MD Anderson Research Highlights: SGO 2022 Special Edition

Key presentations focused on genomic sequencing, standard of care approaches for cervical cancer, disparities in oncofertility and new mutations for targeted therapy

The University of Texas MD Anderson Cancer Center’s Research Highlights provides a glimpse into recent studies in basic, translational and clinical cancer research from MD Anderson experts. This special edition features oral presentations on women’s cancers by MD Anderson researchers at the Society of Gynecologic Oncology (SGO) 2022 Annual Meeting on Women’s Cancer, including genomic sequencing of ovarian cancer, evidence supporting open radical hysterectomy for cervical cancer, disparities in oncofertility, a novel therapeutic target for ovarian cancer and new data on anal human papillomavirus (HPV) infection for at-risk women.

Genomic sequencing shows improved outcomes for MAPK-mutated tumors

Low-grade serous ovarian/peritoneal carcinoma (LGSOC) is a rare type of ovarian cancer that often carries activating mutations in the MAPK pathway, which plays a major role in the pathogenesis of this subtype. Compared to high-grade serous carcinoma, LGSOC is often diagnosed at a younger age in advanced stages and is characterized by prolonged overall survival (OS). In addition, LGSOC is relatively resistant to platinum-based chemotherapy, highlighting the importance of comprehensive genomic analysis to identify new therapeutic targets and improve prognosis of these patients.

In a single-institution study led by David Gershenson, M.D., researchers used next generation sequencing to analyze the genomic profile of 215 LGSOC patient samples and discover potential relationships with clinical outcomes. Most patients had stage III LGSCO and 140 (65%) had one or more mutations in the MAPK pathway, including KRAS, NRAS, BRAF, MAP2K1 and RAF1.

The study found that patients with MAPK-mutated tumors had a significantly longer progression-free survival (PFS) of 31.4 months and OS of 147.8 months compared to those without mutations, who had a PFS of 23.7 months and OS of 89.5 months. Researchers suggest this emphasizes the need to develop novel therapies for women with non-MAPK-mutated LGSOC.

Minimally invasive surgery continues to show worse survival for women with cervical cancer

Open radical hysterectomy is the current surgical standard of care for patients with early cervical cancer, based on initial results from the Laparoscopic Approach to Cervical Cancer LACC trial led by Pedro Ramirez, M.D., which revealed that minimally invasive surgery was associated with four times higher recurrence rates when compared to the open approach.

In an updated analysis at a median follow-up of 4.5 years, results showed that disease-free survival was 96% for patients undergoing open surgery compared to 85% for those undergoing minimally invasive surgery. The recurrence rate remained four times higher and OS was three times worse with the minimally invasive approach.

In an exploratory analysis, the investigators also reported that the recurrence rate was more than four times higher in the minimally invasive approach for tumors larger than 2 centimeters and six times higher for patients who did not have a previous cone biopsy. Additionally, in patients with disease recurrence, the rate of metastasis after minimally invasive surgery was 24% compared to 0% with the open approach.

The results of this study provide further support that the open radical hysterectomy should be considered the standard of care in patients with early-stage cervical cancer.

Disparities in oncofertility among breast, ovarian, cervical and endometrial cancer patients

Therapeutic advancements have improved prognosis and survival rates for cancer patients, but current treatments can have adverse effects on patients’ reproductive ability. Two beneficial approaches are available to preserve fertility, including assisted reproductive technology (ART) —  medical treatments or procedures that handle eggs and sperm to address infertility — and fertility-sparing (FS) oncology care — surgical or medical interventions that retain the uterus and at least one ovary for gynecologic cancers. However, the utilization of ART and FS oncology care in women with a history of gynecologic or breast cancer has historically been understudied.

To better understand the rates of ART and FS oncology care, Kirsten Jorgensen, M.D., and a team of MD Anderson researchers linked population-level databases to characterize disparities in oncofertility. They identified women between the ages of 18 and 45 who were diagnosed with breast, ovarian, cervical or endometrial cancer and assessed receipt of FS oncology care and ART utilization.

They found that ART is underutilized by women following a breast or gynecologic cancer diagnosis. Non-Hispanic Black (NHB) and Hispanic women with a history of breast cancer were less likely to receive ART compared to non-Hispanic White (NHW) women. Conversely, NHB women had slightly higher odds of receiving FS oncology care after a diagnosis of ovarian cancer or endometrial cancer compared to NHW women. In addition, the researchers found lower rates for both ART utilization and FS oncology care among rural and uninsured women, regardless of cancer type. Ultimately, further studies are necessary to understand these disparities given overall infrequent outcomes.

Mutations in PPP2R1A may correlate with exceptional survival in ovarian cancer

Immune checkpoint inhibitors (ICI) offer some patients dramatic and durable disease regression, but response rates in recurrent ovarian cancer have remained low. While emerging data suggest increased activity in patients with ovarian clear cell carcinomas (OCCC), only a minority of patients derive benefit.

Using retrospective and prospective preliminary data from an ongoing clinical trial led by Amir Jazaeri, M.D., a team of researchers investigated biomarkers associated with long-term survival in 28 patients with recurrent, platinum-resistant OCCC who had been treated with anti-CTLA-4 and anti-PD1/L1 ICI. The most commonly mutated genes identified among the patients were ARID1A (72%), PIK3CA (57%) and PPP2R1A (25%). 

Patients with the PPP2R1A hotspot mutation achieved significantly longer OS compared to those without the mutation. Median OS was not reached in seven patients with hotspot inactivation mutations in PPP2R1A, whereas 21 patients with non-PPP2R1A-mutated OCCC achieved a median overall survival of 6.4 months. Notably, several patients achieved prolonged stable disease leading to longer survival after initial progression. In addition, PPP2R1A mutations were associated with more severe grade 3 or higher immune-related adverse events.

While previous studies have shown that the mutation of ARID1A is present in more than 50% of OCCC cases and may be an attractive therapeutic target, preliminary data from this study suggest that PPP2R1A mutations may serve as a better biomarker for long-term survival benefit from ICI. Researchers are conducting ongoing research to determine the causal relationship.

Prospective study shows increased prevalence of anal HPV infection in women with cervical, vaginal and vulvar dysplasia or cancer

High-risk human papillomavirus (HR HPV) infection is known to be the most important risk factor for anal cancer and has been linked to more than 90% of all cases. While its role in the development of anal cancer is well established, there is a lack of evidence-based anal cancer screening guidelines for at-risk women, including those with HPV-related dysplasia and/or cancer of the lower genital tract, including the cervix, vagina and vulva.

In a cross-sectional prospective study led by Kathleen Schmeler, M.D., researchers analyzed the prevalence of anal dysplasia in 324 women, 21 years and older, with cervical, vaginal or vulvar dysplasia or cancer. Primary diagnosis was high-grade dysplasia/cancer of the cervix in 250 patients (77%), followed by vaginal in 28 patients (9%) and vulvar in 46 patients (14%).

The results suggested that women with lower genital tract dysplasia or cancer had a high prevalence of HR anal HPV infection and cytologic abnormalities. Anal cytology was abnormal in 70 patients (23%), including 56 with atypical squamous cells of undetermined significance (80%), 6 with low-grade squamous intraepithelial lesions (9%) and 1 with high-grade squamous intraepithelial lesion (1%). HR anal HPV was detected in 92 patients (28%), while 154 patients (48%) tested positive for HR cervical/vaginal HPV and 60 patients (36%) had both anal and cervical/vaginal HR HPV detected. In contrast, 32 (19%) had positive anal but negative cervical/vaginal HR HPV, and 76 (45%) had negative anal but positive cervical/vaginal HR HPV.

The higher prevalence of HR anal HPV infection and anal cytologic abnormalities in women with cervical, vaginal and vulvar malignancies reinforces the need for further studies to determine the rate of progression to high-grade anal dysplasia and cancer and to inform appropriate screening guidelines in this population.