Exploring Treatment Options Through Genomic Sequencing in Endometrial Cancer

Commentary
Article
Rohit Gosain, MD

Rohit Gosain, MD

Rahul Gosain, MD

Rahul Gosain, MD

Shannon N. Westin, MD, MPH

Shannon N. Westin, MD, MPH

In a recent Treatment Algorithms with the Oncology Brothers program, Rohit Gosain, MD, Rahul Gosain, MD, and Shannon N. Westin, MD, MPH, FACOG, discussed treatment options for endometrial genomic subtypes. Rohit is the medical director of the Roswell Park Hematology Oncology Southtowns and an assistant professor of oncology at Roswell Park Care Network in Buffalo, NY. Rahul is the medical director of the Wilmot Cancer Institute in Webster, NY. Westin is the director of Early Drug Development and Phase I Trials in the Department of Gynecologic Oncology and Reproductive Medicine at the University of Texas MD Anderson Cancer Center in Houston, TX.

These experts first explored treatment paradigms based on cancer grade and staging for endometrial cancers, with a focus on neoadjuvant anticancer strategies. After a discussion about treatment based on cancer staging, the experts discussed endometrial cancer treatment by molecular classification, including regarding the role of chemotherapy, radiotherapy, and immunotherapy in this indication. Additionally, recent bucket approvals for solid tumors were addressed, with an emphasis on the role they may play in treating endometrial cancers.

Identifying Histologies in Endometrial Cancer

The experts began by discussing different histologies associated with endometrial cancer. Westin explained that endometrioid type adenocarcinoma is the most common histology for endometrial cancer and that it typically presents as low grade, but with some instances of more aggressive higher-grade tumors. Then, she expressed that uterine serous carcinoma was the next most common, followed by rarer subtypes, such as clear cell carcinosarcoma and undifferentiated sarcoma, stating that non-endometrioid types are typically more aggressive.

According to Westin, care is progressively favoring molecularly vs histology-driven care, citing the Cancer Genome Atlas Program where endometrial cancers were grouped by molecular aberrations. She then explained that endometrioid-type tumors with no symptoms except bleeding typically are subject to less intensive workups and move to surgery quicker than higher-grade tumors.

“If it is an early grade, endometrioid-type tumor, and the patient does not have any symptoms other than bleeding, we often do not get any other workup. We move almost strictly to surgery,” Westin said. “We do a medical workup, ...but, we do not do a big imaging workout. The main thing I will get sometimes is a transvaginal ultrasound, to make sure the uterus is of a size that I can proceed with my surgery in a minimally invasive fashion.”

For higher-grade 3 endometrioid tumors, which Westin identified as uterine serous carcinoma, clear cell carcinosarcoma, and undifferentiated sarcoma, imaging is essential prior to surgery to ensure that the patient does not have advanced-stage disease and that surgery is viable for them. Alternatively, with patients presenting with stage IV disease, complete removal of all disease at the time of surgery is not feasible, and neoadjuvant techniques are considered for this patient group.

Assessing Molecular Classification of Endometrial Cancer Subtypes

The experts then discussed the molecular classification of endometrial cancer as well as its impact on treatment for patients. Westin explained that NCCN and European recommendations enable the use of molecular testing as a standard of care.1 Westin explained that the first genomic analysis is conducted for POLE mutations, followed by mismatch repair proficient or deficient mutations, and then TP53 mutations or wild types; with confirmation done through immunohistochemistry or next-generation sequencing (NGS).

Expressing that molecular testing was still a work in progress, Westin expressed that the International Federation of Gynecology and Obstetrics (FIGO) incorporates molecular testing, but that accessibility concerns for NGS may preclude patients from having POLE or TP53 assessments done.2

“It is still a work in progress, how we are using [molecular testing] to define the patient in front of us and to define the treatment,” Westin said. “If you look at FIGO staging, they do incorporate molecular testing. It is controversial because of that concern that not everyone, everywhere, all over the world, can [access NGS] that is necessary for POLE and TP53 assessment.”

Westin then highlighted data that suggested that tumors with POLE mutations may only need little to no therapy whereas TP53 mutations may benefit from more aggressive therapy and additional treatment outside of surgery for early-stage disease. She further recommended treating patients with POLE mutations, given a relative lack of data and expressed that additional adjuvant therapy may more effectively treat tumors with TP53 mutations.

Rahul then expressed that in his community practice, testing occurs with NGS rather than looking for pinpoint mutations. He then explained that minimally invasive surgeries were ideal for patients who may more quickly recover from surgery to receive adjuvant treatment.

Selecting Treatment Following Surgery for High-Risk Endometrial Cancer

Rahul asked Westin how she decides which patients receive adjuvant treatment and what treatment regimen is best to use. Westin explained that her practice was utilizing depth of invasion grade and lymphovascular space invasion to decide which patients get adjuvant therapy, before suggesting that most patients with early-stage disease have good outcomes without adjuvant therapy. She then iterated that the combination of grade and overarching risk factors dictate who should receive adjuvant therapy.

“Grade 2, of itself, is [likely] not enough [to receive adjuvant therapy], but grade 2, in the setting of deeper invasion, or in the setting of lymphovascular space invasion––maybe somebody who did not have their lymph nodes assessed––we may be more likely to add something like adjuvant radiotherapy,” Westin said. “Specifically in these early stage, early grade [instances] we would be looking at vaginal cuff brachytherapy. It is when we push into...that higher-intermediate risk––which is the deep invasion, the grade 3 or stage II––that is when we start saying, ‘OK, at the very least, we are going to use pelvic radiotherapy or cuff brachytherapy with chemotherapy.’”

Additionally, Westin highlighted a phase 3 trial (NCT00807768) which evaluated pelvic radiotherapy vs cuff brachytherapy and found that there was no survival benefit with cuff brachytherapy and higher adverse effect incidences compared with pelvic radiation.3 She then identified a broad patient group that undergoes platinum-based chemotherapy, encompassing patients who are stage III and IV, patients with disease recurrence, and patients who received little or no neoadjuvant or adjuvant chemotherapy.

Westin stated utilizing carboplatin and paclitaxel for this patient population, with data suggesting that its use is most effective in the adjuvant setting. Alternatively, for patients who are unresectable, neoadjuvant treatment with carboplatin or paclitaxel is being considered with greater frequency. Additionally, she explained that chemoradiation therapy is still considered a standard-of-care, but more for patients who are stage III with nodal metastases.

Westin then discussed the use of chemoradiation therapy when compared with chemotherapy alone or radiation alone, emphasizing that chemotherapy was important in treating this patient population. She further expressed that the NCCN guidelines did not give a definitive preference for any treatment regimen. Westin suggested that conversations with patients to figure out the best strategy become more relevant. She reiterated that paclitaxel and carboplatin were administered, even with chemoradiation.

Considering Immunotherapy with Chemotherapy

Westin then expressed that immunotherapy with inhibition elicits a greater benefit for patients in combination with chemotherapy, with particular benefits observed with mismatch repair deficient or microsatellite instability groups.

“The best bang for our buck when we give immunotherapy with chemotherapy is going to be for patients with [mismatch repair deficient],” said Westin. “We have FDA approvals across 3 drugs, dostarlimab-gxly [Jemperli], pembrolizumab [Keytruda] and durvalumab [Imfinzi] in that space, however, we still see progression-free survival benefit and even overall survival benefit for 1 of them in the all-comers population.4,5,6 [To anyone that listens from Europe], we also have the opportunity to use durvalumab with olaparib [Lynparza] in this patient population.”7

Westin suggested, despite the observed benefit of immunotherapy, that something better will emerge, citing a need to better treat patients with mismatch repair deficiency. She further expressed that classification based on mismatch repair proficiency was too broad, with a need to better specify classifications with additional biomarkers. She reiterated that chemotherapy combined with checkpoint inhibition therapy was the standard of care that she suggested to her patients.

When considering who should receive adjuvant immunotherapy, Westin suggested that patients even as early as early measurable stage III may benefit from immunotherapy, specifically patient groups who are unresectable. Furthermore, she stated that data on earlier-stage endometrial cancer was being developed as early adjuvant therapy following cuff radiation or early radiation. Westin then highlighted ongoing trials assessing whether removing chemotherapy from immunotherapy treatment entirely can still elicit favorable responses.

“I would be remiss if I did not mention current ongoing trials in the mismatch repair deficient group that are looking to get rid of chemotherapy entirely,” Westin said. “Can we give immunotherapy [alone] like we have seen in some of the other solid tumors? Those trials are ongoing, and hopefully, we will report out over the next few years, so we can answer that question.”

Rahul then asked Westin what her practice does in the event that progression occurs after immunotherapy is used up front in patients with mismatch repair deficiency or microsatellite instability. Westin expressed intrigue by the question and asserted that she could not give a perfect answer, given a lack of data. She expressed that lenvatinib (Lenvima) in combination with pembrolizumab was retrospectively evaluated for this indication, but that testing for other molecular aberrations appears preferable to her practice.

Later-Stage Testing and Chemotherapy Selection

Rohit asked if NGS testing was ever considered at a later stage, and Westin explained that the data were not strong, with small studies generally not showing much genomic change between diagnosis and recurrence. She then expressed that it may provide some benefit 3 or 4 years after diagnosis in the event that it is not too costly for the patient.

“It makes sense, especially if the patient is not going to get charged depending on the coverage...I like getting something that is closer to where we are. Things like proteins can be retested and is a lot less expensive and easier to do,” Westin said.

Furthermore, Rohit asked what chemotherapy Westin uses if a patient is platinum-resistant and has experienced recurrence following immunotherapy. Westin listed paclitaxel and doxorubicin as alternatives with tough toxicities but expressed an affinity for gemcitabine and cisplatin. Citing a study assessing the combination in endometrial cancer, she explained that high responses were attained with the regimen, with an ability to overcome platinum resistance in uterine and ovarian cancers.

PARP Inhibitors

Rohit inquired about the role of PARP inhibitors in endometrial cancers, given Westin’s involvement as the primary investigator of the phase 3 DUO-E trial (NCT04269200),8 which evaluated durvalumab plus carboplatin and paclitaxel with or without olaparib in adult patients with advanced or recurrent endometrial cancer. Westin then expressed excitement for the European approval of durvalumab with olaparib in patients with mismatch repair proficient endometrial cancer, given the additive benefit of olaparib in this patient subgroup.

Additionally, Westin explained that her research team was conducting post hoc analyses to assess whether alternative molecular subtypes derived any benefit, such as homologous recombination mutations. However, these mutations are rare and she reiterated the benefit seen in the mismatch repair proficient group.

Bucket Approvals in HER2, NTRK Genomic Subtypes

Rahul then asked Westin to disclose her thoughts on 2 broad approvals, fam-trastuzumab deruxtecan-nxki (Enhertu, T-DXd) for unresectable or metastatic HER2-positive disease in the frontline setting and repotrectinib (Augtyro) in adult and pediatric patients with NTRK gene fusion-positive solid tumors.9,10 Westin explained that she never had a patient with endometrial cancer test positive for NTRK, despite having tested for that mutation in the majority of patients. She then expressed that HER2 positivity was a common occurrence, in 20% to 30% of endometrial cancers, and even greater with pure immunohistochemistry (IHC) 3+ designation.

Westin explained that she uses T-DXd frequently and has witnessed responses in heavily pretreated patient groups. She also noted that commercial NGS test did not test for IHC designation for HER2, which she stated may miss patients who are HER2 positive.

“I'm 100% a believer in T-DXd. We have tested all our patients,” Westin said. “The one thing I will note...is for a while, some of the commercial tests for NGS were not doing IHC for HER2. They were doing only amplification. You were getting reports that said [patients] were HER2-negative. Go back and check those reports, because if you check that protein, you may [find] some [patients] that are positive that can receive this drug.”

References

  1. NCCN. NCCN clinical practice guidelines in oncology (NCCN Guideines): uterine neoplasms, version 3.2024. Accessed November 22, 2024. https://tinyurl.com/5cs9r7jz
  2. Berek JS, Matias-Guiu X, Creutzberg C, et al. FIGO staging of endometrial cancer: 2023. Int J Gynaecol Obstet. 2023;162(2):282-394. doi:10.1002/ijgo.14923
  3. Randall ME, Filiaci V, McMeekin DS, et al. Phase III trial: adjuvant pelvic radiation therapy versus vaginal brachytherapy plus paclitaxel/carboplatin in high-intermediate and high-risk early-stage endometrial cancer. J Clin Oncol. 2019;37(21):1810-1818. doi:10.1200/JCO.18.01575
  4. FDA expands endometrial cancer indication for dostarlimab-gxly with chemotherapy. FDA. August 1, 2024. Accessed November 22, 2024. https://tinyurl.com/fvtjde2w
  5. FDA approves pembrolizumab with chemotherapy for primary advanced or recurrent endometrial carcinoma. FDA. June 17, 2024. Accessed November 22, 2024. https://tinyurl.com/w2f9wf5u
  6. FDA approves durvalumab with chemotherapy for mismatch repair deficient primary advanced or recurrent endometrial cancer. FDA. June 14, 2024. Accessed November 22, 2024. https://tinyurl.com/ycefy699
  7. Lynparza and Imfinzi combination approved in the EU for patients with mismatch repair proficient advanced or recurrent endometrial cancer. AstraZeneca. August 14, 2024. Accessed November 22, 2024. https://tinyurl.com/3x49jvap
  8. Westin SN, Moore K, Chon HS, et al. Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer: the phase III DUO-E trial. J Clin Oncol. 2023;42(3):283-299. doi:10.1200/JCO.23.02132
  9. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. FDA. April 5, 2024. Accessed November 22, 2024. https://tinyurl.com/5zdbdhda
  10. FDA grants accelerated approval to repotrectinib for adult and pediatric patients with NTRK gene fusion-positive solid tumors. FDA. June 13, 2024. Accessed November 22, 2024. https://tinyurl.com/bdzd66hj
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