Clinical Review
UPDATE: OVARIAN CANCER
New studies add to our understanding of which women may benefit from screening. The goal of improving overall survival among women who have this...
Details of the study by the Cancer Genome Atlas Research Network
The Cancer Genome Atlas Research Network recently published an integrated genomic, transcriptomic, and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. The goal was to provide better insight into disease biology and tumor classification to help guide clinical trials and drug development, with the ultimate goal of achieving personalized cancer care.
The group classified endometrial cancers into four new categories:
- polymerase (DNA-directed) epsilon catalytic subunit (POLE) ultramutated
- microsatellite instability (MSI) hypermutated
- somatic copy number alterations (SCNA) low
- SCNA high.
Most endometrioid tumors had few SCNA or P53 mutations but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A, and KRAS genes. Novel mutations also were discovered in the SWI/SNF chromatin remodeling complex gene ARID5B. About 10% of endometrioid tumors had markedly increased transversion mutations and newly identified mutations in POLE, a gene involved in nuclear DNA replication and repair.
As expected, serous tumors had significantly worse progression-free survival (PFS) than endometrioid tumors (P = .003, log-rank). A subset (25%) of high-grade endometrioid tumors had SCNAs and mutation spectra similar to those of uterine serous carcinomas, suggesting that patients with such tumors might benefit from treatment options that parallel those for serous tumors.
Other overlapping treatment paradigms existed between different organ systems. For example, some molecular features were similar in uterine serous carcinomas, basal-like breast carcinomas, and high-grade serous ovarian carcinomas. All three carcinomas displayed a high frequency of P53 mutations, very low frequency of PTEN mutations, similar focal SCNA patterns, and minimal DNA methylation changes. However, investigators also found several mutations that are unique to uterine serous carcinomas (eg, PIK3CA, FBXW7, PPP2R1A, and ARID1A), providing potential opportunities for targeted pharmacotherapy.
What this evidence means for practice
These studies highlight the etiologic heterogeneity of endometrial cancer. The histologic groundwork laid by Bokhman was not only correct but provided a foundation for molecular characterization of endometrial cancers to drive translational science into targeted therapeutics.
The similar molecular phenotypes of high-grade endometrioid carcinomas and serous endometrial carcinomas strengthens existing evidence that chemotherapy may be preferable to adjuvant radiotherapy for patients with highly mutated endometrioid cancers (eg, SCNA). Current chemotherapy regimens for serous endometrial cancers remain appropriate, given the compelling similarities between these cancers and serous ovarian and basal-like breast cancers. However, the identification of unique molecular features not shared by breast or ovarian cancer may expand standard options to include more targeted therapy.
Overall, this type of research, which encompasses proper histologic classification refined by genomics, has the potential to achieve personalized cancer care.
How we are achieving individualized cancer care: 3 genome-guided clinical trials
Oza AM, Elit L, Tsao MS, et al. Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. J Clin Oncol. 2011;29(24):3278–3285.
Aghajanian C, Sill MW, Darcy KM, et al. Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2011;29(16):2259–2265.
Alvarez EA, Brady WE, Walker JL, et al. Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2013;129(1):22–27.
Women with locally recurrent, advanced, or metastatic endometrial cancer have limited options for treatment. Hormonal therapies have modest effects at best, with a median survival rate of 7 to 12 months.7–9 To address this lack of options, researchers have begun to focus on targeted therapies directed at molecular pathways of cellular proliferation. These therapies include but are not limited to inhibitors of:
- mammalian target of rapamycin (mTOR)
- human epidermal growth factor receptor 2
- epidermal growth factor receptor
- vascular endothelial growth factor (VEGF).
Several studies have produced promising findings in recent years. They involve investigations of temsirolimus and bevacizumab as single agents in two independent clinical trials, and a study of the drugs in combination in women with recurrent or persistent endometrial carcinoma.
mTOR inhibitors elicited a greater response in chemotherapy-naïve women
Phosphatase and tensin homolog (PTEN) is a tumor-suppressor gene more commonly associated with endometrioid endometrial cancers (26%–80%) than with Type II cancers.10 Loss of PTEN expression leads to deregulated signaling of the phosphatidylinositol-3 kinase (PI3K)/serine-threonine kinase (Akt)/mTOR pathway. Disruption of this pathway is thought to provide cells with a selective survival advantage by enhancing angiogenesis, protein translation, and cell-cycle progression.10
Temsirolimus is an mTOR inhibitor recently explored by Oza and colleagues. They performed a multicenter, Phase II study involving 62 patients with recurrent and/or metastatic endometrial cancer as part of the National Cancer Institute of Canada (NCIC) Clinical Trials Group. Patients were divided into two groups on the basis of their treatment history: