KEYNOTE-146: A New Treatment Option for Advanced Endometrial Cancer - Episode 1

Evolving Treatments for Advanced Endometrial Cancer

Transcript:Vicky Makker, MD: I’ll start by discussing just the incidence in mortality of endometrial cancer and also sort of cover the landscape in terms of therapy for patients in the adjuvant disease setting and the advanced disease setting in this disease as well.

Endometrial cancer is the most common gynecological malignancy in the United States. And alarmingly, the incidence and mortality associated with this cancer are actually sharply on the rise. There are a number of factors that are felt to be responsible for this alarming trend in this disease; chief among them is obesity. Obesity causes a number of perturbations that can directly promote tumor genesis.

Obesity is now reaching epidemic proportions in this country. Among the perturbations that can occur as a result of obesity include chronic inflammation. That can be peritumoral and can also occur distantly. It can also lead to hyperglycemia, hyperinsulinemia, insulin resistance, abnormalities in the insulin IGF-1 [insulin-like growth factor 1] signaling pathway that can directly lead to activation of the PI3 kinase AKT/MTOR pathway that can promote tumorigenesis. Obesity can also lead to adipokine pathophysiology alterations, and really other changes that can promote this disease.

This is a very large problem in this cancer specifically. However, thankfully, most patients with this disease are still diagnosed with early-stage disease. However, approximately 21% of patients will have regional spread of disease to either pelvic lymph nodes or adjacent structures, and approximately 9% of patients will have distant metastases at time of diagnosis.

In terms of the management of endometrial cancer patients, the initial step is surgical resection for the vast majority of patients, and that surgical resection—and a proper surgical staging—is very important because the stage informs treatment. Other factors that are very important in this disease in terms of informing treatment include the histology of the disease and also the molecular phenotype of this cancer.

With regards to up-front treatment, adjuvant therapy, the goal is to reduce the chance of recurrence, and it is those dose factors—again, the histology, the stage, and a molecular phenotype, along with adverse risk factors—that really inform adjuvant therapy for patients.

Adverse risk factors in this disease do include aspects of the tumor, such as high grade, advanced age of the patient, lymphovascular invasion, deep myometrial invasion, and then other factors such as lower uterine segment involvement, for example.

With these factors we determine whether patients are high risk or of lesser risk. Patients who are considered high risk include what we classically think of as type 2 endometrial cancers. These are the more rare subtypes of uterine cancers. They include serous, clear cell, carcinosarcoma, and other rare subtypes. And other patients who are considered high risk include the grade 3 endometrioid adenocarcinomas that have deep myometrial invasion. Certainly the stage III, stage IVa patients, regardless of the histology. And the reason these patients are high risk is that they really have aggressive behavior and can lead to early recurrences. For these patients the general approach is multimodality therapy, even for the very early-stage patients.

For patients who are advanced stage and are deemed unresectable, the usual approach is to offer chemotherapy. The role of radiation therapy in these patients is individualized, and it’s based on the bulk of tumor and also location of tumor. The additional factor that I think is very important in endometrial cancer is the molecular phenotype, which I keep alluding to.

And so in 2013, the TCGA [The Cancer Genome Atlas] endeavor really refined our understanding of endometrial cancers and really defined 4 subtypes of endometrial cancers that are associated with different progression-free survival. So these 4 subtypes include the following. The first are what we call POLE [polymerase e] ultramutated subtype. This subtype is associated with hot spot mutations in the catalytic subunit of DNA polymer epsilon. This subgroup includes the endometrioid adenocarcinoma subtypes as far as histology is concerned. And more than 50% of these patients are the grade 3 endometrioid adenocarcinomas. And this subtype actually has the best survival. In fact, it comprises about 1% of the recurrent-disease patient population.

The other, the next subtype is the microsatellite instability hypermutated subtype. This subtype also consists of the endometrioid adeno carcinomas. It is associated with mutations in the DNA mismatch repair genes that are involved DNA replication and repair. And this subtype comprises about 25% of patients in the recurrent-disease patient population. Again, overall, this subtype tends to do well.

The remaining subtypes are what we call copy-number low and copy-number high subtypes. So the copy-number low consist of the low-grade endometrioid adenocarcinomas. These are the grade 1, grade 2 subtypes. The copy-number high group are the serous or serous-like groups. This subtype has a very high number of copy number alterations, has mutations in TP53, and the molecular landscape of this particular subtype overlaps with basal breast cancers and serous cancers of ovarian etiology, but there are notable differences. For example, about 25% of the subgroup has amplifications in ERBB2, which is a target that is relevant in the advanced-disease population.

The copy-number, higher serous-like group is really associated with the worse progression-free survival. So this is a very aggressive subtype that we worry about in the recurrent-disease population.

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Transcript Edited for Clarity.