Emerging Biomarkers for Gynecologic Cancers

A histologic section showing specifically squamous cell carcinoma in the cervix (Papanicolaou’s stain). SOURCE: NCI

This article is part III of a series. View parts I and II:Evolving Paradigms in Gynecologic Cancer> >

MicroRNAs

The search for gynecologic cancer biomarkers that are prognostic or predictive of patient responses to treatment is an active and fruitful area of investigation. As the cost of genetic testing has declined, the possible number of mutations that can be screened has increased dramatically. Also, a better understanding of the interactions between cancers and the immune system has presented new possibilities in the search for clinically useful biomarkers.MicroRNAs (miRNAs) are a promising new source of biomarkers for gynecologic cancers. Discovered in the early 1990s, miRNAs are noncoding regulatory RNA molecules ranging from 18 to 22 nucleotides long that function in the cell principally by selectively repressing translation or enhancing degradation of target-coding RNA transcripts.⁴³Several characteristics of miRNAs make them attractive candidates as gynecologic cancer biomarkers, including evidence that some function as oncogenes or tumor suppressors and the fact that they can be detected in circulating blood and other bodily fluids.

To date, multiple studies have been published that suggest the expression levels of individual or multiple circulating miRNAs could be used as biomarkers for ovarian, endometrial, and cervical cancers.⁴⁴These studies identified associations between clinicopathological disease features and the increased or decreased expression of various miRNAs; however, there is little overlap in the various results.

BRCA

One recently published paper identified increased miR-181a expression as a candidate biomarker for poorer prognosis in advanced EOC and showed a functional role for the transcript in improved cellular survival, migration, invasion, and drug resistance.⁴⁵The authors suggest that miR-181a and the transforming growth factor-b (TGF-b) signaling pathway are not only potentially prognostic biomarkers for advanced EOC, but also targets of therapy.TheBRCA1andBRCA2genes are tumor suppressors involved in DNA damage repair.⁴⁶Mutations in these genes are well known as risk factors for developing breast and ovarian cancers; however, recent research suggests thatBRCAstatus is prognostic of survival time in patients with ovarian cancer. A recent retrospective study reported that mutations of either gene are associated with improved short-term survival rates; however, this advantage decreases over time, andBRCA1mutations become a liability at 5 years post diagnosis.⁴⁷A separate meta-analysis that examinedBRCAstatus and outcomes found that mutations in either gene were associated with improved PFS and OS versus noncarriers.⁴⁸These observations may be important for analysis of OS outcomes in long-term trials in ovarian cancer.

Other Genes

In addition to prognosis, there may be a role for BRCA in selecting the most appropriate treatment strategy. A retrospective analysis of a phase II trial evaluating olaparib maintenance therapy in patients with advanced relapsed ovarian cancer found that patients withBRCAmutations were most likely to benefit from the therapy.³⁷Furthermore, it did not matter whether these mutations were germline or somatic. These results are unsurprising considering that PARP inhibitors, such as olaparib, target cells with homologous recombination defects, such asBRCAmutations, and suggest thatBRCAcould be used to identify patients with advanced ovarian cancer who are likely to respond to PARP-inhibitor therapy.⁴⁹There are many possible individual biomarkers under consideration for gynecologic cancers. The following list of candidate biomarkers is not exhaustive, but intends to provide an overview of some of the current research. Biomarkers relating specifically to targeted treatments that are new to clinical approval, such as antiangiogenic drugs and PARP inhibitors, are not listed here, but are discussed in the “Emerging Treatments and Clinical Trials for Gynecologic Cancers” section.

Ovarian

A method for determining the likelihood that a pelvic mass is malignant or benign using serum levels of human epididymis protein 4 and CA-125 in conjunction with the Risk of Ovarian Malignancy Algorithm⁵⁰has been approved by the FDA, but is not recommended by the NCCN guidelines.⁵

GRB2-associated binding protein 2 (GAB2), an adapter protein that activates signaling through phosphoinositide 3-kinase (PI3K), is an oncogene that is duplicated in many ovarian cancers. The presence of amplified GAB2 can indicate responsiveness to PI3K inhibition.⁵¹

Endometrial

Loss of progesterone receptor is associated with disease progression and decreased patient survival in endometrial cancer. Loss of receptor expression can occur in either the primary tumor or subsequent metastases. The efficacy of treatment with synthetic progesterone depends on progesterone receptor expression, but this is not routinely assayed. For patients who have lost progesterone receptor expression in metastatic lesions, antiproliferative drugs, such as CDK inhibitors like sirolimus, might be effective, although clinical trials will be required to establish their performance in these patients.⁵²

In addition to hormone receptors, the mutation or loss of PTEN and activation of signalling through PI3K and KRAS have been identified as biomarkers early in the development of endometrial cancer. Differences in the rate of mutations in KRAS and inflammatory pathways between obese and nonobese patients with precancerous endometrial lesions suggest that different treatment strategies should be pursued in these 2 populations.⁵³This article is part III of a series. View parts I and II:Evolving Paradigms in Gynecologic Cancer> >

References

43. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function.Cell. 2004;116(2):281-297.

44. Zhao YN, Chen GS, Hong SJ. Circulating MicroRNAs in gynecological malignancies: from detection to prediction.Exp Hematol Oncol. 2014;3:14.

45. Parikh A, Lee C, Peronne J, et al. microRNA-181a has a critical role in ovarian cancer progression through the regulation of the epithelial-mesenchymal transition.Nat Commun. 2014;5:2977.

46. Yoshida K, Miki Y. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage.Cancer Sci. 2004;95(11):866-871.

47. Candido Dos Reis FJ, Song H, Goode EL, et al. Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer.Clin Cancer Res. 2014.

48. Zhong Q, Peng HL, Zhao X, Zhang L, Hwang WT. Effects of BRCA1- and BRCA2-related mutations on ovarian and breast cancer survival: a meta-analysis.Clin Cancer Res. 2014.

49. Foulkes WD. Made-to-measure medicine: BRCA and gynaecological cancer.Lancet Oncol. 2014;15(8):783-785.

50. Moore RG, Miller MC, Disilvestro P, et al. Evaluation of the diagnostic accuracy of the risk of ovarian malignancy algorithm in women with a pelvic mass.Obstet Gynecol. 2011;118(2 Pt 1):280-288.

51. Dunn GP, Cheung HW, Agarwalla PK, et al. In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene.Proc Natl Acad Sci U S A. 2014;111(3):1102-1107.

52. Tangen IL, Werner HM, Berg A, et al. Loss of progesterone receptor links to high proliferation and increases from primary to metastatic endometrial cancer lesions.Eur J Cancer. 2014.

53. Berg A, Hoivik EA, Mjos S, et al. Molecular profiling of endometrial carcinoma precursor, primary and metastatic lesions suggests different targets for treatment in obese compared to non-obese patients.Oncotarget. 2014.

This article is part III of a series. View parts I and II:Evolving Paradigms in Gynecologic Cancer> >