John K. Chan

PURPOSE: To determine factors and survival of patients with ovarian cancer after primary debulking surgery followed by adjuvant chemotherapy (PDS) versus neoadjuvant chemotherapy followed by interval cytoreduction (NAC). METHODS: GOG-262 was a prospective randomized trial evaluating once per week dose dense chemotherapy. The physicians were given the option of performing PDS versus NAC. Chi-squared tests and Kaplan-Meier procedures were used for analyses. RESULTS: Of 192 patients from centers offering both treatment options, 119 (62%) patients had PDS and 73 (38%) underwent NAC. Compared with the PDS group, NAC patients were older (60 years and older) age (67% v 47%; P < .01) and had more advanced (stage IV) disease (41.1% v 26.1%, P < .01) and peritoneal versus ovarian or fallopian tube cancers (16.4% v 5.0%, P < .001). The 5-year unadjusted overall survival of patients after NAC was 41.9 versus 47.8 months in the PDS group. After adjusting for prognostic factors, PDS was not an independent predictor for survival (hazard ratio [HR], 1.08 [95% CI, 0.67 to 1.7]; P = .75), whereas more advanced (IV v II/III)-stage (HR, 1.9 [95% CI, 0.93 to 3.89]; P = .079) and peritoneal versus ovarian or fallopian tube cancers (HR, 4.36 [95% CI, 1.45 to 13.1]; P = .009) were associated with poorer survival. CONCLUSION: Compared with primary surgery followed by chemotherapy, neoadjuvant chemotherapy followed by interval surgery patients were older and had more advanced disease (stage IV v II-III) and more primary peritoneal cancer ( v ovarian and fallopian tube cancer). The survival of these two groups was comparable after adjusting for prognostic factors.

PERK and other potential biomarkers of therapy response in LGSOC. A, pERK IHC examples demonstrating negative (0), weak (1+), moderate (2+), and intense (3+) positivity for histoscore calculation. Scale bars, 50 µm. B, Response to trametinib (top) and physician’s choice SOC (bottom) according to KRAS/BRAF/NRAS mutation status (left), pERK status (middle), and chr1 abnormalities (right). C, pERK histoscore according to KRAS/BRAF/NRAS mutation type. Labels specify the numbers within each group that were evaluable for pERK expression levels. D, pERK histoscore by chr1p-loss status. E, Frequency of pERK status between chr1p-loss and -intact groups. Chr1pq-aberrant, chr1p-loss with concurrent chr1q-gain.

Study case flow diagram for WES of translational specimens from patients enrolled in GOG281. One hundred thirty-four samples underwent successful WES, of which 112 were also evaluable for pERK via IHC. Additionally, 36 samples were evaluable for pERK IHC that did not have matching WES.

Molecular landscape of tumor samples from patients enrolled in GOG281/LOGS. MAPK-associated, MAPK-associated genes as defined in the Gene Ontology Term GO:0000165; Chr1pq-aberrant, chr1p-loss with concurrent chr1q-gain.

Purpose:Low-grade serous ovarian carcinoma (LGSOC) is a distinct form of ovarian cancer characterized by younger patient age and relative chemoresistance. The GOG281/LOGS trial (NCT02101788) investigated the efficacy of the MEK inhibitor trametinib compared with physician’s choice standard-of-care (SOC) in patients with LGSOC with persistent/recurrent disease. The study demonstrated significantly improved progression-free survival (PFS) in the trametinib-treated arm.Experimental Design:Two hundred and sixty patients with recurrent/persistent LGSOC were enrolled and randomly assigned in GOG281. We performed molecular analysis of 170 patients with available tumor specimens, comprising whole-exome sequencing and phospho-ERK (pERK) IHC, to identify biomarkers of clinical benefit from trametinib. The demographics of the translational cohort (n = 170) were comparable with those of the total trial cohort.Results:High tumor pERK expression (greater than the median histoscore of 140) was associated with significantly prolonged PFS with trametinib treatment versus SOC (median 20.1 vs. 5.6 months, log-rank P < 0.0001; test for interaction P = 0.023). Tumors harboring canonical RAS–RAF–MAPK mutations (KRAS/BRAF/NRAS: 44/134, 32.8% of cases) had a higher response rate to trametinib (50.0% vs. 8.3%; Barnard’s P = 0.0004; test for interaction P = 0.054), but KRAS/BRAF/NRAS status was not predictive of prolonged PFS (test for interaction P = 0.719). KRAS amplification (n = 5 without KRAS/NRAS/BRAF mutation) and mutation of MAPK-associated genes (n = 25 without KRAS/NRAS/BRAF mutation or KRAS copy number gain) expanded the number of cases with identifiable MAPK defects to 55.2%, but consideration of these events did not improve the discrimination of trametinib responders. Chr1p loss (49% of cases) was associated with lower pERK expression (P = 0.021).Conclusions:This exploratory analysis suggests that pERK expression and mutation of KRAS/BRAF/NRAS are candidate biomarkers of improved PFS and response to trametinib, respectively.

Demographics of translational research population.

Impact of pERK status and KRAS/BRAF/NRAS mutation status on GOG281 patient outcome. A, PFS of GOG281/LOGS patients with low-pERK tumors (pERK ≤ 140) in trametinib versus SOC arms. B, PFS of GOG281/LOGS patients with high-pERK tumors (pERK > 140) in trametinib versus SOC arms. C, PFS of GOG281/LOGS patients with KRAS/BRAF/NRAS WT tumors in trametinib versus SOC arms. D, PFS of GOG281/LOGS patients with KRAS/BRAF/NRAS-mutant tumors in trametinib versus SOC arms. Labeled HR refer to comparison of trametinib versus SOC arm.

Unsupervised hierarchical clustering of chromosome arm-level copy-number alterations across biospecimens from patients enrolled in GOG281/LOGS.