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Grade 3 Endometrioid Carcinoma With PIK3CA Mutation Linked to Unfavorable Outcome

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Key Points

  • The presence of PIK3CA exon 9 or exon 20 missense mutation was confirmed in 20% of the tumors tested, with no real difference across the histologic types.
  • In grade 3 endometrioid carcinoma but not serous endometrial carcinoma, the presence of PIK3CA missense mutation is associated with an unfavorable outcome.
  • There appears to be a connection between PIK3CA mutation and mismatch repair deficiency and loss of ARID1A expression in grade 3 endometrioid carcinoma.

The presence of PIK3CA missense mutation appears to be associated with shorter disease-specific survival in grade 3 endometrioid but not serous endometrial carcinoma, according to a study in Gynecologic Oncology. Although McIntyre et al found this type of mutation across all histologic types of high-grade endometrial tumors, unfavorable outcomes were seen only with grade 3 endometrioid carcinoma.

Study Details

The investigators performed this study to shed light on the prognostic significance of PIK3CA mutation within various histologic types of high-grade endometrial carcinomas. They evaluated the PIK3CA mutational status in exon 9 and exon 20 hot spots by direct sequencing of DNA obtained via formalin-fixed paraffin-embedded tissue from 99 patients with high-grade endometrial tumors. Of the four major histologic subtypes represented, 57 were grade 3 endometrioid carcinoma, 26 were serous endometrial carcinoma, 11 were clear cell carcinoma, and 5 were dedifferentiated carcinoma.

According to the study demographics, the mean age of the patients was 65.6 years. Of all the patients, 65% had received adjuvant radiation therapy, and nearly half had received adjuvant chemotherapy. In addition, women diagnosed with serous endometrial carcinoma were much older than those diagnosed with grade 3 endometrioid carcinoma.

Greater Dependence on PIK3CA Activation in Grade 3 Endometrioid Carcinoma

The presence of PIK3CA exon 9 or exon 20 missense mutation was confirmed in 20% of the tumors tested, with no real difference across the histologic types (P = .22). Approximately 60% of the mutations were seen in exon 20, compared with about 40% of the mutations found in exon 9. In the grade 3 endometrioid carcinoma cohort, there were eight missense mutations in exon 20 and two missense mutations in exon 9. In the serous endometrial carcinoma cohort, however, there were two missense mutations in exon 20 and five missense mutations in exon 9 (P = .058).

In the grade 3 endometrioid carcinoma histotype, the investigators demonstrated a type-specific association between PIK3CA mutational status and disease-related death. However, this association was not seen in the serous endometrial carcinoma histotype. The authors mentioned that these findings may suggest a greater dependence on PIK3CA activation in grade 3 endometrioid tumors than in serous endometrial tumors.

Poor disease-specific survival outcomes were linked to PIK3CA mutations in grade 3 endometrioid carcinoma. In the entire cohort, disease-specific death was associated with the presence of PIK3CA exon 9 or exon 20 missense mutations. This association was most pronounced in the grade 3 endometrioid carcinoma histotype (relative risk = 4.65; 95% confidence interval [CI] = 1.40–13.7; P = .0029) and not significant in the serous endometrial carcinoma histotype (P = .57). Furthermore, the investigators added, this link to an unfavorable outcome was seen only with exon 20 missense mutations.

Association With Abnormal Mismatch Repair Expression and Loss of ARID1A Expression

Also noted by the investigators was a connection between PIK3CA mutation and mismatch repair deficiency. Defined as a loss of nuclear expression in at least one of these four proteins—MLH1, PMS2, MSH2, and MSH6—abnormal mismatch repair expression was found to be linked to PIK3CA mutation in grade 3 endometrioid tumors (P = .0058). However, again, this significant association was seen only with exon 20 missense mutations (P = .023).

In addition, PIK3CA mutation was correlated with the loss of ARID1A expression in grade 3 endometrioid carcinoma. (Endometrioid types tend to be characterized by genetic mutations such as ARID1A and PTEN.) In contrast, the investigators found no association between PIK3CA mutation and the presence of ESR1 or the absence of PTEN expression. Aberrant TP53 expression within grade 3 endometrioid tumors did not appear to be linked to PIK3CA mutation, they added.

Finally, the investigators briefly noted the differences in the molecular context of serous endometrial carcinoma vs grade 3 endometrioid carcinoma. Although the serous histotype is nearly defined by the presence of TP53 mutations, only a few grade 3 endometrioid tumors harbor TP53 mutations. The investigators emphasized the clinical implications of these findings in regard to potential therapies: The response to PIK3CA inhibition can be modulated by the TP53 mutational status.

In closing, the investigators stated, “The prognostic association of PIK3CA missense mutations within grade 3 endometrioid carcinoma suggests a greater biological relevance and perhaps a promising target for molecular therapy in the endometrioid type.”

Gregg S. Nelson, MD, PhD, FRCSC, of the University of Calgary, is the corresponding author of the article in Gynecologic Oncology.

The study was funded by Calgary Laboratory Services Internal Research Competition. The study authors reported no potential conflicts of interest.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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