Ovarian cancer, still known as the “silent killer,” continues to present a significant clinical challenge despite recent therapeutic advances that include several biologically targeted drugs. The universally applied treatment paradigm is clearly unsuited to the histological, clinical, and molecular heterogeneity of this disease.
Genome sequencing studies have uncovered an array of distinct genomic drivers underlying various ovarian cancer subtypes. If researchers can capitalize on these discoveries, it may offer a path to more individualized and effective treatment options.
The Silent Killer
With more than 14,000 deaths expected in the United States in 2016, ovarian cancer remains the most lethal gynecologic malignancy and weighs in at No. 6 among the leading causes of cancer-related mortality. The ambiguity of early symptoms and lack of effective screening techniques result in more than 70% of patients being diagnosed in the advanced stages of disease.
The current standard of care has remained unchanged for many years and involves surgery and platinum- and taxane-based chemotherapy. Although the vast majority of patients will initially respond, disease recurrence is almost universal. Several targeted therapies have been developed for the treatment of recurrent disease. The realization that angiogenesis, the formation of new blood vessels from preexisting ones, is a hallmark of ovarian cancer led researchers to investigate the potential of bevacizumab (Avastin) and other antiangiogenic therapies.
The addition of bevacizumab to standard chemotherapy in platinum-resistant patients significantly improved progression-free survival in the phase III AURELIA trial and sealed its approval as second-line treatment for ovarian cancer in 2014.
Meanwhile, as in breast cancer, germline mutations in the breast cancer susceptibility genes BRCA1
have also been discovered in ovarian cancer. These mutations impair the homologous recombination (HR) pathway used to fix DNA damage. Inhibitors of the poly(ADP)-ribose polymerase (PARP) enzyme, which plays a role in an alternative DNA repair pathway, have been developed to capitalize on the inability of ovarian cancer cells with defective HR pathways to repair damaged DNA.
In December 2014, olaparib (Lynparza) became the first PARP inhibitor to be granted approval by the FDA for the treatment of patients with BRCA
mutation-positive ovarian cancer following the demonstration of response rates of more than 30% in a single-arm, phase II trial.
The addition of olaparib and bevacizumab to the ovarian cancer armamentarium marked the first new therapies approved for the treatment of ovarian cancer in almost a decade. Yet, only short-term survival gains have been achieved and long-term survival has remained stubbornly low, with 5-year rates of just 45%.
Broadly, ovarian tumors are classed according to the anatomic structures from which they are presumed to originate. Between 90% and 95% of cases are epithelial ovarian carcinomas, while nonepithelial tumors such as sex cord-stromal tumors and malignant ovarian germ cell tumors are considerably rarer.
Epithelial ovarian cancers can be further divided into several different histological subtypes. Most common are serous tumors, responsible for at least 65% of epithelial ovarian cancer cases, followed by endometrioid, mucinous, and clear cell. Historically, it was thought that epithelial ovarian carcinomas were all derived from the ovarian surface epithelium but more recent studies have defined a new model of carcinogenesis that divides epithelial ovarian cancers into 2 categories, designated as type I and type II.
Type I tumors consist of low-grade serous, mucinous, endometrioid, and clear cell tumors, for which precursor lesions within the ovary have been clearly described. Type II tumors include predominantly high-grade serous cancers (HGSCs) as well as carcinosarcomas and high-grade endometrioid and poorly differentiated ovarian cancers.
Precursor ovarian lesions have not been well described for this group of tumors, and it is now thought that they can arise from the epithelium of both the ovarian surface and the fallopian tube. In addition to their histological differences, ovarian cancers also display distinct clinical behaviors.
Type II tumors are typically much more aggressive and more often found at an advanced stage, but they respond well to chemotherapy, with an average response rate of 70%. Type I tumors are more indolent, and are frequently identified earlier on in the course of disease, but are significantly more chemoresistant with a response rate of less than 30%.