Mutations Pass From Primary to Recurrent Endometrial Cancer

Stephanie Wethington, MD

Most recurrent endometrial tumors have the same PI3K/Akt mutation profile as found in the primary tumor, results of a small clinical study show. Mutations in the PI3K/Akt pathway exhibited concordance between primary and recurrent tumors in 24 of 28 women.

The findings have implications for ongoing development of therapies that target the pathway in endometrial cancer, Stephanie Wethington, MD, reported at the Society of Gynecologic Oncology Annual Meeting on Women’s Cancer.

“The majority of recurrent endometrial tumors retain the PI3K/Akt abnormalities identified in the primary tumor,” said Wethington, an oncology resident at Memorial Sloan-Kettering Cancer Center in New York City. “The data suggest that the PI3K/Akt mutation profile of the primary tumor is a reasonable surrogate when tissue from the recurrent tumor is not available for biopsy.”

“The four patients with discordant mutation profiles all received adjuvant therapy, and no treatment or histopathology factors were found to be associated with concordant or discordant profiles,” she added.

Patients with advanced or recurrent endometrial cancer have few treatment options and a median overall survival of less than 15 months. Primary endometrial tumors frequently exhibit dysregulation of the PI3K/Akt pathway, and several new drugs in clinical development target that pathway.

Most patients evaluated for clinical trials have advanced or recurrent disease, and eligibility for the trials often depends upon the presence of mutations targeted by the therapies, Wethington noted. Whether PI3K/Akt abnormalities are preserved between primary and recurrent endometrial cancer had not been carefully examined. Because tumor tissue from recurrent tumors might not be available for assay, knowing the extent of mutational concordance with the primary tumor could provide guidance for clinical decisions about the use of PI3K/Akt inhibitors.

Investigators hypothesized that mutations in the primary tumor would be preserved in recurrent endometrial cancer. To examine the issue, they studied PI3K/Akt abnormalities in paired specimens of primary and recurrent endometrial cancer obtained from the same patient.

Using microdissected tissue from the paired specimens, Wethington and colleagues extracted DNA and performed whole-genome amplification. The mutation status of each specimen was assessed by mass spectrometry, Sanger sequencing, and immunohistochemistry.

The 28 patients had a median age at diagnosis of 62 years, and tumor stage was evenly distributed between stages I-II and III-IV. Half of the patients had endometrioid tumors, 11 had serous tumors, and the remaining three had ambiguous histology. Median time to recurrence was 18 months. Median follow-up was 51 months, and the patients had a median overall survival of 59 months.

By one or more assays, the investigators identified seven types of mutations, the most common involving PTEN (11 patients), PIK3CA (eight), and TP53 (seven). All but four of the patients had either a PI3K/Akt mutation or loss of PTEN.

Paired specimens exhibited discordant mutations in four cases. Two patients had mutations found in the primary tumor but not the recurrent tumor (loss of function), and two patients had mutations in the recurrent tumor that were not present in the primary tumor (gain of function).

Wethington S, Garg K, Makker V, et al. PI3K/AKT pathway alterations in paired primary and recurrent endometrial carcinoma. Presented at the 43rd Annual Meeting of the Society of Gynecologic Oncology; March 24-27, 2012; Austin, TX. Gynecol Oncol. 2012;125(suppl):S1-S188. Abstract 13.