The influence of clinical and genetic factors on patient outcome in small cell carcinoma of the ovary, hypercalcemic type

Abstract

Objective: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an aggressive tumor, with long term survival at ~30% in early stage disease. SCCOHT is caused by germline and somatic SMARCA4 mutations, but the effect of the mutation type on patients remains unknown. Furthermore, the rarity of SCCOHT has resulted in varied treatment, with no standardized protocols. We analyzed 293 cases to determine the effect of treatment modalities and SMARCA4 mutations on patient diagnosis and outcome.

Methods: In 293 SCCOHT patients we collected information on age and stage at diagnosis, treatment modality (surgery, chemotherapy, radiotherapy, and/or high-dose chemotherapy with autologous stem cell rescue (HDC-aSCR)), SMARCA4 mutation origin (germline/somatic), and overall survival. Cox analysis and log-rank tests were performed on 257 cases with available survival data.

Results: The strongest prognostic factors were stage at diagnosis (p=2.72e-15) and treatment modality (p=3.87e-13). For FIGO stages II-IV, 5-year survival was 71% for patients who received HDC-aSCR, compared to 25% in patients who received conventional chemotherapy alone following surgery (p=0.002). Patients aged ≥40 had a worse outcome than younger patients (p=0.04). Twenty-six of 60 tested patients carried a germline SMARCA4 mutation, including all patients diagnosed <15years; carriers presented at a younger age than non-carriers (p=0.02).

Conclusions: Stage at diagnosis is the most significant prognostic factor in SCCOHT and consolidation with HDC-aSCR may provide the best opportunity for long-term survival. The large fraction of SMARCA4 germline mutations carriers warrants genetic counseling for all patients.

Keywords: Chemotherapy; Mutation; Ovarian cancer; SCCOHT; SMARCA4; Stem cell rescue.

Figure 1.

Diagram of cases included in each analysis. Of 3 patients who did not fit treatment categories, 2 died before surgery, and one had chemotherapy with no surgery.

Figure 2.

Kaplan-Meier curves showing the effect of clinical factors on patient outcome. P-values were determined by log-rank tests. (A) Survival of SCCOHT patients according to stage at diagnosis. (B-C) Survival of patients according to treatment received for primary tumor in stage I patients (B) and stage II-IV patients (C). (D) Kaplan-Meier survival curves of SCCOHT patients according to age at diagnosis in years. Patients over 40 have a significantly worse outcome than younger patients as found by multivariate Cox analysis (p = 0.04). Surg, surgery only; Surg + Chemo, Surgery and chemotherapy; Surg+RT, Surgery and Radiotherapy; Surg+Chemo+RT, Surgery, Chemotherapy, and Radiotherapy; Surg+Chemo/RT+HDC, Surgery with chemotherapy and/or radiotherapy and high-dose chemotherapy with autologous stem cell rescue.

Figure 3.

The effect of mutation origin on SCCOHT patients. (A) Stripchart showing difference in age at diagnosis between patients with germline mutations and those with somatic mutations only. Each dot represents one patient. Black bars are mean and standard error. Median age at diagnosis was 21.5 for patients with germline mutations and 26 for patients with somatic mutations only. P = 0.02 by Mann-Whitney U test. (B) Kaplan-Meier survival curves of SCCOHT patients according to SMARCA4-carrier status. The difference between somatic and germline patients only was not significant by log-rank test (p = 0.09). We suspect that the slight difference in survival between tested and non-tested patients is due to ascertainment bias. (C) Distribution of stage at diagnosis of patients with germline mutations or somatic mutations only. No significant difference was seen between the two groups (p = 0.53, Chi-squared test).