13 patients with TNBC, 38 patients with HER2+BC. This trial will open Fall 2019 at the National Institutes of Health (Bethesda, MD). For more information contact the PI, Margaret.gatti-mays@nih.gov. Citation Format: Margaret E Gatti-Mays, Claudia Palena, Sofia R Gameiro, Renee N Donahue, Caroline Jochems, Seth Steinberg, Stan Lipkowitz, Alexandra Zimmer, Deneise Francis, Julius Strauss, Houssein Abdul Sater, Lisa Cordes, Jason Redman, Fatima Karzai, Marijo Bilusic, Ravi A Madan, James L Gulley, Jeffrey Schlom. A phase Ib trial of sequential combinations of BN-brachyury, entinostat, ado-trastuzumab emtansine (T-DM1) and bintrafusp alfa (M7824) in advanced stage breast cancer (BrEAsT) [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 OT1-08-01.

The development of liquid biopsy for research and clinical practice in lymphomas: Report of the 15-ICML workshop on ctDNA.

This report summarizes a closed workshop cosponsored by the American Association for Cancer Research, the European School of Oncology, and the 15th-International Conference on Malignant Lymphoma to discuss critical open questions on liquid biopsy in lymphoid malignancies, develops a roadmap for their analytical and clinical validation, and prioritizes research areas.

Physician Attitudes on Kidney Biopsies for Research: A Survey Study

Physician Attitudes on Kidney Biopsies for Research: A Survey Study

Abstract B58: A phase I/II study of durvalumab and stereotactic radiotherapy in locally advanced pancreatic cancer

Abstract Purpose/Objective: Blockade of the PD-1/PD-L1 pathway with radiotherapy (RT) can enhance both local and systemic control in varying tumor types. Yet, no significant responses have been seen in pancreatic cancer (PC). We have previously shown that RT induces PD-1 and PD-L1 in PC following upregulation of interferon-gamma. This mechanism of adaptive immune resistance by PC may serve as an ideal therapeutic target for combined RT and PD-L1 blockade. We report interim results of an ongoing phase 1/2 clinical trial in locally advanced (LA) and borderline resectable (BR) PC (NCT03245541). Materials/Methods: Patients with LA or BR PC treated with standard-of-care gemcitabine and nab-paclitaxel for 3 to 6 cycles were enrolled. Treatment consisted of durvalumab (750 mg Q14 days) on D1. Stereotactic ablative radiotherapy (SABR; 6.6 Gy/fraction) was delivered every other day x 5 fractions beginning D8. Durvalumab continued as maintenance Q14 days until resection or progression. The run-in phase I utilized a standard 3+3 design prior to phase 2 expansion. Dose-limiting toxicities (DLTs), adverse events (AEs), and serious adverse events (SAEs) were assessed during the first 10 weeks of study treatment. CT scans were obtained every 2 months for response assessment. Endoscopic research biopsies were obtained pre- and 6-8 weeks post-SABR, and weekly blood samples were obtained on D1, weekly for 10 weeks, and then every 2 months until resection or progression to assess for immune correlates of response. Results: From 8/2017-5/2019, 18 of 30 planned patients were enrolled of whom 13 (72%) were LA and 5 (28%) were BR. Median age was 70 and 44% were female. No DLTs were identified in the phase 1 run in, and enrollment in the phase 2 study continues. Median follow-up from diagnosis is 14 months (range 6-26 months). Median cycles of chemotherapy received prior to enrollment were 4. Grade 3 toxicities have been identified in 2 patients (nausea, anorexia). No patients experienced dose-limiting toxicities. Median PFS was 14 months with median OS not reached. 9 of 18 patients have undergone resection and all were margin negative. BOR: PR (54%); CR (6%), SD (34%), PD (6%). Conclusion: To our knowledge, this is the first report of a PD-L1 inhibitor-RT combination in LA PC. The regimen was safe, well tolerated and appears to be clinically active with high rates of margin-negative resection. Citation Format: Richard Tuli, Nicholas Nissen, Simon Lo, Mourad Tighiouart, Veronica Placencio, Andrew Hendifar. A phase I/II study of durvalumab and stereotactic radiotherapy in locally advanced pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B58.

CD20 Targeted CAR-T for High-Risk B-Cell Non-Hodgkin Lymphomas

Background: Chimeric antigen receptor T-cells (CAR-T) targeting CD19 have shown clinical efficacy in high-risk B-cell lymphomas, which has led to approval of 2 such therapies (axicabtagene ciloleucel and tisagenlecleucel) for large B-cell lymphoma after 2 lines of treatment. Despite the promising results, complete remission (CR) is achieved in ~ 50% of patients, and with longer follow-up progression-free survival is around 40%. Therefore, finding effective treatments for high-risk B-NHLs remains an unmet need. CD20 is a proven therapeutic target for B-Cell Non-Hodgkin Lymphomas (B-NHL), supported by previously approved naked and radiolabeled anti-CD20 monoclonal antibodies and a number of studies investigating novel bispecific antibodies targeting this antigen. CD20-targeted CAR-T is another potential adoptive immunotherapy option that could be utilized in combination or sequentially before or after CD19 CAR-T, depending on efficacy. Here, we present our ongoing phase I/II clinical trial investigating safety and efficacy of CD20 CAR-T for high-risk B-NHLs (NCT03277729). Methods: MB-106 is a fully human third-generation CD20 targeted CAR-T with both 4-1BB and CD28 costimulatory domains. In the phase I portion of the study we use a continual reassessment method dose escalation design to find the maximally tolerated dose. Lymphodepletion (LD) chemotherapy consists of fludarabine and cyclophosphamide. Patients (pts) will undergo a mandatory biopsy before LD to confirm the diagnosis and CD20 expression. A repeat research biopsy will be done between 10-16 days after CAR-T infusion (Figure 1). Except for the first patient of each dose cohort, treatment is given in the outpatient setting (Fred Hutch/Seattle Cancer Care Alliance) and pts will only be admitted to the University of Washington Medical Center if clinically indicated after CAR-T infusion. Response to treatment will be assessed on day 28 using Lugano criteria. Patients with relapsed or refractory CD20 positive B-NHL are eligible, including but not limited to DLBCL, primary mediastinal lymphoma, follicular lymphoma or other indolent histologies, and mantle cell lymphoma. Prior treatment with CD19 CAR-T is permitted as long as there is evidence of B-cell recovery in peripheral blood (≥ 20 B cells/µl) as a functional test to rule out persistent CD19 CAR-Ts. Patients need to meet standard organ function criteria and have adequate blood counts (ANC >750, Hb >8.5, Plts >50,000). Patients with significant neurologic conditions, active CNS lymphoma, or need for systemic immunosuppressive therapy are excluded from the study. Disclosures Shadman: Mustang Bio: Research Funding; Verastem: Consultancy; Genentech: Consultancy, Research Funding; Atara Biotherapeutics: Consultancy; Pharmacyclics: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Celgene: Research Funding; Sound Biologics: Consultancy; TG Therapeutic: Research Funding; Acerta Pharma: Research Funding; Sunesis: Research Funding; Gilead: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; BeiGene: Research Funding; Astra Zeneca: Consultancy. Gopal:Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding. Smith:Pharmacyclics: Research Funding; Genentech: Research Funding; Ignyta (spouse): Research Funding; Portola Pharmaceuticals: Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Ayala (spouse): Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma BV: Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Incyte Corporation: Research Funding; Seattle Genetics: Research Funding; Denovo Biopharma: Research Funding. Lynch:Juno Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A: Research Funding; Takeda Pharmaceuticals: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Incyte Corporation: Research Funding; T.G. Therapeutics: Research Funding. Ujjani:Pharmacyclics: Honoraria; PCYC: Research Funding; Gilead: Consultancy; Astrazeneca: Consultancy; Atara: Consultancy; Genentech: Honoraria; AbbVie: Honoraria, Research Funding. Turtle:T-CURX: Membership on an entity's Board of Directors or advisory committees; Humanigen: Other: Ad hoc advisory board member; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Caribou Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Allogene: Other: Ad hoc advisory board member; Juno Therapeutics: Patents & Royalties: Co-inventor with staff from Juno Therapeutics; pending, Research Funding; Nektar Therapeutics: Other: Ad hoc advisory board member, Research Funding; Kite/Gilead: Other: Ad hoc advisory board member; Novartis: Other: Ad hoc advisory board member. Yeung:Pfizer: Research Funding; OBI Pharmaceutical: Research Funding; Merck: Consultancy; DiaCarta: Consultancy. Sersch:Mustang Bio: Employment. Maloney:Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; Celgene,Kite Pharma: Honoraria, Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria; A2 Biotherapeutics: Honoraria, Other: Stock options . Till:Mustang Bio: Patents & Royalties, Research Funding.

Mandatory Research Biopsy Requirements Delay Initiation of Clinical Trials.

Background: There has been an increasing requirement for fresh tumor tissue to enroll in clinical trials in order to look for specific biomarkers. This has been shown to increase screening duration and increase screen failure rates. It was important to corroborate these results in other centers.Methods: This study is a non-randomized retrospective analysis of patients in one subset of patients seen by research nurses who operated in the standard head/neck and lung team not including patients in the phase 1 program. All patients were enrolled in clinical trials from January 16, 2013 to May 28, 2018 at USC Norris Comprehensive Cancer Institute in Los Angeles. Patients who were required to give fresh research biopsies prior to intervention were part of the research biopsy group.Results: In total, 76 patients were analyzed in this study. Thirty-three patients were in the research biopsygroup and 43 patients were in the no biopsy group. Trials that required a fresh biopsy had a longer median screening duration (30 vs. 14 days) than trials that did not require a biopsy (p < 0.0001).Conclusions: Our study shows that requiring biopsies prior to clinical trial treatment results in a statistically significant delay in treatment. The informed consent forms that were part of clinical trials involving mandatory research biopsies did not reflect this delay in treatment. However, these delays did not result in a statistically significant decrease in number of days on trial or days until progression of disease.

1886P - Prospective pathological experience with research biopsies in the context of clinical trials at Vall d’Hebron Institute of Oncology

1886P - Prospective pathological experience with research biopsies in the context of clinical trials at Vall d’Hebron Institute of Oncology

MA18.07 Identification of Neuroendocrine Transformation in Anaplastic Lymphoma Kinase Rearranged (ALK+) Tumors After Tyrosine Kinase Inhibitors

Acquired resistance after ALK tyrosine kinase inhibitors treatment has multiple known mechanisms: new mutations or gene amplifications, bypass signaling and rarely neuroendocrine histological transformation. Here we describe results of a program utilizing routine biopsy post-progression in ALK+ patients for clinical and research purposes. Since 2014, ALK+ lung cancer patients treated at the Princess Margaret Cancer Centre have undergone routine biopsies at disease progression time points upon failure of an ALK-tyrosine kinase inhibitor (TKI) for both clinical purposes and research purposes, in particular to obtain tissue for primary derived xenograft (PDX) engraftment. All 9/9 patients consented for research sampling during clinical biopsy procedures (median 2 extra cores/passes); 2 patients were biopsied more than once; 3 PDX models from 2 patients have engrafted; 3 additional models are too early to assess engraftment. Engraftment occurred in patients with clinically aggressive tumors and poor survival outcomes. In this process, we identified 2 patients with neuroendocrine transformation post-second generation ALK TKI: (a) a 59 yo Asian female, never smoker, diagnosed six years prior with metastatic disease, heavily pretreated with crizotinib (12 months), pemetrexed (16 months), ceritinib (25 months), alectinib (6 months) and brigatinib (3 months); post-alectinib biopsy showed no transformation, while post-brigatinib liver biopsy demonstrated transformation to large cell neuroendocrine carcinoma; (b) a 75 yo Caucasian female, never smoker, diagnosed eight months prior and started on alectinib with a partial response, progressed in a single site; endobronchial biopsy demonstrated high grade neuroendocrine transformation. Both biopsies were positive for neuroendocrine markers (chromogranin and synaptophysin), TTF-1 and diffusely co-expressed ALK on immunohistochemistry. Assessment of PDX engraftment of these models is ongoing. Routine combined clinical and research biopsy of ALK+ patients at time of TKI failure helped to identify these recent cases of neuroendocrine transformation as a possible mode of resistance and provide tissue for model development. This is the first time that ALK+ transformation to large cell neuroendocrine carcinoma is reported in the literature. (PP, AFF, SNMF, LN contributed equally).

Ethical Framework for Including Research Biopsies in Oncology Clinical Trials: American Society of Clinical Oncology Research Statement.

In contrast to clinical biopsies, where tissue is collected to inform patient care, research biopsies are performed for scientific purposes to potentially enhance understanding of the biologic bases of cancer and drug action, thereby improving diagnosis and treatment, but they may offer no direct benefit to participants and have known risks. The widespread use of research biopsies that do not have the potential to directly benefit participants has come under scrutiny, with critics raising ethical concerns related to the adequacy of participant protections, informed consent, and participant understanding of the risks and benefits, as well as the scientific impact of research biopsies on drug development and treatment. This manuscript presents the American Society of Clinical Oncology's (ASCO's) ethical framework for incorporation of research biopsies in trials. The framework provides guidance on the circumstances to include optional and mandatory biopsies, as well as provides recommendations to stakeholders on necessary steps for improving the conduct of research biopsies overall.