Abstract
Objective:
Mirvetuximab may be a potentially effective therapeutic option for ovarian low-grade serous carcinoma (LGSC), but the prevalence of folate receptor α (FRα) overexpression in this tumor type is unknown. We sought to characterize FRα expression in LGSC and its association with clinical and molecular features.
Methods:
FRα immunohistochemistry was performed on a tissue microarray comprised of 89 LGSCs and 42 ovarian serous borderline tumors (SBTs). Clinical tumor-normal panel-based sequencing was performed on 78 LGSCs. Associations between FRα-high status and clinicopathologic characteristics and survival outcomes were examined.
Results:
Of 89 LGSCs, 36 (40%) were FRα-high (≥75% of viable tumor cells exhibiting moderate-to-strong membranous expression). Of 9 patients with LGSC and samples from different timepoints, 4 (44%) had discordant results, with conversion from FRα-negative to FRα-high in 3 (33%) cases. There was no association between FRα-high status with age, race, or progression-free/overall survival. A MAPK pathway genetic alteration, most commonly involving KRAS (n=23), was present in 45 (58%) LGSCs. Those lacking MAPK pathway alterations were more likely to be FRα-high compared to MAPK-altered LGSCs (61% vs 20%, p<0.001). In SBTs, FRα-high expression was associated with high-risk (micropapillary) histology and/or subsequent LGSC recurrence compared to conventional SBTs without malignant recurrence (53% vs 9%, p=0.008).
Conclusions:
Future studies of mirvetuximab in patients with LGSC are warranted. Discordant FRα status at recurrence suggests potential benefit for retesting. A biomarker-driven approach to direct treatment selection in LGSC is recommended. As high FRα expression is more common amongst tumors lacking MAPK pathway genetic alterations, FRα testing to determine eligibility for mirvetuximab therapy is particularly recommended for this subgroup.
Keywords: ovarian cancer, folate receptor alpha, antibody-drug conjugate
Introduction
Approximately 80% of patients with advanced-stage low-grade serous carcinoma (LGSC) of the ovary will achieve remission after initial treatment; however, most will recur. Compared to ovarian high-grade serous carcinoma (HGSC), LGSC responds poorly to cytotoxic chemotherapy, and effective options for recurrent disease are limited[1]. The biological and molecular underpinnings for chemoresistance are poorly understood[2]. Recent advances in targeted therapies, including MEK inhibitors, have broadened treatment options for patients with recurrent LGSC, but response rates to MEK inhibitors remain relatively low (16%–26%) [3, 4]. Novel strategies to extend remission duration and optimize survival outcomes are needed.
Mirvetuximab soravtansine, an antibody-drug conjugate (ADC) targeting folate receptor alpha (FRα), is an option for patients with recurrent FRα-high ovarian cancer. Based on initial studies demonstrating FRα overexpression in ovarian HGSC [5–8], clinical investigation of mirvetuximab has largely been limited to HGSC. Based on data from the single-arm phase II SORAYA trial (NCT04296890)[9], the US Food and Drug Administration (FDA) granted approval in November 2022 for mirvetuximab in patients with FRα-high, platinum-resistant epithelial ovarian cancer and 1 to 3 prior systemic therapies[10]. Improved efficacy of mirvetuximab over chemotherapy (median overall survival of 16.5 vs 12.8 months, hazard ratio 0.67, 95% CI: 0.50–0.89) was confirmed in the subsequent phase III MIRASOL trial (NCT04209855)[11]. Of note, all patients treated in the SORAYA and MIRASOL trials had HGSC.
Selective delivery of a higher cytotoxic payload to FRα may lead to enhanced therapeutic efficacy over conventional chemotherapeutic agents. Therefore, despite the relative chemoresistance of LGSC, folate receptor ADCs may be a viable therapeutic option if the tumor overexpresses the target.
Limited evidence suggests that FRα expression varies across tumor histologic subtypes and grades; however, data are difficult to contextualize, as definitions of FRα positivity have changed over time[12]. Moreover, ovarian serous carcinomas are often diagnosed at advanced stage and have high rates of recurrence; whether assessment of FRα expression on a tumor sample from a single site at the time of primary diagnosis is representative of FRα status at other sites of involvement or at recurrence is undetermined. In this study, we sought to assess levels of FRα expression in a clinically annotated cohort of low-grade serous neoplasms (ovarian serous borderline tumors [SBTs] and LGSCs), to identify clinical and molecular associations with FRα-high expression, and to assess concordance of FRα status in patient-matched tumor samples obtained from either different locations or timepoints.
Methods
Case selection and FRα immunohistochemical analysis
A tissue microarray (TMA) was constructed using archival tissue from patients with LGSC and SBT seen at a single institution from January 2001 to December 2022 and consented to this Institutional Review Board-approved study. All tumor samples were from resections performed at Memorial Sloan Kettering Cancer Center (MSK) and underwent central pathology review. Each sample was represented in triplicate cores, measuring 2.0 or 3.0 mm in diameter.
Immunohistochemistry (IHC) was performed on TMA sections using a folate receptor 1 (FOLR1) primary antibody (clone FOLR1–2.1, ready-to-use concentration; Ventana, Tucson, AZ). Staining was performed on the BenchMark ULTRA system (Roche Diagnostics, Indianapolis, IN), with the following conditions: antibody concentration, pre-diluted; antibody incubation, 32’; antigen retrieval, CC1 64’; detection kit, OptiView DAB IHC (Ventana). One sample of normal fallopian tube tissue, serving as positive control for the assay, was sectioned onto each TMA slide. As a quality control measure, IHC slides were inspected to ensure moderate-to-strong intensity staining (2+/3+) in fallopian tube epithelial cells in the on-slide positive tissue control.
Slides were digitized at 20X objective magnification, and digital image analysis was performed using QuPath v.0.4.3 software by a board-certified gynecologic pathologist (MHC). Following cell and membrane detection, tumor segmentation was performed using an automated random forest classifier trained on representative tumor areas and manually verified for each tumor core; retraining of the classifier was performed as necessary. The stain intensity threshold for classifying a cell as “positive” was defined by adjusting the “Membrane DAB OD max” to a single threshold value that resulted in ≥95% of cells in the positive control tissue being classified as positive and equivalent to at least 2+/3+ staining intensity. For each tumor, the percentage of positive cells was determined and averaged across triplicate cores; tumors were classified as FRα-high if the percentage of positive cells was ≥75% or FRα-negative if below this threshold, based on criteria reported in the SORAYA and FORWARD I (NCT02631876) trials[9, 13].
Massively parallel sequencing analysis and genomic data extraction
Massively parallel sequencing was performed on available LGSC samples and matched normal blood using the FDA-approved MSK-IMPACT (MSK-Integrated Mutation Profiling of Actionable Cancer Targets) assay targeting 341 to 505 cancer-related genes[14]. Identified variants were independently assessed and manually curated, applying current standards for variant classification by the American College of Medical Genetics and Genomics, to define pathogenic or likely pathogenic mutations[15].
Association of FRα scoring with clinical outcomes and genomic data
Clinicopathologic variables were collected from the electronic medical record. Stage at diagnosis was per the International Federation of Gynaecology and Obstetrics [FIGO] 2014 staging system. Genetic alterations of interest included mitogen-activated protein kinase (MAPK) pathway alterations in KRAS, HRAS, NRAS, BRAF, NF1, NF2, MAP2K1, MAP2K2, MAP2K4, MAP3K13, MAP3K14, MAPK1, MAPK3, MAPKAP1, ERBB2, DUSP4, RRAS, RRAS2, or RAF1.
Associations between FRα positivity and clinical variables as well as somatic genetic alterations were determined. Associations between continuous clinicopathologic variables were compared using the Wilcoxon rank sum test. Associations between categorical variables were performed using Fisher exact test. For SBTs, those with micropapillary histology, a known adverse prognostic factor associated with increased risk of LGSC recurrence [16], and/or those that did subsequently recur as LGSC, were compared to SBTs with conventional histology and without malignant recurrence.
Progression-free survival (PFS) was defined as the time from diagnosis to disease progression or recurrence, death, or last follow-up, whichever occurred first. Overall survival (OS) was defined as the time from diagnosis to death or last follow-up, whichever occurred first. Survival analyses were conducted for patients treated at MSK from the time of diagnosis. Patients were required to sign consent for tumor collection for biomarker/molecular studies, and left-truncation methodology was applied to account for the time between the dates of diagnosis and consent[17]. For one patient, consent and MSK-IMPACT occurred after disease progression; hence, this patient was excluded from PFS analyses but included in OS analyses. Median survival and survival rate at 3 years were obtained using Kaplan-Meier method with left-truncation method. Hazard ratio (HR) and P values were obtained using Cox proportional hazards model with left truncation. P<.05 was considered significant. All tests were 2-sided. Statistical analyses were performed using R v4.3.1 (https://cran.r-project.org/).
Results
Demographic and clinicopathologic characteristics of LGSCs
In total, 89 LGSC samples from 89 patients were represented on the TMA; 41 patients had samples collected at diagnosis and 48 had samples collected at recurrence (Table 1). Seventeen patients had samples available from multiple sites at the same timepoint, and 12 had samples available from different timepoints. Median age was 51 years (range, 15–85). Among patients with known race/ethnicity, 70 (83%) were White, non-Hispanic. Among patients with staging information, 81 (92%) had stage III or IV disease. At time of primary cytoreductive surgery, 47 patients (60%) underwent complete gross resection and 24 (31%) had optimal residual disease (≤1 cm). Postoperatively, 84 patients (94%) received platinum-based chemotherapy, 3 (3%) underwent hormonal treatment, and 2 (2%) underwent observation; 33 patients (37%) received maintenance treatment.
Table 1:
Patient Characteristics and Associations with Folate Receptor Alpha (FRα) Status
| Characteristic | LGSC (total n=89) | FRα-negative (n=53) | FRα-high (n=36) | P-value1 | SBT (total n=42) | FRα-negative (n=33) | FRα-high (n=9) | P-value1 |
|---|---|---|---|---|---|---|---|---|
| %FRα-positive cells (median, range) | 60.1% (0.0–100.0%) | 24.1% (0.0–72.9%) | 85.5% (77.5%–100.0%) | 21.0% (0.0–93.2%) | 12.2% (0.0–73.4%) | 83.0% (75.0%-93.2%) | ||
| Age at diagnosis, y (median, range) | 51 (15–85) | 51 (23–78) | 51 (15–85) | .71 | 54 (20–79) | 49 (20–79) | 60 (38–71) | .034 |
| Race/ethnicity, n (%) | Test not done * | Test not done * | ||||||
| White, non-Hispanic | 70 (83%) | 41 (59%) | 29 (41%) | 37 (90%) | 29 (78%) | 8 (22%) | ||
| Asian | 7 (8%) | 4 (57%) | 3 (43%) | 0 (0%) | 0 (0%) | 0 (0%) | ||
| Black, non-Hispanic | 3 (4%) | 3 (100%) | 0 (0%) | 2 (5%) | 2 (100%) | 0 (0%) | ||
| White, Hispanic | 4 (5%) | 3 (75%) | 1 (25%) | 2 (5%) | 1 (50%) | 1 (50%) | ||
| Missing | 5 | 2 | 3 | 1 | 1 | 0 | ||
| Stage, n (%) | .19 | >.99 | ||||||
| I/II | 7 (8%) | 3 (43%) | 4 (57%) | 30 (71%) | 23 (77%) | 7 (23%) | ||
| III | 64 (73%) | 36 (56%) | 28 (44%) | 12 (29%) | 10 (83%) | 2 (17%) | ||
| IV | 17 (19%) | 13 (76%) | 4 (24%) | 0 (0%) | 0 (0%) | 0 (0%) | ||
| Missing | 1 | 1 | 0 | 0 | 0 | 0 | ||
| Residual disease at primary surgery, n (%) | .36 | Test not done * | ||||||
| Complete gross resection | 47 (60%) | 28 (60%) | 19 (40%) | 35 (83%) | 27 (77%) | 8 (23%) | ||
| Optimal resection (≤ 1 cm) | 24 (31%) | 17 (71%) | 7 (29%) | 6 (14%) | 5 (83%) | 1 (17%) | ||
| Suboptimal resection (> 1 cm) | 7 (9.0%) | 3 (43%) | 4 (57%) | 1 (2%) | 1 (100%) | 0 (0%) | ||
| Missing | 11 | 5 | 6 | 0 | 0 | 0 | ||
| MAPK pathway alteration, n (%) | <.001 | .018 | ||||||
| Absent | 33 (42%) | 13 (39%) | 20 (61%) | 4 (13%) | 1 (25%) | 3 (75%) | ||
| Present | 45 (58%) | 36 (80%) | 9 (20%) | 26 (87%) | 23 (88%) | 3 (12%) | ||
| Missing | 11 | 4 | 7 | 12 | 9 | 3 | ||
| BRAF-V600E mutation, n (%) | .042 | .024 | ||||||
| Wildtype | 71 (91%) | 42 (59%) | 29 (41%) | 17 (57%) | 11 (65%) | 6 (35%) | ||
| Mutant | 7 (9%) | 7 (100%) | 0 (0%) | 13 (43%) | 13 (100%) | 0 (0%) | ||
| Missing | 11 | 4 | 7 | 12 | 9 | 3 |
Wilcoxon rank sum test; Fisher exact test.
Test not done: P value not provided if patient count ≤3.
LGSC, low-grade serous ovarian carcinoma; FRα, folate receptor alpha; SBT, serous borderline tumor; MAPK, mitogen-activated protein kinase.
Targeted clinical next-generation sequencing was available for 78 patients (88%); 45 sequenced tumors (58%) had an MAPK pathway alteration, most commonly, KRAS-G12V (n=11), KRAS-G12D (n=10), NRAS-Q61R/K (n=8), and BRAF-V600E (n=7).
Folate receptor expression in LGSC
Levels of FRα expression were highly variable across LGSCs (median percentage of FRα-positive [2+/3+ intensity] tumor cells, 60.1%; range, 0.0–100.0%). Using 75.0% of cells with 2+/3+ staining as the threshold for designating FRα-high status, 36 samples (40%) were considered FRα-high (median percentage of FRα-positive cells, 85.5% [range, 77.5%–100.0%]), and 53 samples (60%) were considered FRα-negative (median percentage of FRα-positive cells, 24.1% [range, 0.0–72.9%]) (Figure 1, Supplementary Figure S1). There was a significant negative association between FRα-high expression and MAPK pathway genetic alteration; 9 (20%) of 45 LGSCs with a MAPK pathway alteration were FRα-high, compared to 20 (61%) of 33 without a MAPK pathway alteration (P<0.001) (Figure 2). Of the 7 BRAF-V600E-mutated LGSCs, none were FRα-high. There was no association between FRα-high expression and patient age, race/ethnicity, disease stage, or residual disease (Table 1).
Figure 1: Folate receptor alpha (FRα) immunohistochemistry in low-grade serous carcinoma.
Representative examples of FRα-negative tumors: samples from different patients taken from ovary (left) and colon metastasis (right), and FRα-high tumors: samples from different patients taken from ovary (left) and peritoneal metastasis (right). The percentage of FRα-positive tumor cells (2+/3+ intensity) is indicated for each sample.
Figure 2: Folate receptor alpha (FRα)-high expression is enriched amongst low-grade serous carcinomas lacking MAPK pathway genetic alterations.
Oncoprint showing indicated MAPK pathway genetic alterations, with folate receptor alpha (FRα) status and expression level (percentage of FRα-positive tumor cells) per sample.
Of 41 patients included in PFS analysis, median follow-up was 44.8 months (range, 2.4–326.0) among patients without progression. No patients received mirvetuximab at any time in their treatment course. There was no association between FRα status and PFS (HR: 1.6, 95% CI: 0.39–6.4) (Supplementary Figure S2A). Of 42 patients included in OS analysis, median follow-up was 45.8 months (range, 2.5–326.0) among survivors. There was no association between FRα status and OS (HR: 1.78, 95% CI: 0.17–18.49), although estimates were limited by event and sample sizes (Supplementary Figure S2B).
Clinical characteristics and FRα expression in SBTs
For 42 SBTs, including primary (n=39) and recurrent (n=3) tumors, patient median age was 54 years (range, 20–79). Overall, 37 patients (88%) were White, non-Hispanic, and among patients with staging information, 25 (60%) had stage I disease.
Median percentage of FRα-positive cells was 21.0% (range, 0.0–93.2%) amongst all tested SBTs. Nine SBTs (21%) were FRα-high (median percentage of FRα-positive cells: 83.0%, range: 75.0%–93.2%), while 33 SBT (79%) were considered FRα-negative (median percentage of FRα-positive cells: 12.2%, range: 0.0–73.2%). There was no association between FRα-high expression and patient age, race/ethnicity, disease stage, or residual disease (Table 1). FRα expression was higher in high risk/clinically aggressive SBTs (those with micropapillary histology, n=11, recurrence as LGSC, n=2, or both, n=5; median percentage of FRα-positive cells: 53.2% [range, 1.6%–87.9%]), compared to conventional SBTs without malignant recurrence on follow-up (n=24, median percentage of FRα-positive cells: 8.7% [range, 0.0–93.2%]; p=.008).
Concordance of FRα status across different sites and/or timepoints
FRα expression assessed on patient-matched tumors sampled from different anatomic sites revealed a high rate of concordance (14 of 17, 82.4%) (Figure 3). For the 3 patients with discordant FRα status across matched samples, some FRα expression was present even in tumors classified as FRα-negative (based on the 75% threshold); the percentages of FRα-positive cells in these tumors were: Patient #1: 62% (peritoneal biopsy) and 76% (uterine serosa); Patient #2: 96% (abdominal wall); and Patient #3: 65% (bowel wall); 85% (ovary) and 48% (peritoneal nodule). Tumor cellularity was similar across matched samples from these patients.
Figure 3: Concordance of folate receptor alpha (FRα) status in patient-matched samples.
Summarized FRα results for patient-matched tumor samples collected from different anatomic sites at the same point, as well as matched primary and recurrent tumors.
Conversion of FRα-negative status at the time of primary diagnosis to FRα-high disease at recurrence was observed in 3 (33%) of 9 patients with FRα expression assessed at different timepoints (Figure 3); the proportions of FRα cells in these tumors were: Patient #1: 7% (psoas nodule) and 97% (bowel wall); Patient #2: 57% (pelvic nodule) and 85% (peritoneal nodule); and Patient #3: 5% (peritoneal nodule) and 81% (peritoneal nodule) (Supplementary Figure S3). Another patient with FRα-high LGSC (95% FRα-positive cells in liver biopsy) was FRα-negative at recurrence (5% FRα-positive cells in lymph node biopsy).
Discussion
Treatment options are limited for patients with recurrent LGSC, and response rates to conventional cytotoxic agents are poor, ranging from 13% to 24%[1, 4]. Patients with platinum-resistant HGSC also have poor response rates to conventional chemotherapy (12% to 27%)[18]. However, mirvetuximab has recently emerged as a novel treatment option for platinum-resistant ovarian cancer. Following encouraging results from the single-arm Phase II SORAYA trial of mirvetuximab in FRα-high bevacizumab-pretreated, platinum-resistant HGSC [9], the Phase III MIRASOL trial demonstrated improved response rates and survival outcomes (PFS and OS), as well as fewer adverse events, in platinum-resistant HGSC patients treated with mirvetuximab compared to investigator’s choice of chemotherapy[11]. These studies provided support for FDA approval of mirvetuximab for FRα-high epithelial ovarian, fallopian tube or primary peritoneal cancer[10].
While approximately 20% of LGSCs will respond to platinum in the recurrent setting [1, 4], the role of mirvetuximab is unknown, as FRα expression in this tumor subtype has not been widely tested. In this study, we report a relatively high rate of FRα-high LGSCs (40%). Given this frequency is comparable to that seen in platinum-resistant HGSC in the SORAYA trial (36%)[9], further clinical investigation of mirvetuximab in patients with FRα-high LGSC is warranted.
While SBTs are not treated with systemic therapy, and thus clinical applicability of FRα expression is limited, we found that SBTs with high-risk (micropapillary) histology or associated with malignant recurrence had higher levels of FRα expression, suggesting that FRα expression should be investigated as a potential prognostic biomarker in this patient population. Despite a limited sample size, no LGSCs with BRAF-V600E mutations in our cohort were FRα high. Previous findings that BRAF-V600E mutation is a favorable prognostic factor in SBTs further suggests that upregulation of FRα expression may be associated with a biologically aggressive phenotype[19, 20].
In our study, patients with FRα-high LGSC were less likely to have tumors with MAPK pathway genetic alterations. Previous studies have shown that patients with MAPK pathway-altered tumors have better PFS and OS compared to those without [2], and may respond better to novel MAPK pathway targeted therapies, such as MEK inhibitors[3, 21]. In contrast, LGSCs lacking MAPK pathway genetic alterations are largely resistant to MEK inhibitor therapy, with modest ORRs at 8% for trametinib [3] and 13% for binimetinib [21]. Newer combination targeted treatments, such as those inhibiting RAF/MEK and FAK, have reported ORRs of 29% to 44% in patients with KRAS wildtype tumors; however, patient numbers are low and the proportion of patients with an alteration in another MAPK pathway gene is unknown[22, 23]. We observed higher rates of FRα-high disease in patients without an MAPK pathway alteration, suggesting a future triage mechanism whereby patients with a MAPK pathway alteration could receive MAPK pathway targeted therapy, and patients with FRα-high disease and no MAPK alteration could receive FRα-directed therapy, such as mirvetuxumab.
We also investigated rates of concordance in FRα expression among patients with multiple tumor samples collected from different sites and times. A phase I study demonstrated a 71% concordance rate between FRα expression in archival tissues and fresh biopsy ovarian cancer samples[7]. Our findings are similar, as 82% of patients had concordant results when multiple tumor sites were tested for FRα, and 69% had concordant results at different timepoints. These data suggest there is likely low clinical utility of FRα testing on samples from multiple tumor sites. Conversely, 3 (33%) of 9 patients with FRα-negative LGSC at initial testing had FRα-high disease at recurrence. Although more data are needed, these findings suggest re-biopsy may be useful to expand patient eligibility for FRα-directed therapy at time of recurrence.
Strengths of this study include the large cohort with granular data, which allowed for integration of clinicopathologic and outcomes data. A high percentage of patients underwent tumor sequencing, which provided a molecularly annotated cohort and enabled correlation of FRα with MAPK pathway alterations. Limitations of this study include those inherent to retrospective design. Accuracy of clinical data relied on the quality of the medical record, and the high rate of advanced disease in this cohort may limit applicability of findings to patients with early-stage disease. Furthermore, some samples from over 20 ago were included and treatment paradigms have shifted significantly since then.
The one-size-fits-all approach to ovarian cancer systemic therapy has proven inadequate for patients with LGSC given the low response rates to current treatments. Molecularly guided MAPK- and FRα-directed treatments could be useful in recurrent LGSC. While clinical data are needed to validate our findings, improvements in targeted therapy may increase remission duration and survival in patients with LGSC.
Supplementary Material
Highlights.
Approximately 40% of low-grade serous ovarian carcinomas (LGSOCs) are folate receptor α (FRα)-high
LGSOCs lacking MAPK pathway genetic alterations are more likely to be FRα-high
Change in FRα status at recurrence suggests a possible benefit to re-testing
Mirvetuximab should be investigated as a treatment option for LGSOC, particularly for MAPK non-altered tumors
Consent Statement:
This study was approved by the Institutional Review Board at Memorial Sloan Kettering Cancer Center, and all patients provided consent.
Funding:
This work was supported in part by a National Institutes of Health/National Cancer Institute Cancer Center Support Grant (P30 CA008748). Drs. Chui and Grisham are supported by a grant from the STAAR Ovarian Cancer Foundation.
Footnotes
Conflict of Interest Disclosure Statement: Y.L. Liu reports research funding from AstraZeneca, GSK, and Repare Therapeutics, outside the submitted work. A. Iasonos reports consulting fees from Mylan. D.S. Chi reports personal fees from Apyx Medical, Verthermia Inc., Biom ‘Up, and AstraZeneca, as well as recent or current stock/options ownership of Apyx Medical, Verthemia, Intuitive Surgical, Inc., TransEnterix, Inc., Doximity, Moderna, and BioNTech SE. C. Aghajanian reports grant support paid to the institution from Abbvie, Clovis, Genentech, and AstraZeneca; consulting fees from Eisai/Merck, Mersana Therapeutics, Roche/Genentech, Abbvie, AstraZeneca/Merck, and Repare Therapeutics; advisory board participation for Blueprint Medicine; and unpaid participation on the Board of Directors of the GOG Foundation and NRG Oncology. R.N. Grisham reports honoraria from GSK, AstraZeneca, Natera, Springworks, Corcept, MJH, and PER. R.E. O’Cearbhaill reports personal fees from Tesaro/GSK, Regeneron, R-PHARM, Seattle Genetics, Fresenius Kabi, Gynecologic Oncology Foundation, Bayer, Curio, Miltenyi, 2seventybio and Immunogen, and other from Hitech Health, all outside the submitted work. She is a non-compensated steering committee member for the PRIMA, Moonstone (Tesaro/GSK), and DUO-O (AstraZeneca) studies and a non-compensated advisor for Carina Biotech. Her institute receives funding for clinical research from Bayer/Celgene/Juno, Tesaro/GSK, Merck, Ludwig Cancer Institute, Abbvie/StemCentrx, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Sellas Therapeutics, Genentech, Kite Pharma, Acrivon, Lyell Immunopharma, and Gynecologic Oncology Foundation. K. Long Roche reports travel support from Intuitive Surgical. The other authors have no conflicts of interest to report.
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