Mirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody-drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant ovarian cancer in the United ...States.
We conducted a phase 3, global, confirmatory, open-label, randomized, controlled trial to compare the efficacy and safety of MIRV with the investigator's choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received one to three lines of therapy and had high FRα tumor expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive MIRV (6 mg per kilogram of adjusted ideal body weight every 3 weeks) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary end point was investigator-assessed progression-free survival; key secondary analytic end points included objective response, overall survival, and participant-reported outcomes.
A total of 453 participants underwent randomization; 227 were assigned to the MIRV group and 226 to the chemotherapy group. The median progression-free survival was 5.62 months (95% confidence interval CI, 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001). An objective response occurred in 42.3% of the participants in the MIRV group and in 15.9% of those in the chemotherapy group (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001). Overall survival was significantly longer with MIRV than with chemotherapy (median, 16.46 months vs. 12.75 months; hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P = 0.005). During the treatment period, fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%).
Among participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.).
Background
Mismatch‐repair (MMR)/microsatellite instability (MSI) status has therapeutic implications in endometrial cancer (EC). The authors evaluated the concordance of testing and factors ...contributing to MMR expression heterogeneity.
Methods
Six hundred sixty‐six ECs were characterized using immunohistochemistry (IHC), MSI testing, and mut‐L homolog 1 (MLH1) methylation. Select samples underwent whole‐transcriptome analysis and next‐generation sequencing. MMR expression of metastatic/recurrent sites was evaluated.
Results
MSI testing identified 27.3% of cases as MSI‐high (n = 182), MMR IHC identified 25.1% cases as MMR‐deficient (n = 167), and 3.8% of cases (n = 25) demonstrated discordant results. A review of IHC staining explained discordant results in 18 cases, revealing subclonal loss of MLH1/Pms 1 homolog 2 (PMS2) (n = 10) and heterogeneous MMR IHC (mut‐S homolog 6 MSH6, n = 7; MLH1/PMS2, n = 1). MSH6‐associated Lynch syndrome was diagnosed in three of six cases with heterogeneous expression. Subclonal or heterogeneous cases had a 38.9% recurrence rate (compared with 16.7% in complete MMR‐deficient cases and 9% in MMR‐proficient cases) and had abnormal MMR IHC results in all metastatic recurrent sites (n = 7). Tumors with subclonal MLH1/PMS2 demonstrated 74 differentially expressed genes (determined using digital spatial transcriptomics) when stratified by MLH1 expression, including many associated with epithelial–mesenchymal transition.
Conclusions
Subclonal/heterogeneous MMR IHC cases showed epigenetic loss in 66.7%, germline mutations in 16.7%, and somatic mutations in 16.7%. MMR IHC reported as intact/deficient missed 21% of cases of Lynch syndrome. EC with subclonal/heterogeneous MMR expression demonstrated a high recurrence rate, and metastatic/recurrent sites were MMR‐deficient. Transcriptional analysis indicated an increased risk for migration/metastasis, suggesting that clonal MMR deficiency may be a driver for tumor aggressiveness. Reporting MMR IHC only as intact/deficient, without reporting subclonal and heterogeneous staining, misses opportunities for biomarker‐directed therapy.
Plain Language Summary
Endometrial cancer is the most common gynecologic cancer, and 20%–40% of tumors have a defect in DNA proofreading known as mismatch‐repair (MMR) deficiency.
These results can be used to guide therapy.
Tests for this defect can yield differing results, revealing heterogeneous (mixed) proofreading capabilities.
Tumors with discordant testing results and mixed MMR findings can have germline or somatic defects in MMR genes.
Cells with deficient DNA proofreading in tumors with mixed MMR findings have DNA expression profiles linked to more aggressive characteristics and cancer spread.
These MMR‐deficient cells may drive tumor behavior and the risk of spreading cancer.
Intratumoral heterogeneity, including subclonal and heterogeneous mismatch‐repair (MMR) expression, can yield discordant results from diagnostic assays, such as immunohistochemistry and polymerase chain reaction‐based microsatellite instability testing. Within endometrial cancers, subclonal or heterogeneous MMR expression may be attributed to germline or somatic mutations in MMR proteins, and the authors demonstrate that these tumors are characterized by clonal selection favoring the propagation of MMR deficiency at sites of metastasis or recurrence.
To determine associations between adoption of Medicaid expansion (ME) and changes in insurance status, early stage diagnosis, and cancer survival among women with endometrial carcinoma (EC).
The ...National Cancer Database (NCDB) was queried for patients diagnosed with EC between the age 40–64 from 2004 to 2015. Difference-in-differences analysis quantified the impact of ME on the proportion of new EC diagnoses with insurance (vs. uninsured), the proportion diagnosed with stage I (vs. II-IV), and overall survival.
156,253 patients were included. Among 65,019 women living in ME states, ME is associated with an increase in the percent of EC cases who are insured of 1.4% (95% CI 0.9–2.0%, p < 0.0001), with strongest effects among Hispanic women, women in the lowest income quartile, and women in the second age quartile (age 53–57). There was no overall impact of ME on stage, though an increase of early stage diagnoses by 2.4% (95% CI 0.3–4.5%, p = 0.022) was observed among women age 53–57. There was a trend towards improved overall survival with ME, which was strongest in women age 53–57 (HR = 0.83, 95% CI 0.70–0.99, p = 0.037).
Among women with EC, ME positively impacted insurance coverage, an important hurdle in accessing health care. In women aged 53–57, ME was associated with earlier stage at diagnosis and improved survival, suggesting that the magnitude of the improvement in insurance coverage may correlate with important clinical outcomes. Efforts should continue to understand the complexity of barriers to health care access and to develop effective strategies to surmount them.
•Medicaid expansion improves insurance coverage for endometrial cancer patients.•Expansion improves coverage to a larger extent for some groups.•Some groups that experience a larger increase in coverage present at earlier stage.
Racial and ethnic disparities in gynecologic cancer care have been documented. Treatment at academic facilities is associated with improved survival, yet no study has examined independent ...associations between race and ethnicity with facility type among gynecologic cancer patients.
We used the National Cancer Database and identified 484,455 gynecologic cancer (cervix, ovarian, uterine) patients diagnosed between 2004 and 2020. Facility type was dichotomized as academic vs. non-academic, and we used logistic regression to estimate multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) between race and ethnicity and facility type. Secondarily, we examined joint effects of race and ethnicity and facility type on overall survival using Cox proportional hazards regression.
We observed higher odds of treatment at academic (vs. non-academic) facilities among American Indian/Alaska Native (OR = 1.42, 95% CI = 1.28–1.57), Asian (OR = 1.64, 95% CI = 1.59–1.70), Black (OR = 1.69, 95% CI = 1.65–1.72), Hispanic (OR = 1.70, 95% CI = 1.66–1.75), Native Hawaiian/Pacific Islander (OR = 1.74, 95% CI = 1.57–1.93), and other race (OR = 1.29, 95% CI = 1.20–1.40) patients compared with White patients. In the joint effects survival analysis with White, academic facility-treated patients as the reference group, Asian, Hispanic, and other race patients treated at academic or non-academic facilities had improved overall survival. Conversely, Black patients treated at academic facilities Hazard Ratio (HR) = 1.10, 95% CI = 1.07–1.12 or non-academic facilities (HR = 1.19, 95% CI = 1.16–1.21) had worse survival.
Minoritized gynecologic cancer patients were more likely than White patients to receive treatment at academic facilities. Importantly, survival outcomes among patients receiving care at academic institutions differed by race, requiring research to investigate intra-facility survival disparities.
•Minoritized gynecologic cancer patients were more likely than White patients to receive treatment at an academic facility.•Compared with White, academic facility-treated patients, Asian and Hispanic patients had improved overall survival.•Black patients had worse survival, regardless of treatment facility, when compared with White, academic facility-treated patients.
OBJECTIVETo determine the prevalence of Type 2 diabetes mellitus (T2DM) diagnoses during the peri-operative and survivorship periods in patients following surgical management of endometrial cancer ...(EC). METHODSAn IRB-approved, retrospective single-institution cohort study was performed in patients who underwent surgical management of EC from 2014 to 2020. The perioperative period was defined as the 30 days before and after surgery. T2DM diagnoses occurring during survivorship were recorded. T2DM diagnoses were defined by a HgbA1c ≥6.5% or a random blood glucose ≥200 mg/dL. Sequelae of peri-operative T2DM and predictors of future T2DM were examined utilizing univariate analysis. RESULTSOf 519 patients meeting inclusion criteria, 37 (7.1%) were diagnosed with T2DM in the perioperative period. Patients diagnosed with T2DM in the perioperative period had significantly higher BMI (p = 0.006) compared to no T2DM, but there were no significant differences in age (p = 0.20), ethnicity/race (p > 0.05) or ECOG score (p = 0.19). The rates of intraoperative complications between groups did not significantly differ, except for vascular complications (p = 0.005), and the incidence of any postoperative complication was higher in the perioperative T2DM group (p = 0.01). With a median follow-up of 29 months range 11.6-49.0 months, an additional 18.3% (n = 88) of the cohort met diagnostic criteria for T2DM. BMI (p < 0.001), perioperative glucose (p < 0.001), and HgbA1c (p = 0.002) demonstrate risk for a T2DM diagnosis during survivorship. CONCLUSION(S)In this retrospective cohort of EC patients, 25.4% were diagnosed with T2DM, with the majority diagnosed in the survivorship period. Surgical management and subsequent surveillance of EC presents an opportunity to diagnose at-risk patients with T2DM.
We sought to evaluate the contribution of mismatch repair (MMR) status to traditional risk stratification algorithms used to predict nodal involvement and recurrence in a large single-institution ...cohort.
Endometrioid endometrial cancer (EC) cases from 2014-2020 were evaluated. MMR immunohistochemistry (IHC) was performed universally. Uterine factors assessed in the Mayo criteria were used to retrospectively classify patients as low or high risk for lymphatic spread. Patients were classified according to risk for recurrence using GOG 99 and PORTEC criteria. Associations were evaluated using chi-square and t-tests and contributing factors assessed using logistic regression models.
1,514 endometrioid EC were evaluated; 392 (25.9%) were MMR (MMR) deficient of which 80.4% of MMR defects were associated with epigenetic silencing of
. Epigenetic MMR defects were significantly more likely to be high risk for lymph node (LN) metastasis based on Mayo criteria (74.9% vs 60.6%,
=<0.001) and with the presence of LN metastasis (20.3 vs 10.5%,
=0.003) compared to MMR proficient tumors. Tumors with epigenetic MMR defects were significantly more likely to be classified as high or high intermediate risk using GOG99 and PORTEC criteria. Furthermore, cases with epigenetic MMR defects classified as low or low intermediate risk were significantly more likely to recur (GOG99
=0.013; PORTEC
=0.008) and independently associated with worse disease-free survival (DFS). MMR status was found to be independently associated with worse DFS (HR 1.90; 95% CI 1.34-2.70;
=0.003) but not overall survival.
While MMR deficient EC has been associated with poor prognostic features in prior reports; we demonstrate that only epigenetic MMR defects have poorer outcomes. Epigenetic MMR defect were independently associated with lymph node metastasis after controlling for risk criteria. Epigenetic MMR deficiency was found to be an independent predictor of recurrence beyond the factors considered in traditional risk stratification algorithms. Traditional uterine-based risk stratification algorithms may not fully reflect the risk for recurrence in MMR deficient tumors. Consideration should be given to implementing MMR status and
hypermethylation alongside traditional risk stratification algorithms. Performing MMR IHC on preoperative pathologic specimens may aid in risk stratification and patient counseling.
Most women diagnosed with endometrial cancer undergo primary surgical management with hysterectomy. Although racial disparities in readmission risk following hysterectomy for non-cancerous conditions ...have been reported, data among women with endometrial cancer are absent. This study evaluates racial differences in readmission risk among women undergoing endometrial cancer-related hysterectomy.
In the National Cancer Database, women who underwent surgical management for endometrial cancer from 2004 to 2018 were identified. Readmission and minimally invasive hysterectomy (MIH) proportions were plotted according to year of diagnosis and race/ethnicity. Multivariable logistic regression models were used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations between readmission risk and epidemiological, facility, tumor, and surgical characteristics. A base model was sequentially adjusted to incorporate significant covariates.
There were 350,631 patients included in the study. The proportion of MIH increased among all race/ethnicities over the study period; however, MIH rates were lower among Black women. Readmission proportions were 2.7% among White, 4.2% among Black, 2.9% among Hispanic, 2.4% among Asian, 2.1% among American Indian/Alaska Native, and 3.1% among Native Hawaiian/Pacific Islander women. In the fully adjusted model incorporating surgical approach, Black women (OR: 1.20, 95% CI = 1.13, 1.28) and Native Hawaiian/Pacific Islander women (OR: 1.54, 95% CI = 1.09, 2.18) were more commonly readmitted compared to White women.
In this study, Black and Native Hawaiian/Pacific Islander women with endometrial cancer had significantly higher readmission risk than White women. Optimizing perioperative care for minority women is an essential component of overcoming racially disparate endometrial cancer outcomes.
•Black and Native Hawaiian/Pacific Islander women are more likely than White women to be readmitted following hysterectomy.•Readmission rates consistently declined over the study period for White and Black women but varied among other groups.•Minimally invasive hysterectomy increased among women of all race/ethnicity groups during the study period.•In analyses stratified by procedure type, readmission was higher among Black as compared with White women.
The use of a platinum doublet for the treatment of platinum-sensitive epithelial ovarian cancer (EOC) recurrence is well established. The impact of the non‑platinum chemotherapy used as part of a ...platinum doublet on PARP inhibitor (PARPi) and platinum sensitivity it not known. We aimed to describe oncologic outcomes in cases of recurrent EOC receiving PARPi as maintenance therapy based on preceding platinum doublet.
Retrospective study of patients with platinum-sensitive recurrent ovarian, fallopian tube or primary peritoneal cancer treated with platinum doublet followed by maintenance PARPi from 1/1/2015 and 1/1/2022. Comparisons were made between patients receiving carboplatin + pegylated liposomal doxorubicin (CD) versus other platinum doublets (OPDs). Descriptive statistics, Kaplan-Meier and univariate survival analyses were performed.
100 patients received PARPi maintenance following a platinum doublet chemotherapy regimen for platinum-sensitive recurrence. 25/100 (25%) received CD and 75/100 (75%) received OPDs. Comparing CD and OPDs, median progression-free survival was 8 versus 7 months (p = 0.26), median time to platinum resistance was 15 versus 13 months (p = 0.54), median OS was 64 versus 90 months (p = 0.28), and median OS from starting PARPi was 25 versus 26 months (p = 0.90), respectively.
Using pegylated liposomal doxorubicin as part of a platinum doublet preceding maintenance PARPi for platinum-sensitive recurrence does not seem to hasten PARPi resistance or platinum resistance compared to OPDs. Although there was a non-significant trend towards increased OS among patients who received a platinum doublet other than CD prior to PARPi, the OS from PARPi start was similar between groups. Given the retrospective nature of this study and small study population, further research is needed to evaluate if the choice of platinum doublet preceding PARPi maintenance impacts PARPi resistance, platinum resistance and survival.
•The impact of platinum doublet for platinum-sensitive treatment on PARP inhibitor/platinum resistance has been questioned.•There was no difference in the development of PARP/platinum resistance between the different platinum doublets.•Further study is needed to better understand mechanisms of resistance to PARP inhibitors and platinum.
Uterine cancers are associated with a high risk for venous thromboembolisms. The American Society of Clinical Oncology practice guidelines recommend that all patients undergoing pelvic surgery for ...cancer should receive extended pharmacologic thromboprophylaxis with the duration being dependent on risk. However, risk stratification for patients with uterine cancer is not clearly defined. The Caprini score is the most widely used risk assessment model but it has been found to have limited use in the gynecologic oncology population. A modified Caprini score has been explored in other populations. The Khorana score is an additional risk assessment model that has not been studied in this context.
Our objective was to evaluate the ability of a modified Caprini model and the Khorana score to risk stratify patients with uterine cancer for postoperative venous thromboembolisms within 90 days of surgery.
Following institutional review board approval, a retrospective cohort study was performed, and all patients with uterine cancer who underwent a hysterectomy over a 4-year period were included. The Caprini and Khorana scores were calculated for each patient. The Caprini score cutoff for highest risk was evaluated at ≥7, ≥8, and ≥9 (modified Caprini) and the Khorana score cutoff was evaluated at ≥2 and ≥3. To determine the prognostic use of each score and other clinico-pathologic criteria related to the development of a venous thromboembolism, univariate analyses were performed using independent t tests, chi-square tests, or Fisher’s exact tests; a multivariate analysis was performed using logistic regression.
A total of 954 patients were included. The rate of venous thromboembolism development was 1.7% (16/954). A minimally invasive surgical approach was used in 90.5% (863/954) of patients. The mean Caprini score for patients with a venous thromboembolism was 10.3 compared with 8.1 for patients without a venous thromboembolism (95% confidence interval, 1.17–3.33; P<.0001). The mean Khorana score for the venous thromboembolism group was 2.4 vs 1.9 for those without (95% confidence interval, 0.04–0.82; P=.03). Both the Caprini and Khorana scores were found to be associated with venous thromboembolisms, but only a Caprini score with a cutoff of ≥8 or ≥9 was statistically significant (risk ratio, 31.25; 95% confidence interval, 1.88–519.49; risk ratio, 4.59; 95% confidence interval, 1.49–14.13, respectively), with high accuracy based on the area under the curve (0.75 and 0.68, respectively). Of the minimally invasive subgroup, 11.7% (101/863) of patients had same-day discharge with no postoperative thromboprophylaxis; none of these patients developed venous thromboembolisms. Despite extended prophylaxis among the laparotomy patients (30 days), the rate of venous thromboembolisms was more than 3 times that of the minimally invasive group (5.49% vs 1.7%). Advanced tumor stage and leukocytosis were noted to be independent risk factors for venous thromboembolisms.
Our study suggests that using a modified Caprini score could help to identify the highest-risk patients who would benefit from prolonged thromboprophylaxis, could reduce the incidence of postoperative venous thromboembolisms, and could minimize the cost and harm of overtreatment. These findings need to be validated in a prospective manner, and further research is needed to determine the optimal duration of therapy.
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