Ovarian cancer

Making its own rules—again

Authors


  • See original referenced article on pages 548–54, this issue.

Abstract

The field of ovarian cancer research has made marked progress in better understanding ovarian cancer and redefining its types. New information is putting into doubt that mutations in KRAS and/or BRAF always portend poor outcome, at least not in low-grade serous ovarian cancers.

Once again, we find epithelial ovarian carcinoma forging its own path rather than following the classical paths forged by other carcinomas. These classical paths describe carcinomas as having a select cell of origin, spreading by nodal extension and hematogenous dissemination, generally metastasizing to first encountered capillary beds, and more recently, having mutational activation of a signaling pathway that creates a dominant driving event. This dominant driving event portends poor outcome and, when interrupted therapeutically, results in clinical benefit. We are learning that what we have known as epithelial ovarian cancer is really a collection of cancers of Mullerian origin.1 These Mullerian cancers shed into and spread within the peritoneal cavity long before lymphovascular dissemination, and their genetic and genomic events are varied.

The recent and significant growth in our understanding of epithelial ovarian cancers has led us to recognize its increasingly divergent behavior. The 2-type system proposed by Shih and Kurman in 20041 is now generally accepted. Type 2 cancers encompass the high-grade serous cancers, both more common and also accounting for the frequent late-stage diagnosis and worse outcome.2-4 Type 2 tumors contain mutant p53 and frequently have abnormalities in homologous recombination DNA repair pathways, including BRCA1/2 (breast cancer, early onset, type 1 and 2) mutations, resulting in genomic instability and varied genomic signatures, rather than subsets with definable drivers.5-7 They grow rapidly with a high mitotic index and are responsive to platinum-based chemotherapy. Provocative data suggest that these cancers arise from the distal fallopian tube.8, 9 There are equally strong arguments that type 1 ovarian cancers, currently encompassing the low-grade serous, clear cell, low-grade endometrioid, and transitional cell histologies, need to be broken out into types, rather than subtypes. These different types can be readily separated by a combination of histologic and genomic analyses (Fig. 1).10, 11 Thus, this “reinvention” of the component parts of epithelial ovarian cancers leaves great opportunities to better understand what each means to the patient.

Figure 1.

Epithelial ovarian cancers are now divided into 2 categories. Type 1 cancers are now recognized to have 4 types, low-grade serous, low-grade endometrioid, clear cell, and mucinous histologies. Type 2 cancers include in one unit, both the high-grade serous and now most agree, also the high-grade endometrioid histologies. Abbreviations: ARID1A, AT-rich interactive domain 1A; BRCA, breast cancer, early onset; HER2, human epidermal growth factor receptor 2; HRD, homologous recombination deficient, growth and mental retardation, and dysmorphism; KRAS, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; OPCML, opioid binding protein/cell adhesion molecule-like. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

The article presented by Grisham and colleagues12 in this issue of Cancer furthers our understanding of the molecular basis and behavior of type 1 low-grade serous ovarian tumors. Markedly different from type 2 high-grade serous cancers, there are strong arguments that low-grade serous cancers arise in or from serous borderline tumors of the ovary.13-15 They are slowly growing tumors with a low mitotic index and are now believed to be poorly responsive to platinum-based chemotherapy, yet are associated with 10-year survival rates superior to that of the type 2 high-grade serous cancers. These low-grade serous borderline tumors and cancers are genetically stable and, as a class, have wild-type p53 and BRCA1/2 genes.

This type 1 ovarian cancer subtype is characterized by mutations in a number of genes, most commonly KRAS and BRAF.1, 16, 17 Grisham and colleagues report that 57% of tumors harbored a BRAF (n = 26) or KRAS (n = 17) mutation within the 75 patients whose tumors were analyzed. All BRAF mutations (35%) were Val600Glu (V600E), and all KRAS mutations were codon 12, either G12D (n = 11) or G12V (n = 6). BRAF and KRAS mutations were mutually exclusive. The sites of mutation, V600E in BRAF and codon 12 in KRAS, are long recognized to be oncogenic.18, 19 What do we know of solid tumors bearing KRAS and BRAF mutations? In colon cancer, melanoma, and thyroid cancers, tumors bearing KRAS and BRAF mutations are more aggressive than their wild-type counterparts.20-23 Only the recent application of BRAF-targeted therapeutics has changed the survival landscape of the BRAF-mutated melanoma.22, 24 Vemurafenib, a selective BRAF-targeted agent, was recently approved by the US Food and Drug Administration for V600E BRAF mutant melanoma. Paradoxically, although rare at 5% of cases, colon cancers with a V600E BRAF mutation responded poorly to therapy,25 and it is well recognized that presence of KRAS mutation is associated with poor response to EGFR inhibitors.26, 27 This lack of response occurred due to the up-regulation of epidermal growth factor receptor (EGFR) causing activation of the downstream survival protein AKT. This also explains why attempts to treat colon tumors bearing BRAF V600E or KRAS mutations with an EGFR inhibitor were unsuccessful.

If ovarian cancer was to follow the trend of other solid tumors, then those tumors with a BRAF or KRAS mutation should behave poorly. Yet, this is not the case, because low-grade serous cancers and serous borderline tumors have long been recognized to have a better prognosis. The article by Grisham et al shows us that, also contrary to the genetic progression usually seen in solid tumors, there is loss rather than gain of the BRAF or KRAS mutation. Grisham and coworkers demonstrate that the highest frequency of mutation is in the borderline tumors, with mutational loss with progression to micropapillary tumor and low-grade serous carcinoma. Finally, they show that those low-grade serous cancers that have the BRAF mutation did not recur, with no deaths at a median follow-up of 43 months. This is the antithesis of what we expect with these oncogenic mutations.

How do we capitalize on these new findings? The earlier recognition of the presence of BRAF and KRAS mutations in low-grade serous cancers led to the logical choice of targeted therapy, using a MEK inhibitor, selumetinib (AZD6244; GOG-239 trial).28 MEK is immediately downstream of BRAF (Fig. 2) in the RAS→RAF pathway and would be expected to be activated downstream of the mutation, and thus is a logical site to target. GOG-239 (NCT00551070) was a single-arm 2-step phase 2 trial of selumetinib given at 50 mg twice daily continuously, specifically for low-grade serous ovarian cancer patients; results were reported at the 2012 Society for Gynecologic Oncology meeting.28 A total of 52 women were entered in the trial, and of those for whom mutational analysis was completed at the time of the report, 41% had KRAS mutations and 6% had BRAF mutations. There was an overall 16% response rate and median progression-free survival of approximately 7 months. The BRAF mutation carriers were less likely to be the responders, suggesting the MEK pathway may be important in low-grade serous cancers with other driving pathways. As pointed out by Grisham and colleagues, this could also be interpreted that those patients' BRAF mutations did not recur and therefore are underrepresented in this multi-institutional cohort.

Figure 2.

Diagram shows RAF→RAS signaling. Receptor tyrosine kinases (RTK) signal through Src-homology-2 domains to Src. It in turn activates the pathway to KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), RAF, to ultimately activate the mitogen-activated protein kinase (MAPK) pathway via MEK to extracellular signal-regulated kinase (ERK). An activating mutation in KRAS (shown in red), such as the codon 12 and 13 mutations described in low-grade serous ovarian cancer, can drive downstream activation of the MAPK pathway without the otherwise needed upstream stimulation by RTK. An activating mutation in BRAF (shown in green), such as Val600Glu (V600E), can act in a similar fashion. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Grisham and colleagues have added important new findings of our understanding of the molecular basis and clinical behavior of type I ovarian cancers. These findings are important in that they can lead to triage decisions to reduce overtreatment of those women whose cancers are unlikely to recur. Continued evaluation of the molecular and proteomic pathway events underlying ovarian cancers will lead to improvements in our clinical trial directions and designs, and ultimately to improved quality and quantity of life for our patients.

FUNDING SOURCES

This work was supported by the Intramural Program of the Center for Cancer Research, National Cancer Institute, to Dr. Kohn.

CONFLICT OF INTEREST DISCLOSURE

The authors made no disclosures.

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