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Factors associated with genetic testing in BRCA1 and BRCA2 mutation carriers with advanced ovarian carcinoma
Abstracts
Methods: Kaiser Permanente Northern California (KPNC) has guidelines for referral of women at risk for inherited breast/ovarian cancer to genetic counseling. We conducted a retrospective chart review to identify women with cancer who met KPNC guidelines according to their pathology report. The guidelines used for the study were limited to the following: invasive breast cancer ≤age 40, nonmucinous epithelial ovarian, fallopian tube or peritoneal cancer ≤age 60, and women with synchronous or metachronous primary cancers of the breast and ovaries. We assessed compliance with guidelines for genetic counseling referral as well as outcome of genetic counseling among those referred. Phase two was a small prospective quality project (January–June 2010) to identify patients with pathology or diagnosis codes who met study guidelines for genetics referral. This was a preliminary study with a small sample size and limited power. The managing surgeon/oncologist was notified by an electronic letter of the patient's indication for referral to genetic counseling. Compliance with guidelines and outcome of patient follow up, counseling, and testing were evaluated. A review was conducted to assess referral rates within 3–6 months of the notification. Results: A total of 340 patients with new breast and ovarian cancers were identified between January and June 2008. Of the 105 patients identified who met the pathology specific referral guidelines, 47 (45%) were referred and of these, 27 (57%) completed their genetic visit. Of those with breast cancer, more than half (59 %) were referred. In contrast, less than one-in-five of those with ovarian, peritoneal or tubal cancer were referred (18%) (P-value for difference< 0.0001). In the prospective quality project, during the first half of 2010, 78 patients at 20 facilities met study referral guidelines, 30 (38%) of whom had already been referred at the time of chart review. Because the initial rates of referral were clinically different in the control and intervention sites, (18.1 ± 34.9 and 41.7 ± 44.2 respectively), we used adjusted regression models to test for differences between 6 month referral rates in the two groups. Intervention group had a 30.6 ± 12.6 percentage point higher referral rate, adjusted for initial rate of referral (P = 0.0266). Conclusion: In 2008, 45% of KPNC patients at risk meeting pathology guidelines were referred to genetic counseling which is comparable to rates published by comprehensive cancer centers (Meyer, LA et al, Obgyn survey 2010 (65) pp 436–437). It is feasible to identify patients at risk for BRCA 1 and 2 cancers by pathology report and referral rates may be improved with a letter to the oncologist. A larger randomized study is indicated to determine if this trend holds in comparable groups and if results are different for different cancer types. doi:10.1016/j.ygyno.2011.07.052
Factors associated with genetic testing in BRCA1 and BRCA2 mutation carriers with advanced ovarian carcinoma B. Norquist, T. Walsh, C. Pennil, M.K. Lee, S. Casadei, A.M. Thornton, A. S. Nord, R. Garcia, M.C. King, E. Swisher University of Washington, Seattle, WA, USA Objective: Not all women with ovarian, tubal or peritoneal carcinoma undergo genetic testing for BRCA1 and BRCA2 (BRCA1/2) mutations. Our institution recently identified a group of women with advanced ovarian carcinoma found to have BRCA1/2 mutations using a nextgeneration sequencing approach called the BROCA test, who had not had prior clinical genetic testing. These women were compared with known BRCA1/2 mutation carriers and sporadic cases to determine factors associated with obtaining genetic testing and to determine the fraction of hereditary risk missed in routine clinical practice. Methods: Women with advanced ovarian, tubal or peritoneal carcinoma were identified from the University of Washington gynecologic oncology tissue bank. Three groups were compared, women
435
with BRCA1/2 mutations identified using the BROCA test who had not previously undergone standard genetic testing (BROCA), women with known BRCA1/2 mutations identified by standard clinical genetic testing (KNOWN), and women with ovarian carcinoma negative for comprehensive genetic testing using the BROCA test (sporadic). Medical records were reviewed to compare demographic and clinical data. Results: There were 30 BROCA BRCA1/2 mutation carriers, 56 KNOWN BRCA1/2 mutation carriers, and 239 sporadic. The BROCA group had a median age of 58 (range 43–77), significantly older than the KNOWN group with a median age of 53 (range 33–76), p = 0.02, (Mann– Whitney). 51/56 (91.1%) of the KNOWN group had a strong family history suggestive of a BRCA1/2 mutation, compared with 13/30 (43.3%) of the BROCA group, p < 0.0001, (Fisher's Exact). There was no difference in the rate of optimal debulking, proportion of BRCA1 vs. BRCA2 carriers, or the percentage with a history of breast carcinoma between the BROCA and KNOWN groups. Median overall survival was significantly worse for the BROCA group compared to the KNOWN group, 53 vs. 83 months, p = 0.01, Log-rank test. Median overall survival was improved for all BRCA1/2 mutation carriers (KNOWN and BROCA) compared with sporadic cases, 69 vs. 47 months, p = 0.003, (Log-rank test), however there was no difference in overall survival between the sporadic and BROCA groups. In all women in the BROCA series, 26% of the women with germline mutations had no first or second degree relatives with breast or ovarian carcinoma and the likelihood of identifying a mutation was equally high between women diagnosed in their 40s, 50s or 60s. Conclusion: Older age, the absence of a strong family history, and poor survival are all associated with not obtaining genetic testing through standard methods. While BRCA1/2 mutation carriers in this series had improved overall survival compared with sporadic cases, this difference was driven by the group already known to have mutations. Using age and family history criteria to direct genetic testing will miss a significant percentage of mutation carriers.
doi:10.1016/j.ygyno.2011.07.053
Chemotherapy response and survival in serous ovarian cancer patients with BRCA mutations J.K. Chan a, T.K. Kiet a, L. Chen a, R. Ruskin a, A.E. Sherman a, B.J. Monk b, D.S. Kapp c, T.C. Krivak d a Division of Gynecology Oncology, Department of Obstetrics, Gynecology & Reproductive Sciences, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA, b Division of Gynecology Oncology, Creighton University School of Medicine at St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA c Department of Radiation Oncology, Stanford Cancer Center, Stanford, CA, USA, dDepartment of Obstetrics, Gynecology & Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA Objective: To compare the demographic, clinico-pathologic, treatment response, and survival of patients with BRCA (germline and somatic) mutations. Methods: Genomic and clinical data were obtained from The Cancer Genome Atlas supplemented with data from Sloan-Kettering Hospital. Chi-square, Kaplan–Meier methods, and cox-proportional hazards model were used for statistical analyses. Results: Of 315 patients (median age: 59 years; range: 34–87) with complete sequence and clinical data, 90.8%, 3.2%, 3.2%, and 2.9% were White, Black, Asian, and other, respectively. 7.8% had grade 2 and 91.2% had grade 3 serous tumors. 88.3% had primary surgery, of which 74.5% were optimally debulked (<1 cm residual). Stage II, III, and IV disease comprised of 4.5%, 78.7% and 16.9%. Based on sequence data, 69 (22%) out of 315 women had BRCA1/2 mutations (16% germline
Methods: Kaiser Permanente Northern California (KPNC) has guidelines for referral of women at risk for inherited breast/ovarian cancer to genetic counseling. We conducted a retrospective chart review to identify women with cancer who met KPNC guidelines according to their pathology report. The guidelines used for the study were limited to the following: invasive breast cancer ≤age 40, nonmucinous epithelial ovarian, fallopian tube or peritoneal cancer ≤age 60, and women with synchronous or metachronous primary cancers of the breast and ovaries. We assessed compliance with guidelines for genetic counseling referral as well as outcome of genetic counseling among those referred. Phase two was a small prospective quality project (January–June 2010) to identify patients with pathology or diagnosis codes who met study guidelines for genetics referral. This was a preliminary study with a small sample size and limited power. The managing surgeon/oncologist was notified by an electronic letter of the patient's indication for referral to genetic counseling. Compliance with guidelines and outcome of patient follow up, counseling, and testing were evaluated. A review was conducted to assess referral rates within 3–6 months of the notification. Results: A total of 340 patients with new breast and ovarian cancers were identified between January and June 2008. Of the 105 patients identified who met the pathology specific referral guidelines, 47 (45%) were referred and of these, 27 (57%) completed their genetic visit. Of those with breast cancer, more than half (59 %) were referred. In contrast, less than one-in-five of those with ovarian, peritoneal or tubal cancer were referred (18%) (P-value for difference< 0.0001). In the prospective quality project, during the first half of 2010, 78 patients at 20 facilities met study referral guidelines, 30 (38%) of whom had already been referred at the time of chart review. Because the initial rates of referral were clinically different in the control and intervention sites, (18.1 ± 34.9 and 41.7 ± 44.2 respectively), we used adjusted regression models to test for differences between 6 month referral rates in the two groups. Intervention group had a 30.6 ± 12.6 percentage point higher referral rate, adjusted for initial rate of referral (P = 0.0266). Conclusion: In 2008, 45% of KPNC patients at risk meeting pathology guidelines were referred to genetic counseling which is comparable to rates published by comprehensive cancer centers (Meyer, LA et al, Obgyn survey 2010 (65) pp 436–437). It is feasible to identify patients at risk for BRCA 1 and 2 cancers by pathology report and referral rates may be improved with a letter to the oncologist. A larger randomized study is indicated to determine if this trend holds in comparable groups and if results are different for different cancer types. doi:10.1016/j.ygyno.2011.07.052
Factors associated with genetic testing in BRCA1 and BRCA2 mutation carriers with advanced ovarian carcinoma B. Norquist, T. Walsh, C. Pennil, M.K. Lee, S. Casadei, A.M. Thornton, A. S. Nord, R. Garcia, M.C. King, E. Swisher University of Washington, Seattle, WA, USA Objective: Not all women with ovarian, tubal or peritoneal carcinoma undergo genetic testing for BRCA1 and BRCA2 (BRCA1/2) mutations. Our institution recently identified a group of women with advanced ovarian carcinoma found to have BRCA1/2 mutations using a nextgeneration sequencing approach called the BROCA test, who had not had prior clinical genetic testing. These women were compared with known BRCA1/2 mutation carriers and sporadic cases to determine factors associated with obtaining genetic testing and to determine the fraction of hereditary risk missed in routine clinical practice. Methods: Women with advanced ovarian, tubal or peritoneal carcinoma were identified from the University of Washington gynecologic oncology tissue bank. Three groups were compared, women
435
with BRCA1/2 mutations identified using the BROCA test who had not previously undergone standard genetic testing (BROCA), women with known BRCA1/2 mutations identified by standard clinical genetic testing (KNOWN), and women with ovarian carcinoma negative for comprehensive genetic testing using the BROCA test (sporadic). Medical records were reviewed to compare demographic and clinical data. Results: There were 30 BROCA BRCA1/2 mutation carriers, 56 KNOWN BRCA1/2 mutation carriers, and 239 sporadic. The BROCA group had a median age of 58 (range 43–77), significantly older than the KNOWN group with a median age of 53 (range 33–76), p = 0.02, (Mann– Whitney). 51/56 (91.1%) of the KNOWN group had a strong family history suggestive of a BRCA1/2 mutation, compared with 13/30 (43.3%) of the BROCA group, p < 0.0001, (Fisher's Exact). There was no difference in the rate of optimal debulking, proportion of BRCA1 vs. BRCA2 carriers, or the percentage with a history of breast carcinoma between the BROCA and KNOWN groups. Median overall survival was significantly worse for the BROCA group compared to the KNOWN group, 53 vs. 83 months, p = 0.01, Log-rank test. Median overall survival was improved for all BRCA1/2 mutation carriers (KNOWN and BROCA) compared with sporadic cases, 69 vs. 47 months, p = 0.003, (Log-rank test), however there was no difference in overall survival between the sporadic and BROCA groups. In all women in the BROCA series, 26% of the women with germline mutations had no first or second degree relatives with breast or ovarian carcinoma and the likelihood of identifying a mutation was equally high between women diagnosed in their 40s, 50s or 60s. Conclusion: Older age, the absence of a strong family history, and poor survival are all associated with not obtaining genetic testing through standard methods. While BRCA1/2 mutation carriers in this series had improved overall survival compared with sporadic cases, this difference was driven by the group already known to have mutations. Using age and family history criteria to direct genetic testing will miss a significant percentage of mutation carriers.
doi:10.1016/j.ygyno.2011.07.053
Chemotherapy response and survival in serous ovarian cancer patients with BRCA mutations J.K. Chan a, T.K. Kiet a, L. Chen a, R. Ruskin a, A.E. Sherman a, B.J. Monk b, D.S. Kapp c, T.C. Krivak d a Division of Gynecology Oncology, Department of Obstetrics, Gynecology & Reproductive Sciences, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA, b Division of Gynecology Oncology, Creighton University School of Medicine at St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA c Department of Radiation Oncology, Stanford Cancer Center, Stanford, CA, USA, dDepartment of Obstetrics, Gynecology & Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA Objective: To compare the demographic, clinico-pathologic, treatment response, and survival of patients with BRCA (germline and somatic) mutations. Methods: Genomic and clinical data were obtained from The Cancer Genome Atlas supplemented with data from Sloan-Kettering Hospital. Chi-square, Kaplan–Meier methods, and cox-proportional hazards model were used for statistical analyses. Results: Of 315 patients (median age: 59 years; range: 34–87) with complete sequence and clinical data, 90.8%, 3.2%, 3.2%, and 2.9% were White, Black, Asian, and other, respectively. 7.8% had grade 2 and 91.2% had grade 3 serous tumors. 88.3% had primary surgery, of which 74.5% were optimally debulked (<1 cm residual). Stage II, III, and IV disease comprised of 4.5%, 78.7% and 16.9%. Based on sequence data, 69 (22%) out of 315 women had BRCA1/2 mutations (16% germline