OVARIAN CANCER: MAKING ITS OWN RULES—AGAIN

Abstract

Epithelial ovarian cancer, once categorizing all epithelial cancers of the ovary and fallopian tube, is now recognized to be an umbrella term. We are recognizing two categories of ovarian cancer, with the “type 1” cancers containing further types, including low grade serous cancers, mucinous, clear cell, and low grade endometrioid. These types are genetically and histologically as different as is their outcome. The paper accompanying this editorial further dissects low grade serous cancers to show that those carrying oncogenic KRAS or BRAF mutations have an unexpectedly excellent clinical outcome. We discuss this newest unexpected behavior of ovarian cancer.

Once again we find epithelial ovarian cancer 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 two type system proposed by Shih and Kurman in 2004 ¹ 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 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 histology and genomics (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 two 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.

The paper presented by Grisham and colleagues in this edition 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 ^12–14. 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 survivals superior to 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 ^1,15,16. 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 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 ^17,18. What do we know of solid tumors bearing KRAS and BRAF mutations? In colon cancer, melanoma, and thyroid cancers, KRAS and BRAF mutation-bearing tumors are more aggressive than their wild-type counterparts ^19–22. Only the recent application of BRAF-targeted therapeutics has changed the survival landscape of the BRAF-mutated melanoma ^21,23. Vemurafenib, a selective BRAF-targeted agent, was recently FDA-approved for V600E BRAF mutant melanoma. Paradoxically, though rare at 5% of cases, colon cancers with a V600E BRAF mutation responded poorly to therapy ²⁴ and it is well recognized that presence of KRAS mutation is associated with poor response to EGFR inhibitors ^25,26. This lack of response occurred due to the upregulation of EGFR causing activation of the downstream survival protein, AKT. This also explains why attempts to treat BRAF V600E or KRAS mutant bearing colon tumors 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 as low grade serous cancers and serous borderline tumors, have long been recognized to have a better prognosis. Grisham’s paper 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 the highest frequency of mutation is in the borderline tumors, with mutational loss with progression to micropapillary tumor and low grade serous carcinoma. Lastly, 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; Farley et al, presented at the 2012 Society for Gynecologic Oncology meeting, Austin TX). 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 a logical site to target. GOG-239 (NCT00551070) was a single arm two-step phase 2 trial of selumetinib 50mg twice daily continuously, specifically for low grade serous ovarian cancer patients; results were reported at the 2012 Society for Gynecologic Oncology meeting. A total of 52 women were entered, 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 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 under-represented in this multi-institutional cohort.

Figure 2. RAF→RAS signaling.

Receptor tyrosine kinases (RTK) signal through Srchomology-2 domains to Src. It in turn activates the pathway to KRAS, RAF, to ultimately activate the mitogen-activated kinase, MAPK, pathway via MEK to 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 upstream the otherwise needed upstream stimulation by RTK. Similarly, an activating mutation in BRAF (shown in green), such as V600E

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.