To assess safety and efficacy of niraparib + bevacizumab as a first-line maintenance therapy for patients with newly diagnosed advanced ovarian cancer.
This multicenter, phase II, single-arm, ...open-label study enrolled adult patients with stage IIIB to IV ovarian, fallopian tube, or primary peritoneal cancer (NCT03326193). Patients were required to have an attempt at debulking surgery and have a complete response, partial response, or no evidence of disease following first-line, platinum-based chemotherapy with ≥3 cycles of bevacizumab. The primary endpoint was the progression-free survival (PFS) rate at 18 months. Secondary endpoints included PFS, overall survival, and safety.
Among the 105 evaluable patients, the PFS rate at 18 months was 62% (95% CI 52–71%) in the overall population and 76% (95% CI 61–87) in the homologous recombination deficient (HRd), 47% (95% CI 31–64%) in the HR proficient (HRp), and 56% (95% CI 31–79%) in the HR not determined (HRnd) subgroups (December 24, 2020, cutoff). After a median follow-up time of 28.7 months (IQR, 23.9–32.5 months), median PFS was 19.6 months (95% CI 16.5–25.1) in the overall population (N = 105) and 28.3 months (95% CI 19.9–NE), 14.2 months (95% CI 8.6–16.8), and 12.1 months (95% CI 8.0–NE) in the HRd, HRp, and HRnd subgroups, respectively (June 16, 2021, cutoff). The most common any-grade treatment-related adverse events (related to niraparib and/or bevacizumab) were thrombocytopenia (74/105), fatigue (60/105), and anemia (55/105; December 24, 2020, cutoff).
Niraparib + bevacizumab first-line maintenance therapy displayed promising PFS results. Safety was consistent with the known safety profiles of niraparib and bevacizumab as monotherapy.
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•OVARIO enrolled patients with primary advanced-stage ovarian cancer, including high-risk cases.•In the overall population, 62% of patients were progression-free at the 18-month primary endpoint.•After a median follow-up of 28.7 months, median PFS was 19.6 months (overall), 28.3 months (HRd), and 14.2 months (HRp).•The most common any-grade adverse events related to niraparib and/or bevacizumab were thrombocytopenia, fatigue, and anemia.
To improve our understanding of ovarian cancer, we performed genome-wide analyses of 45 ovarian cancer cell lines. Given the challenges of genomic analyses of tumors without matched normal samples, ...we developed approaches for detection of somatic sequence and structural changes and integrated these with epigenetic and expression alterations. Alterations not previously implicated in ovarian cancer included amplification or overexpression of ASXL1 and H3F3B, deletion or underexpression of CDC73 and TGF-beta receptor pathway members, and rearrangements of YAP1-MAML2 and IKZF2-ERBB4. Dose-response analyses to targeted therapies revealed unique molecular dependencies, including increased sensitivity of tumors with PIK3CA and PPP2R1A alterations to PI3K inhibitor GNE-493, MYC amplifications to PARP inhibitor BMN673, and SMAD3/4 alterations to MEK inhibitor MEK162. Genome-wide rearrangements provided an improved measure of sensitivity to PARP inhibition. This study provides a comprehensive and broadly accessible resource of molecular information for the development of therapeutic avenues in ovarian cancer.
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•Compendium of somatic sequence and structural variants in ovarian cancer cell lines•Development of Trellis algorithm for tumor-only structural variant detection•Integration of DNA, mRNA, and methylation alterations to predict drug sensitivity
The overall survival of patients with late-stage ovarian cancer is dismal. To identify therapeutic opportunities, Papp et al. integrate genomic, epigenomic, and expression analyses to provide a resource of molecular abnormalities in ovarian cancer cell lines and use these to identify tumors sensitive to PARP, MEK, and PI3K inhibitors.
Recent progress in understanding the molecular biology of epithelial ovarian cancer has not yet translated into individualized treatment for these women or improvements in their disease outcome. Gene ...expression has been utilized to identify distinct molecular subtypes, but there have been no reports investigating whether or not molecular subtyping is predictive of response to bevacizumab in ovarian cancer.
DASL gene expression arrays were performed on FFPE tissue from patients enrolled on the ICON7 trial. Patients were stratified into four TCGA molecular subtypes. Associations between molecular subtype and the efficacy of randomly assigned therapy with bevacizumab were assessed.
Molecular subtypes were assigned as follows: 122 immunoreactive (34%), 96 proliferative (27%), 73 differentiated (20%), and 68 mesenchymal (19%). In univariate analysis patients with tumors of proliferative subtype obtained the greatest benefit from bevacizumab with a median PFS improvement of 10.1 months HR, 0.55 (95% CI, 0.34-0.90),
= 0.016. For the mesenchymal subtype, bevacizumab conferred a nonsignificant improvement in PFS of 8.2 months HR 0.78 (95% CI, 0.44-1.40),
= 0.41. Bevacizumab conferred modest improvements in PFS for patients with immunoreactive subtype (3.8 months;
= 0.08) or differentiated subtype (3.7 months;
= 0.61). Multivariate analysis demonstrated significant PFS improvement in proliferative subtype patients only HR, 0.45 (95% CI, 0.27-0.74),
= 0.0015.
Ovarian carcinoma molecular subtypes with the poorest survival (proliferative and mesenchymal) derive a comparably greater benefit from treatment that includes bevacizumab. Validation of our findings in an independent cohort could enable the use of bevacizumab for those patients most likely to benefit, thereby reducing side effects and healthcare cost.
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Abstract Background It is unclear whether the transcriptional subtypes of high grade serous ovarian cancer (HGSOC) apply to high grade clear cell (HGCCOC) or high grade endometrioid ovarian cancer ...(HGEOC). We aim to delineate transcriptional profiles of HGCCOCs and HGEOCs. Methods We used Agilent microarrays to determine gene expression profiles of 276 well annotated ovarian cancers (OCs) including 37 HGCCOCs and 66 HGEOCs. We excluded low grade OCs as these are known to be distinct molecular entities. We applied the prespecified TCGA and CLOVAR gene signatures using consensus non-negative matrix factorization (NMF). Results We confirm the presence of four TCGA transcriptional subtypes and their significant prognostic relevance (p < 0.001) across all three histological subtypes (HGSOC, HGCCOC and HGEOCs). However, we also demonstrate that 22/37 (59%) HGCCOCs and 30/67 (45%) HGEOCs form 2 additional separate clusters with distinct gene signatures. Importantly, of the HGCCOC and HGEOCs that clustered separately 62% and 65% were early stage (FIGO I/II), respectively. These finding were confirmed using the reduced CLOVAR gene set for classification where most early stage HGCCOCs and HGEOCs formed a distinct cluster of their own. When restricting the analysis to the four TCGA signatures (ssGSEA or NMF with CLOVAR genes) most early stage HGCCOCs and HGEOC were assigned to the differentiated subtype. Conclusions Using transcriptional profiling the current study suggests that HGCCOCs and HGEOCs of advanced stage group together with HGSOCs. However, HGCCOCs and HGEOCs of early disease stages may have distinct transcriptional signatures similar to those seen in their low grade counterparts.
Currently, antiangiogenic strategies in metastatic breast cancer have demonstrated modest improvements in progression-free survival (PFS) but not improved quality or duration of survival, warranting ...evaluation of new agents in a placebo-controlled setting. Ramucirumab is a human immunoglobulin G1 antibody that binds vascular endothelial growth factor receptor-2 and blocks ligand-stimulated activation. The ROSE/TRIO-012 trial evaluated ramucirumab with docetaxel in unresectable, locally recurrent, or metastatic breast cancer.
In this double-blind, placebo-controlled, randomized, multinational phase III trial, 1,144 patients with human epidermal growth factor receptor 2 (HER2) -negative breast cancer who had not received cytotoxic chemotherapy in the advanced setting were randomly assigned at a two-to-one ratio to receive docetaxel 75 mg/m(2) plus ramucirumab 10 mg/kg or docetaxel 75 mg/m(2) plus placebo once every 3 weeks. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria. Patients were stratified by previous taxane therapy, visceral metastasis, hormone receptor status, and geographic region. An independent data monitoring committee oversaw the trial. The primary end point was investigator-assessed PFS.
Median PFS in patients treated with ramucirumab plus docetaxel was 9.5 months, compared with 8.2 months in patients who received placebo plus docetaxel (hazard ratio HR, 0.88; P = .077). Median overall survival was 27.3 months in patients who received ramucirumab plus docetaxel, compared with 27.2 months in patients who received placebo plus docetaxel (HR, 1.01; P = .915). Toxicities seen at significantly higher rates in patients receiving ramucirumab included fatigue, hypertension, febrile neutropenia, palmar-plantar erythrodysesthesia syndrome, and stomatitis.
Addition of ramucirumab to docetaxel in HER2-negative advanced breast cancer did not meaningfully improve important clinical outcomes.
We aimed to validate whether pathologic response (pR) to neoadjuvant chemotherapy (NACT) using a three-tier chemotherapy response score (CRS) is associated with clinical outcome in ovarian cancer ...(OC) and could be used as surrogate marker for survival.
We conducted a retrospective study of OC patients with FIGO stage III/IV disease who received NACT and graded response as no or minimal (CRS 1), partial (CRS 2), or complete/near-complete (CRS 3) pR using tissue specimens obtained from omentum. Uni- and multivariate survival analyses were performed accounting for age, FIGO stage, debulking and BRCA status as well as neoadjuvant use of bevacizumab.
CRSs 1, 2 and 3 were found in 41(31%), 62 (47%) and 30 (22%) of the 133 examined cases. Response to NACT was associated with significantly improved progression-free (PFS, p < 0.001) and overall survival (OS, p = 0.011). Complete/ near-complete pathologic response (CRS3) was associated with improved PFS (median 24.8 vs. 12.5 months, unadjusted HR 0.28 95%CI 0.15–0.54, p < 0.001; adjusted hazard ration (aHR) 0.31 95% CI 0.14–0.72, p = 0.007) and OS (median 63.3 vs. 32.1 months, unadjusted HR 0.27 95%CI 0.10–0.68, p = 0.006; aHR 0.32 95% CI 0.09–1.11, p = 0.072) when compared to no or minimal response (CRS1).
We validate a three-tier CRS for assessment of pathologic response to NACT in OC and demonstrate its prognostic independence of BRCA status or neoadjuvant bevacizumab use. Improving pR rates may be a useful goal of NACT in OC with the expectation of improved survival. The CRS may be a useful endpoint in clinical trials in OC.
•The chemotherapy response score (CRS) assesses the pathologic response to neoadjuvant chemotherapy in ovarian cancer.•Complete/near complete (CRS3) response to chemotherapy is associated with improved progression free and overall survival.•The prognostic relevance of CRS is independent of BRCA mutation status or neoadjuvant bevacizumab use.•A three-tier scoring system has the potential to become a surrogate marker for accelerated drug development in OC.
Background: Trastuzumab, a humanized anti-HER2 antibody, increases the clinical benefit of first-line chemotherapy in patients with metastatic breast cancers that overexpress HER2. We characterized ...interactions between trastuzumab and chemotherapeutic agents commonly used in the treatment of breast cancer. Methods: Multiple drug effect/combination index isobologram analysis was used to study the efficacy of chemotherapeutic drug plus trastuzumab combinations tested against four HER2-overexpressing breast cancer cell lines (SK-BR-3, BT-474, MDA-MB-361, and MDA-MB-453). Combination index values were derived from parameters of the median effect plots, and statistical tests were used to determine whether the mean combination index values at multiple effect levels were statistically significantly different from a combination index value of 1.0. Values less than 1.0 indicate synergistic interactions, values greater than 1.0 indicate antagonistic interactions, and values equal to 1.0 indicate additive interactions. Results: At a wide range of clinically achievable drug concentrations, synergistic interactions were observed in all four breast cancer cell lines for trastuzumab plus carboplatin (mean combination index values ranged from 0.32 P<.001 to 0.53 P<.001), 4-hydroxycyclophosphamide (mean combination index values ranged from 0.38 P<.001 to 0.73 P = .010), docetaxel (mean combination index values ranged from 0.30 P<.001 to 0.62 P<.001), and vinorelbine (mean combination index values ranged from 0.24 P<.001 to 0.78 P<.034). Additive interactions were observed in all four cell lines with trastuzumab plus doxorubicin, epirubicin, and paclitaxel. Interactions between trastuzumab and gemcitabine were synergistic at low concentrations of gemcitabine and antagonistic at high concentrations. A synergistic interaction was observed with a three-drug combination of docetaxel plus carboplatin plus trastuzumab in SK-BR-3 cells (mean combination index value = 0.09; P<.001). Conclusion: Consistent synergistic interactions of trastuzumab plus carboplatin, 4-hydroxycyclophosphamide, docetaxel, or vinorelbine across a wide range of clinically relevant concentrations in HER2-overexpressing breast cancer cells indicate that these are rational combinations to test in human clinical trials.
Abstract Objective Comparisons of The Cancer Genome Atlas (TCGA) with high grade serous ovarian cancer (HGSOC) cell lines used in research reveal that many common experimental models lack defining ...genomic characteristics seen in patient tumors. As cell lines exist with higher genomic fidelity to TCGA, this study aimed to evaluate the utility of these cell lines as tools for preclinical investigation. Methods We compared two HGSOC cell lines with supposed high genomic fidelity to TCGA, KURAMOCHI and OVSAHO, with the most commonly cited ovarian cancer cell line, SKOV3, which has poor genomic fidelity to TCGA. The lines were analyzed for genomic alterations, in vitro performance, and growth in murine xenografts. Results Using targeted next generation sequencing analyses, we determined that each line had a distinct mutation profile, including alterations in TP53 , and copy number variation of specific genes. KURAMOCHI and OVSAHO better recapitulated serous carcinoma morphology than SKOV3. All lines expressed PAX8 and stathmin, but KURAMOCHI and OVSAHO did not express CK7. KURAMOCHI was significantly more platinum sensitive than OVSAHO and SKOV3. Unlike SKOV3, KURAMOCHI and OVSAHO engrafted poorly in subcutaneous xenografts. KURAMOCHI and OVSAHO grew best after intraperitoneal injection in SCID mice and recapitulated miliary disease while SKOV3 grew in all murine systems and formed oligometastatic disease. Conclusions The research utility of HGSOC cell line models requires a comprehensive assessment of genomic as well as in vitro and in vivo properties. Cell lines with closer genomic fidelity to human tumors may have limitations in performance for preclinical investigation.
Immune checkpoints including programmed death-ligand 1/programmed death-1/ (PD-L1/PD-1), cytotoxic T lymphocyte antigen 4 (CTLA-4), and indolaimine-2, 3-deoxygenase (IDO) have recently emerged as ...effective candidates for treatment against a range of human malignancies. We have investigated their expression in the uterine mesenchymal tumors.
Sixty-eight mesenchymal tumors were categorized into 6 diagnostic groups. We assessed PD-L1, PD-1, CTLA-4, and IDO expression on paraffin embedded tissue blocks of the uterine tumors using the respective antibodies. Immunohistochemical (IHC) stains were classified as positive when the reactions were present in at least 1% of the cell membranes for PD-L1/PD-1 or in cytoplasm for CTLA-4 and IDO, regardless of intensity. Student's t-test and McNemar's chi-square tests were carried out to analyze the results.
The mesenchymal neoplasms had expressed the immune checkpoints in the tumor and/or the lymphoid cells at the rate of 49% and 54% respectively. The tumor cells were positive in 10 (18%, PD-L1), 0 (0%, PD-1), 18 (32%, CTLA-4), and 13 (23%, IDO) cases while the infiltrating lymphoid cells were positive in 10 (18%, PD-L1), 23 (40%, PD-1), 18 (32%, CTLA-4), and 13 (23%, IDO) cases. Overall, comparison of paired tumor vs lymphoid cells resulted in p-values of ≤ 0.04.
Nearly 50% of the uterine tumors express at least one of the immune checkpoints in tumor and/or the infiltrating lymphoid cells. However, expression of the proteins in the two cellular components are mutually exclusive. Namely, when tumor cells express an immune checkpoint, the infiltrating lymphoid cells do not, and vice versa. Since the leiomyosarcomas are reportedly resistant to the immunotherapy when PD-L1 is expressed in the tumor cells, it can be posited that presence of the IHC positive lymphoid cells may be a better indicator of response to the treatment.
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