Title:Unmet Needs in Ovarian Cancer: Dividing Histologic Subtypes to Exploit Novel Targets and Pathways
VOLUME: 13 ISSUE: 6
Author(s):Vijaya Galic, Robert L. Coleman and Thomas J. Herzog
Affiliation:Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Columbia University Medical Center, Herbert Irving Comprehensive Cancer Center, 161 Ft. Washington Avenue, New York, NY 10032.
Keywords:Adenocarcinoma-clear cell, adenocarcinoma-endometrioid, adenocarcinoma-mucinous, catalytic subunit alpha
(PI3KCA), cystadenocarcinoma-serous, breast cancer 1, early onset (BRCA1) and breast cancer 2, early onset (BRCA2),
ovarian cancer, poly (ADP-ribose) polymerase 1 (PARP1), phosphatidylinositol-4, 5-bisphosphate 3-kinase, TP53.
Abstract:Ovarian cancer (OC) carries a poor prognosis; however, accumulating molecular data for the major histologic
subtypes may lead to subtype-specific treatment paradigms. The present review discusses what is currently understood
about the major molecular and histologic subgroups of OC. Areas specifically addressed include hormonal pathways,
tumor protein p53 (TP53) and AT rich interactive domain 1A (SWI-like; ARID1A) mutation, and the breast cancer 1/2,
early onset (BRCA1/2) mutation/poly (ADP-ribose) polymerase 1 (PARP1), phosphatidylinositol-4,5-bisphosphate 3-
kinase, catalytic subunit alpha (PI3KCA)/v-akt murine thymoma viral oncogene homolog 1 (AKT1)/mechanistic target of
rapamycin (MTOR), and mitogen-activated protein kinase kinase 1 and 2 (MAP2K1/2) pathways. This molecular
characterization only very recently has impacted clinical research efforts to develop targeted therapies for both common
and rare OC subtypes. This targeted strategy is illustrated by ongoing low-grade serous, clear-cell, and mucinous subtypeexclusive
clinical trials evaluating agents based on common molecular abnormalities among patients (i.e., PARP1
inhibitors for BRCA1/2 mutation-positive OC). This report also reviews the published clinical trial efficacy data for
investigational therapies within specific subgroups, and summarizes the currently active clinical trials evaluating these
agents (e.g., temsirolimus, sunitinib, TP53 immunotherapy, olaparib, iniparib, veliparib). Available data suggest that
histologic profiles and molecular tumor markers are valuable resources for identifying patients who may benefit from
these specific agents, and future research should focus on targeting molecules and signaling pathways that are most
commonly altered in each subtype.
