Objective To evaluate the combination of pembrolizumab, cisplatin and gemcitabine in recurrent platinum-resistant ovarian cancer. Methods Patients received six cycles of chemotherapy with gemcitabine ...and cisplatin on day 1 and day 8 of a 21-day treatment cycle. Pembrolizumab was administered on day 1 of cycles 3-6 and as maintenance monotherapy in cycles 7-34. Palliative radiation to a non-target symptomatic lesion was allowed. The primary objective was overall response rate by RECIST 1.1 criteria. Secondary objectives included safety, progression-free survival, time to progression, duration of response and overall survival. Results An interim analysis for futility was performed at 18 evaluable patients. Overall response rate was 60%, duration of response was 4.9 months and time to progression was 5.2 months. Progression-free survival at 6 and 12 months was 43% and 5%. Median progression-free survival was 6.2 months and median overall survival was 11.3 months. In all patients, CA125 levels reflected response and progression. There were no pseudoprogression events. After receiving palliative radiation during pembrolizumab maintenance, a patient with recurrent ovarian clear cell carcinoma had an exceptional and durable response that is ongoing for greater than 2 years. After consultation with the sponsor, based on the modest duration of response observed at the interim analysis for futility, the decision was made to close the trial to further accrual. Conclusions The addition of pembrolizumab to cisplatin and gemcitabine did not appear to provide benefit beyond chemotherapy alone in patients with recurrent platinum-resistant ovarian cancer.
Late-line treatment options for patients with ovarian cancer are few, with the proportion of patients achieving an overall response typically less than 10%, and median overall survival after ...third-line therapy of 5–9 months. In this study (QUADRA), we investigated the activity of niraparib monotherapy as the fourth or later line of therapy.
QUADRA was a multicentre, open-label, single-arm, phase 2 study that evaluated the safety and activity of niraparib in adult patients (≥18 years) with relapsed, high-grade serous (grade 2 or 3) epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with three or more previous chemotherapy regimens. The study was done in the USA and Canada, and 56 sites screened patients (50 sites treated at least one patient). Patients received oral niraparib 300 mg once daily continuously, beginning on day 1 and every cycle (28 days) thereafter until disease progression. The primary objective was the proportion of patients achieving an investigator-assessed confirmed overall response in patients with homologous recombination deficiency (HRD)-positive tumours (including patients with BRCA and without BRCA mutations) sensitive to their last platinum-based therapy who had received three or four previous anticancer therapy regimens (primary efficacy population). Efficacy analyses were additionally done in all dosed patients with measurable disease at baseline.
Between April 1, 2015 and Nov 1, 2017, we screened 729 patients for eligibility and enrolled 463 patients, who were initiated on niraparib therapy. At the time of database lock (April 11, 2018), enrolment had closed and the study was ongoing, with 21 patients still on treatment. Patients had received a median of four (IQR 3–5) previous lines of therapy, and the median follow-up for overall survival was 12·2 months (IQR 3·7–22·1). 151 (33%) of 463 patients were resistant and 161 (35%) of 463 patients were refractory to the last administered platinum therapy. 13 (28%) of 47 patients in the primary efficacy population achieved an overall response according to RECIST (95% CI 15·6–42·6; one-sided p=0·00053). The most common drug-related grade 3 or worse treatment-emergent adverse events were anaemia (113 24% of 463 patients) and thrombocytopenia (95 21% of 463 patients). The most common treatment-emergent serious adverse events were small intestinal obstruction (34 7% of 463 patients), thrombocytopenia (34 7% of 463 patients), and vomiting (27 6% of 463 patients). One death due to gastric haemorrhage was considered treatment related.
We observed clinically relevant activity of niraparib among women with heavily pretreated ovarian cancer, especially in patients with HRD-positive platinum-sensitive disease, which includes not only patients with a BRCA mutation but also a population with BRCA wild-type disease. We identified no new safety signals. Our data support expansion of the treatment indication for poly(ADP-ribose) polymerase inhibitors to include patients with HRD-positive ovarian cancer beyond those with BRCA mutations.
Tesaro.
In their fiscal year 2021 reports, the US House and Senate Appropriations Committees requested that the National Institutes of Health (NIH) evaluate current research related to women's health and ...topics that include stagnant cervical cancer survival. In response, the NIH Office of Research on Women's Health, with input from women's health experts; members of the public; representatives from NIH institutes, centers, and offices; and members of the NIH Advisory Committee on Research on Women's Health, reviewed the public health needs and current NIH activities on cervical cancer. The Advancing NIH Research on the Health of Women: A 2021 Conference held in October 2021 reviewed these findings and allowed the identification of opportunities to strengthen research. In this review, the authors summarize public health needs related to cervical cancer and NIH activities in this realm. Cervical cancer has become a rare disease in the United States, yet significant portions of the US population remain under screened or unscreened for cervical cancer, human papillomavirus vaccination rates remain low, access to high‐quality treatment remains a challenge for many, and large inequities by race and ethnicity persist. Novel, inclusive, and intentional research is needed to produce improvements in cervical cancer survival within the United States.
Mortality from cervical cancer is a direct reflection of resource distribution. Future research to decrease mortality must account for systemic failures to eradicate inequities in addition to the development of novel agents against this disease.
Oral tyrosine kinase inhibitors (TKIs) have new indications for treatment in gynecologic malignancies. These targeted drugs have both unique and overlapping toxicities, which require careful ...attention and management. New combination therapies with immune-oncology agents have demonstrated promise in endometrial cancer. This review examines common adverse events associated with TKIs and provides readers with an evidence-based review on current uses and strategies for the management of these medications.
A comprehensive review of the medical literature on TKI use in gynecologic cancer was undertaken by a committee approach. Details of each drug, its molecular target, and relevant data on both clinical efficacy and side effects were compiled and organized for clinical use. Information on drug-related secondary effects and management strategies for specific toxicities, including dose reduction and concomitant medications, were gathered.
TKIs can potentially offer improved response rates and durable responses for a group of patients who were previously without an effective standard second-line therapy. The combination of lenvatinib and pembrolizumab represents a more targeted approach to the drivers of endometrial cancer; however, there remains significant drug-related toxicity, and thus dose reduction and dose delay are frequently required. Toxicity management requires frequent check-ins and management strategies to help patients find the highest tolerable dose. TKIs are expensive and patient financial toxicity is as critical a measure of a drug's utility as any drug side effect. Many of these drugs have patient assistance programs, which should be fully utilized to minimize cost.
Future studies are needed to expand the role of TKIs into new molecularly driven groups. Attention to cost, durability of response, and long-term toxicity management is needed to ensure all eligible patients have access to treatment.
•Tyrosine kinase inhibitors are increasingly used as single agents or combined with immunotherapy in gynecologic cancers.•Recognition and appropriate management of their unique toxicities is crucial.•Special considerations for use of TKIs in gynecologic malignancies are reviewed.
Background
In the United States, inequities in preventive health behaviors such as cervical cancer screening have been documented. Sexual orientation, gender identity, and race/ethnicity all ...individually contribute to such disparities. However, little work has investigated their joint impact on screening behavior.
Methods
Using sampling weighted data from the 2016 and 2018 Behavioral Risk Factor Surveillance System, we assessed differences in two metrics via chi-square statistics: 1) lifetime uptake, and 2) up-to-date cervical cancer screening by sexual orientation and gender identity, within and across racial/ethnic classifications.
Results
Within all races, individuals who identify as members of sexual and gender minority (SGM) communities reported higher rates of never being screened (except for Black transgender men) than straight or cisgender individuals (
p
< 0.0001).
*START*
Across all races, the Asian/Pacific Islander transgender population (32.4%; weighted n (
w.n.
) = 1,313) had the lowest proportion of lifetime screening, followed by the Asian/Pacific Islander gay/lesbian (53.0%,
w.n.
= 21,771), Hispanic transgender (58.7%;
w.n.
= 24,780), Asian/Pacific Islander bisexual (61.8%,
w.n.
= 54,524), and Hispanic gay/lesbian (69.6%,
w.n.
= 125,781) populations.
*END*
Straight or cisgender Non-Hispanic White (
w.n.
= 40,664,476) individuals had the highest proportion of lifetime screening (97.7% and 97.5%, respectively). However, among individuals who had been screened at least once in their lifetime, identifying as SGM was not associated with a decreased proportion of up-to-date screening within or between races.
Conclusions
Due to small sample sizes, especially among Asian/Pacific Islander and Hispanic populations, confidence intervals were wide. Heterogeneity in screening participation by SGM status within and across racial/ethnic groups were observed.
Impact
These screening disparities reveal the need to disaggregate data to account for intersecting identities and for studies with larger sample sizes to increase estimate reliability.
Purpose
This paper reports the efficacy of the poly (ADP‐ribose) polymerase inhibitor olaparib alone and in combination with the antiangiogenesis agent cediranib compared with cediranib alone in ...patients with advanced endometrial cancer.
Methods
This was open‐label, randomized, phase 2 trial (NCT03660826). Eligible patients had recurrent endometrial cancer, received at least one (<3) prior lines of chemotherapy, and were Eastern Cooperative Oncology Group performance status 0 to 2. Patients were randomly assigned (1:1:1), stratified by histology (serous vs. other) to receive cediranib alone (reference arm), olaparib, or olaparib and cediranib for 28‐day cycles until progression or unacceptable toxicity. The primary end point was progression‐free survival in the intention‐to‐treat population. Homologous repair deficiency was explored using the BROCA‐GO sequencing panel.
Results
A total of 120 patients were enrolled and all were included in the intention‐to‐treat analysis. Median age was 66 (range, 41–86) years and 47 (39.2%) had serous histology. Median progression‐free survival for cediranib was 3.8 months compared with 2.0 months for olaparib (hazard ratio, 1.45 95% CI, 0.91‐2.3 p = .935) and 5.5 months for olaparib/cediranib (hazard ratio, 0.7 95% CI, 0.43–1.14 p = .064). Four patients receiving the combination had a durable response lasting more than 20 months. The most common grade 3/4 toxicities were hypertension in the cediranib (36%) and olaparib/cediranib (33%) arms, fatigue (20.5% olaparib/cediranib), and diarrhea (17.9% cediranib). The BROCA‐GO panel results were not associated with response.
Conclusion
The combination of cediranib and olaparib demonstrated modest clinical efficacy; however, the primary end point of the study was not met. The combination was safe without unexpected toxicity.
Randomized study of cediranib compared with olaparib and the combination for advanced or recurrent endometrial cancer demonstrated progression‐free survival of 3.8, 2.0, and 5.5 months respectively. The treatment toxicities were manageable but the study did not meet its primary end point.
To investigate the joint impact of sexual orientation, gender identity, and race/ethnicity on colorectal and breast cancer screening disparities in the United States.
Utilizing sampling weighted data ...from the 2016 and 2018 Behavioral Risk Factor Surveillance System, we assessed differences in two metrics via chi-square statistics: 1) lifetime uptake, and 2) up-to-date colorectal and breast cancer screening by sexual orientation and gender identity, within and across racial/ethnic classifications.
Within specific races/ethnicities, lifetime CRC screening was higher among gay/lesbian (within NH-White, Hispanic, and Asian/Pacific Islander) and bisexual individuals (Hispanic) compared to straight individuals, and lowest overall among transgender women and transgender nonconforming populations (p < 0.05). Asian transgender women had the lowest lifetime CRC screening (13.0%; w.n. = 1,428). Lifetime breast cancer screening was lowest among the Hispanic bisexual population (86.6%; w.n. = 26,940) and Hispanic transgender nonconforming population (71.8%; w.n. = 739); within all races, SGM individuals (except NH-White, Hispanic, and Black bisexual populations, and NH-White transgender men) had greater breast cancer screening adherence compared to straight individuals.
Due to small, unweighted sample sizes, results should be interpreted with caution. Heterogeneity in screening participation by SGM status within and across racial/ethnic groups were observed, revealing the need to disaggregate data to account for intersecting identities and for studies with larger sample sizes to increase estimate reliability.
•Lifetime CRC and breast screening are lowest among transgender women, especially among Hispanic and Asian populations.•Individuals who identified as a sexual minority often had higher lifetime screening rates than straight individuals.•Heterogeneity illustrates the need to disaggregate data to account for intersecting identities.•Larger, more representative studies necessary to improve estimate reliability.
This retrospective observational study examined trends, characteristics, and survival of women with synchronous endometrial and ovarian cancer (SEOC) in the Surveillance, Epidemiology, and End ...Results Program between 1973 and 2013. Among 235,454 women with primary endometrial cancer, synchronous ovarian cancer was seen in 4,082 (1.7%) women with the proportion being decreased from 2.0% to 1.6% between 1983 and 2013 (
=0.049); and the proportion of concurrent endometrioid tumors in the two cancer sites has increased from 24.2% to 49.9% among SEOC women (
<0.001). When compared to endometrial cancer without synchronous ovarian cancer, endometrioid histology in the two cancer sites was associated with improved cause-specific survival while non-endometrioid histology in the ovarian cancer was associated with decreased cause-specific survival (adjusted-
<0.01). Among 110,063 women with primary epithelial ovarian cancer, synchronous endometrial cancer was seen in 3,940 (3.6%) women with the proportion being increased from 2.2% to 4.4% between 1973 and 2013 (
<0.001); and the proportion of concurrent endometrioid tumors in the two cancer sites had increased from 24.3% to 50.2% among SEOC women (
<0.001). When compared to primary epithelial ovarian cancer without synchronous endometrial cancer, SEOC was associated with better cause-specific survival if ovarian cancer is endometrioid type or if endometrial cancer is endometrioid type (adjusted-
<0.001). Across the two cohorts, the proportion of SEOC reached to the peak in the late-40 years of age and then decreased significantly (
<0.001). In conclusion, our study suggests that synchronous ovarian cancer has decreased among endometrial cancer whereas synchronous endometrial cancer has increased among epithelial ovarian cancer.
Background Little is known about the role of global DNA methylation in recurrence and chemoresistance of high grade serous ovarian cancer (HGSOC). Methods We performed whole genome bisulfite ...sequencing and transcriptome sequencing in 62 primary and recurrent tumors from 28 patients with stage III/IV HGSOC, of which 11 patients carried germline, pathogenic BRCA1 and/or BRCA2 mutations. Results Landscapes of genome-wide methylation (on average 24.2 million CpGs per tumor) and transcriptomes in primary and recurrent tumors showed extensive heterogeneity between patients but were highly preserved in tumors from the same patient. We identified significant differences in the burden of differentially methylated regions (DMRs) in tumors from BRCA1/2 compared to non-BRCA1/2 carriers (mean 659 DMRs and 388 DMRs in paired comparisons respectively). We identified overexpression of immune pathways in BRCA1/2 carriers compared to non-carriers, implicating an increased immune response in improved survival (P = 0.006) in these BRCA1/2 carriers. Conclusion These findings indicate methylome and gene expression programs established in the primary tumor are conserved throughout disease progression, even after extensive chemotherapy treatment, and that changes in methylation and gene expression are unlikely to serve as drivers for chemoresistance in HGSOC. Keywords: High grade serous ovarian cancer, Methylation, Chemoresistance, Epigenetics, Whole genome bisulfite sequencing, Computational methods, Translational research
BRCA mutation carriers are at increased risk of developing breast cancer. However, the incidence of breast cancer after a diagnosis of epithelial ovarian cancer (EOC), one of the tubal/peritoneal ...cancers collectively referred to as pelvic serous carcinomas, is not well known. Optimal breast cancer surveillance and detection for these patients have also not been well characterized.
To determine the incidence of breast cancer after a diagnosis of EOC and to evaluate the need for breast cancer surveillance for these patients.
A retrospective database review of 364 patients who underwent BRCA mutation testing for EOC (stages I-IV) between 1998 and 2012 at an academic medical center with gynecologic and breast cancer centers.
Incidence of breast cancer and methods of surveillance.
Of 364 patients, 135 (37.1%) were found to carry a germline BRCA1 or BRCA2 mutation. The mean age of patients at diagnosis of EOC was 49.5 years (range, 28-89 years). Of the 135 patients, 12 (8.9%) developed breast cancer. The median time from diagnosis of EOC to diagnosis of breast cancer was 50.5 months. Annual mammography was performed for 80 patients (59.3%), with annual magnetic resonance imaging of the breasts performed for 60 patients (44.4%). Thirteen patients (9.6%) underwent a bilateral prophylactic mastectomy at a median of 23 months following EOC diagnosis. Breast cancer was most commonly diagnosed by mammography for 7 of the 12 patients (58.3%), 3 (25.0%) of whom had a palpable mass and 2 (16.7%) of whom had incidental breast cancer detected during a prophylactic mastectomy. Seven patients with breast cancer (58.3%) underwent a bilateral mastectomy. All patients had early-stage breast cancer (stages 0-II). Four patients (33.3%) received adjuvant chemotherapy. At a median follow-up of 6.3 years, 4 of the 12 patients (33.3%) died of recurrent EOC after a diagnosis of breast cancer. The overall 10-year survival rate for the entire cohort of 135 patients was 17.0%.
The risk of metachronous breast cancer is low in patients with known BRCA mutations and EOC. A majority of these cases of breast cancer at an early stage are detected by use of mammography. Despite the small number of patients in our study, these results suggest that optimal breast cancer surveillance for patients with BRCA-associated EOC needs to be reevaluated given the low incidence of breast cancer among these high-risk patients. Confirmation of our findings from larger studies seems to be indicated.
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