Clinical Review

2016 Update on cancer

Immunotherapy is alive and well, and endometrial cancer may be the prototype

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In this Article

  • The prognostic significance of tumors with POLE mutations
  • Can the immune system kill MMR-deficient endometrial cancer?


 

References

Each year approximately 60,000 women are diagnosed with endometrial cancer. The majority of the identified tumors will be low grade—cancer found at an early stage that may be treated with surgery alone. Unfortunately, however, too many of the 60,000 patients will have poor prognostic features, such as serous or clear cell histology (high-grade cancer), lymphovascular space invasion, or positive lymph node status.

Advances in technology and the state of science have come a long way since the dichotomy of Type I (endometrioid) and Type II (serous and clear cell) tumors were described by Dr. J. Bokhman in the early 1980s.1 Our previous Update from several years ago stressed the importance of further understanding of the molecular rationale of high-risk, Type II tumors.2 To review, The Cancer Genome Atlas project (TCGA) performed a genomic and proteomic characterization in 373 endometrial carcinomas demonstrating the traditional p53 mutations of serous tumors and PTEN or KRAS genes of endometrioid tumors.3 Most interestingly, they identified numerous other mutations and proposed 4 new genomic categories:

  1. polymerase (DNA-directed) epsilon catalytic subunit (POLE) ultramutated
  2. microsatellite instability (MSI) hypermutated
  3. somatic copy number alterations high (serous tumors)
  4. somatic copy number alterations low (endometrioid cancer).

In 2016, we are now understanding the molecular basis of disease and how it affects survival; these 4 categories have different survival. But why? Perhaps the answer lies within the endogenous immune system. Tumor-infiltrating lymphocytes are associated with improved survival in multiple types of cancer, including endometrial. Whether these lymphocytes are regulatory or cytotoxic T-cells convolutes the matter further.4 To understand these intricacies we need to further categorize how a tumor’s genetic mutations affect antigen exposure to the immune system, quantitate the clinical impact of the findings, and selectively target patients with novel therapeutics.

In this Update, we look at data on POLE mutations, exploring 2 studies that help us to better understand why these types of mutations have uniquely positive prognostic implications (when they logically should not have good survival rates). In addition, we discuss 2 studies that examined mismatch repair defects, in endometrial cancer specifically, and the programmed death (PD)-1 pathway in both endometrial and other cancer types. Are these molecular entities of tumors associated with better or worse prognosis, and why?

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