IJC International Journal of Cancer

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1 IJC International Journal of Cancer Short Report Oncotype Dx recurrence score among BRCA1/2 germline mutation carriers with hormone receptors positive breast cancer Naama Halpern 1, Amir Sonnenblick 2, Beatrice Uziely 2, Luba Divinsky 2, Yael Goldberg 2, Tamar Hamburger 2, Tamar Peretz 2 and Luna Kadouri 2 1 Institute of Oncology, The Chaim Sheba Medical Center, Tel Hashomer, Israel 2 Sharett Institute of Oncology, Hebrew University-Hadassah Medical Center, Jerusalem, Israel Gene expression assays are widely used to predict risk of recurrence in early breast cancer (BC). We report the 21-gene expression assay (Oncotype Dx) recurrence score (RS) distribution of 27 BRCA carriers with estrogen receptor (ER) positive BCs, identified at Hadassah Medical Center, combined with 2 previous studies. Treatment decision and outcomes of the 27 BRCA carriers were compared with an Israeli cohort of 1594 patients published recently. We found Oncotype Dx RS low (<18), intermediate (18 30) and high (>30) among 12 (21.4%), 23 (41.1%) and 21 (37.5%) of 56 BRCA1 carriers compared with 15 (17.2%), 49 (56.3%) and 23 (26.4%) of 87 BRCA2 carriers (p 5 0.2). The corresponding distribution in a population of 82,434 women published by Genomic Health was 53.4%, 36.3% and 10.3% for low, intermediate and high RS (p < for BRCA1 and BRCA2). Treatment decision regarding chemotherapy according to RS was similar in BRCA1, BRCA2 and the control group. Two of 27 carriers had distant recurrence: a BRCA1 carrier with RS of 18 and a BRCA2 carrier with RS of 22; both have an excellent response to chemotherapy. We found an approximately ~3 fold increased rate of high RS among BRCA1 and 2 carriers with ER positive BC compared with the general BC population. These data might indicate that hormone positive BC in BRCA carriers are molecularly unique. The surprisingly good response to chemotherapy in the metastatic setting in 2 patients may suggest that the predictive value of low-intermediate RS in carriers merits further studies. Up to 10% of breast cancers (BC) are attributed to pathogenic mutations in the BRCA1 and BRCA2 genes. 1,2 While the majority of BC in BRCA1 carriers is triple negative, the rate of estrogen receptor (ER) positive BC in these patients is not negligible. Analysis of over 6000 BCs from BRCA carriers reported ER positive rates of 22% and 77%, among BRCA1 and BRCA2 mutation carriers, respectively. 3 Additional studies report similar rates of 20 30% ER positive BCs in BRCA1 carriers and 45 72% ER positive BCs in BRCA2 carriers. 2,4,5 Whether ER positive BC in BRCA1 carriers is a sporadic event or related to the BRCA1 mutation is not clear. Hormone receptor positive BC among BRCA2 carriers is frequently characterized by a higher grade than tumors in noncarriers. 4 Less is known about the clinical behavior of this tumor group. Rennert et al. reports similar outcomes for BRCA positive and negative BC patients when corrected to hormone receptor status and stage. 2 Key words: BRCA1, BRCA2, oncotype Dx, recurrence score, breast cancer DOI: /ijc History: Received 18 Oct 2016; Accepted 12 Jan 2017; Online 24 Jan 2017 Correspondence to: Luna Kadouri, Sharett Institute of Oncology, Hadassah Medical Center, Jerusalem 91120, Israel, Tel.: [972 (0) ], Fax: 1[972 (0) ], E mail: luna@hadassah.org.il Gene expression assays are widely used to assess prognosis and guide treatment decisions among early BC patients. The 21-gene expression assay Oncotype DX (Genomic Health, Redwood City, CA) quantifies the likelihood of BC recurrence and the potential benefit of chemotherapy in ER positive BC patients. The test was developed on archival pathology blocks from ER positive, Tamoxifen treated BC patients participating in prospective studies. Three risk groups were defined; low, intermediate and high with recurrence scores (RS) of <18, and >30, respectively, corresponding to a 10 years distant recurrence risk of <10, and >20%. 6 The aim of this retrospective study is to evaluate Oncotype Dx RS distribution in ER positive BC patients with germline BRCA mutation. We report treatment decision and clinical outcome in a group of 27 mutation carriers, to evaluate whether this test can be used for risk assessment in BRCA carriers. We combine our cohort with cohorts from three previously reported studies and assess RS distribution in a larger population of carriers. Material and Methods Patients The Oncotype Dx assay has been used at Hadassah Medical Center since 2004 on specimens from over 700 patients. Among them 13 BRCA1 and 14 BRCA2 mutation carriers

2 2146 Oncotype Dx RS among BRCA1/2 germline mutation carriers What s new? A significant minority of breast cancers in BRCA1 and BRCA2 carriers are ER-positive, and these cancers may have unique molecular properties. A new study investigates a 21-gene expression assay, used to quantify recurrence risk in ER-positive breast cancers. The assay, Oncotype Dx, has not been extensively evaluated in BRCA1 and 2 carriers. The authors compared the proportion of low, medium, and high recurrences scores from the Oncotype Dx. They found 3 times as many high recurrence scores among BRCA1 and 2 carriers than among the general population of ER-positive breast cancers, suggesting there may be molecular interaction warranting further study. were identified. We combined our data with 3 recent studies of RS distribution in carriers 7 9 and compared the entire cohort to data in the general BC population of 82,434 women published by Genomic Health. 10 Patients from Israeli Clalit Health Services HMO described in our population data were excluded from the combined analysis to prevent overlap with the study population based on Clalit HMO database of Lewin et al. 9 Clinical and pathological characteristics, treatment and outcome were retrieved from medical files of the 27 BRCA carriers treated at Hadassah Medical Center and compared with a cohort of 1594 Israeli patients which was recently published. 11 Statistical analysis RS distributions were compared using Fisher-exact test. Small numbers in each group limited statistical power; therefore, treatment and outcome according to Oncotype Dx RS categories are described, but not statistically compared between carriers and noncarriers. Results The Oncotype Dx RS distribution of our carrier group and that of three previous studies 7 9 compared with the general BC population 10 are presented in Table 1. McAndrew et al. 7 reported similar RS distribution among carriers and noncarriers while our series and the other two BRCA populations 8,9 exhibited significantly higher RS among carriers compared with controls. We combined our data with the RS distribution found in these three studies to enlarge BRCA population for comparison. The combined distribution of Oncotype Dx RS low (<18), intermediate (18 30) and high (>30) was found in 12 (21.4%), 23 (41.1%) and 21 (37.5%) of 56 BRCA1 carriers compared with 15 (17.2%), 49 (56.3%) and 23 (26.4%) of 87 BRCA2 carriers (p 5 0.2). The corresponding distribution in a population of 82,434 BC women published by Genomic Health 10 was 53.4, 36.2 and 10.3% for low, intermediate and high RS (p < compared with BRCA1 and compared with BRCA2). Patient and tumor characteristics of BRCA1, BRCA2 carriers compared with a large control group of Israeli general BC population 11 are described in Table 2. A high grade disease was more frequent in BRCA1 carriers than in BRCA2 carriers and the general BC population. Grade 3 disease was found in 9/12 (75%) of BRCA1 carriers in 3/13 (23.1%) of BRCA2 carriers (p ) and 18% of the general population (p for BRCA1 and p for BRCA2). ER expression was high (13) in 85% of tumors in both BRCA 1 and 2 carriers. Among BRCA1 carriers, lymph node involvement (LN1) was recorded in 5/13 [microscopic disease (Nmic) in %], of the 14 BRCA2 carriers, 3 patients had positive lymph nodes (Nmic in 2, 14.3%) compared with 10% of the controls with Nmic disease. To assess if positive lymph nodes tumors are associated with higher RS we combined the LN1 patients in our population and that of Lewin et al. series 9 (again, excluding from the combined analysis our Clalit HMO LN1 patients to prevent overlap); of 14 LN1 patients low RS was found in 3 (21.4%), intermediate in 6 (42.8%) and high RS in 5 of them (35.7%), which is similar to the entire carrier population (p ). Treatment and outcome according to Oncotype Dx RS categories is shown in Table 3. Treatment with adjuvant chemotherapy was given in 10/27 of carriers (37%) compared with 317/1594 of noncarriers (19.9%, p 5 0.9), however the analyses according to RS risk categories is limited due to small numbers. Chemotherapy was given to the majority of high RS patients; carriers (7/8, 87.5%) and noncarriers (150/ 169, 89%), while the rate of adjuvant chemotherapy was lower in the low-intermediate RS categories also in carriers (3/ 19, 15.8%). Treatment decisions might have been influenced by knowing BRCA status, with 13 (48.1%) patients known carriers at the time of BC diagnosis. Two patients (7.4%) in our carrier group had distant recurrence during a median follow up of 3.9 years. Additionally, one patient had a second primary BC and one patient had lymphoma. All other patients had no evidence of disease. The first patient with recurrence was a BRCA2 carrier; she had a T1Nmic, grade 2 IDC with a RS of 25. She did not receive adjuvant chemotherapy. At recurrence the tumor was still hormone receptor positive on biopsy, however, she did not respond to subsequent hormonal treatments and she had near complete response to capecitabine for 12 months and ongoing. The second patient was a BRCA1 carrier, had a T1Nmic grade 2 IDC with a RS of 18. She also did not get adjuvant chemotherapy. ER positive and PR negative tumor was found at recurrence and treatment with carboplatin resulted in complete response for >3 years. Discussion Our analysis confirms previous observations 8,9 of significantly higher Oncotype Dx RS among BRCA1 and 2 carriers. When

3 Halpern et al Table 1. Oncotype Dx RSs distributions in BRCA1 and BRCA2 carriers compared with the general population 10 Oncotype Dx RS studies RS Distributions Genomic Health female (n 5 82,434) BRCA 1 n BRCA2 n Low (<18) Halpern 1/13 (7.7%) 5/14 (35.7%) Lewin et al. 9 3/20 (15%) 7/38 (18.4%) Shah et al. 8 5/19 (26.3%) 3/31 (9.7%) McAndrew et al. 7 4/9 (44.4%) 3/8 (37.5%) Total 121/56 (21.4%) 151/87 (17.2%) 53.40% Intermediate (18 30) Halpern 6/13 (46.2%) 7/14 (50%) Lewin et al. 9 7/20 (35%) 20/38 (52.6%) Shah et al. 8 9/19 (47.4%) 19/31 (61.3%) McAndrew et al. 7 4/9 (44.4%) 4/8 (50%) Total 23 1 /56 (41.1%) 49 1 /87 (56.3%) 36.30% High (>30) Halpern 6/13 (46.2%) 2/14 (14.3%) Lewin et al. 9 10/20 (50%) 11/38 (28.9%) Shah et al. 8 5/19 (26.3%) 9/31 (28.9%) McAndrew et al. 7 1/9 (11.1%) 1/8 (12.5%) Total 21 1 /56 (37.5%) 23/87 (26.4%) 10.30% p < vs. BRCA1 p p < vs. BRCA2 1 Patients from Israeli Clalit Health Services HMO included in our data were excluded from the combined analysis to prevent overlap with the study population based on Clalit HMO database of Lewin et al. Table 2. Patient and tumor characteristics of BRCA1 and BRCA2 carriers compared with large control group of the general population 11 BRCA1 n513 BRCA2 n514 General Population n Age: median (range) 59 (36 76) 55 (42 72) 61 (25 85) T stage: T1 9 (75%) 11 (78.6%) Missing T2 3 (25%) 3 (21.4%) Missing T3 0 0 Missing Missing 1 0 Node:N0 8 (61.5%) 11 (78.6%) 90% Nmic (<2 mm) 4 (30.8%) 2 (14.3%) 10% N1 1 (7.7%) 1 (7.7%) 0 Grade (23.1%) 15% 2 3 (25%) 7 (53.8%) 49% 3 9 (75%) 3 (23.1%) 18% Missing % ER Missing 12 2 (15.3%) 2 (14.3%) Missing (84.6%) 12 (85.7%) Missing distributions in our series were combined with three previous studies 6 8 we found an 3 fold increased rate of high RS among BRCA carriers with ER positive tumors compared with the general BC population. 10 Distribution did not differ significantly between 56 BRCA1 and 87 BRCA2 carriers. These findings suggest hormone positive BC in BRCA carriers are molecularly different than in noncarriers. The population of carriers slightly varied between the studies with regard to age, lymph node involvement and grade, which may impact variation in RS distribution.

4 2148 Oncotype Dx RS among BRCA1/2 germline mutation carriers Table 3. Treatment and outcome of BRCA1, BRCA2 carriers compared with a control group of the general population 11 BRCA1 n 5 13 BRCA2 n 5 14 General Population n Low RS (<18) 1 (7.7%) 5 (35.7%) 813 (51%) Chemo use 0 1/5 (20%) 8/813 (1%) Distant recurrence /813 (2.1%) 5y distant recurrence rate (KM) 0.5% Intermediate RS (18 30) 6 (46.2%) 7 (50%) 612 (38%) Chemo use 1/6 (16.7%) 1/7 (14.3%) 159/612 (26%) Distant recurrence 1/6 (16.7%) 1/7 (14.3%) 33/612 (5.4%) 5 y distant recurrence rate (KM) 1.2% High RS (> 5 31) 6 (46.2%) 2 (14.3%) 169 (11%) Chemo use 5/6 (83.3%) 2/2 (100%) 150/169 (89%) Distant recurrence /169 (14.2%) 5y distant recurrence rate (KM) 6.9% Median follow up (y) However, separate analyses in 3 of the studies: our population, Lewin et al. 9 among 58 BRCA Israeli carriers as well as that of Shah et al. 8 of 50 carriers, found significantly higher RS in the carriers compared with the general BC population. Only McAndrew et al. 7 reported similar RS distribution comparing 18 carriers to the general BC population. While in their study only carriers with stage 1 disease were included, 7 the population in the Shah et al. study 8 included T2 disease; Lewin et al. 9 and our series included also lymph node positive disease. Lewin et al. 9 reported similar RS distribution regardless of nodal status. Indeed, in the combined 14 LN positive patients we found similar RS distribution as in the entire carrier population. Our combined analyses in a large population of carriers represent the RS distribution among patients that were selected to the Oncotype Dx test by the treating oncologist when considering to omit adjuvant chemotherapy and therefore may not represent the exact RS distribution in consecutive ER positive carrier population. Treatment decision regarding chemotherapy according to RS was similar in BRCA1 carriers, BRCA2 carriers and the control group. 11 This may not represent the impact of BRCA status on treatment decision since the latter was known only for half of the patients at time of BC diagnosis and Oncotype Dx testing. Shah et al. 8 found higher rate of adjuvant chemotherapy among carriers, which is related to the higher RS rate among this population. However, when stratified according to RS risk categories, adjuvant chemotherapy rate was similar among carriers and noncarriers. Patients with high RS are offered adjuvant chemotherapy regardless of their BRCA status. Several studies show better response to chemotherapy in BRCA1 carriers, the majority of whom had triple negative tumors and high grade disease; contradictory results were observed in BRCA2 carriers. 2,4,12,13 Whether hormone positive tumors in BRCA carriers respond better to chemotherapy remains to be determined. The unexpected good response to chemotherapy of two patients from our cohort, which presented with metastatic disease raises two important questions. Firstly, the homologous recombination machinery is not evaluated by the Oncotype Dx assay, and may affect the predictive value of the test regarding the response to chemotherapy among carriers. Assays for homologous recombination deficiency may complement the predictive value of these tests in ER positive BRCA associated tumors. Secondly, tumor heterogeneity should be considered, especially in BRCA1 associated tumors. On the biopsy performed from one patient with metastatic disease ER positive but PR negative disease was found. Gyanchandani et al. 14 report 25% of intratumor heterogeneity in Oncotype Dx RS in heterogeneous tumors. Therefore, the majority of ER positive, intermediate RS tumors in BRCA1 and 2 carriers should be considered to harbor less hormone responsive tumor cells and may have even triple negative clones. These patients, especially with larger tumors or lymph nodes positive disease should be treated accordingly. Our data raise the clinical dilemma of whether chemotherapy should be spared from the small group of BRCA carriers with hormone receptors positive tumors and low-intermediate RS. This study is the first to report long term outcomes including response to treatment in the metastatic setting in BRCA1 and 2 mutation carriers undergoing Oncotype DX analysis. Previous studies report patient outcomes in term of recurrence but do not describe metastatic disease course. Response to treatment in the metastatic disease serves as a surrogate for the predictive value of the Oncotype Dx assay. Combined analysis of our data with previous publications results in a relatively large sample size and strengthens our findings of different RS distribution among BRCA carriers. Our study has several limitations. Control groups of the general population might include BRCA1 and 2 carriers. This number would be lower than the estimation of 5 10%

5 Halpern et al BRCA carrier among BC patients of the general population since ER positive BC comprise only 30% of BRCA1 carriers and the lower use of Oncotype Dx among young premenopausal patients. Our sample size was small so we could not conduct statistical analysis of some parameters. To summarize, our data support recent publications of significantly higher Oncotype Dx RS among BRCA1 and BRCA2 germline mutation carriers. We describe a surprisingly good response to chemotherapy in two patients with intermediate RS and a recurrent metastatic disease. These preliminary findings warrant additional studies. References 1. Malone KE, Daling JR, Doody DR, et al. Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35 to 64 years. Cancer Res 2006;66: Rennert G, Bisland-Naggan S, Barnett-Griness O, et al. Clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 mutations. N Engl J Med 2007;357: Mavaddat N, Barrowdale D, Andrulis IL, et al. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev 2012;21: Goodwin PJ, Phillips KA, West DW, et al. Breast cancer prognosis in BRCA1 and BRCA2 mutation carriers: an International Prospective Breast Cancer Family Registry population-based cohort study. J Clin Oncol 2012;30: Tung N, Wang Y, Collins LC, et al. Estrogen receptor positive breast cancers in BRCA1 mutation carriers: clinical risk factors and pathologic features. Breast Cancer Res 2010;12:R Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 2006;24: McAndrew NP, Maxwell KN, Stopfer J, et al. Oncotype DX scores in BRCA1 and BRCA2 associated breast cancer ASCO Annual Meeting. J Clin Oncol 2015; Shah PD, Patil S, Dickler MN, et al. Twenty-onegene recurrence score assay in BRCA-associated versus sporadic breast cancers: differences based on germline mutation status. Cancer 2016;122: Lewin R, Sulkes A, Shochat T, et al. Oncotype- DX recurrence score distribution in breast cancer patients with BRCA1/2 mutations. Breast Cancer Res Treat 2016;157: Shak P, Palmer G, Boehner FL, et al. Molecular characterization of male breast cancer by standardized quantitative RT-PCR analysis: First large genomic study of 347 male breast cancers compared to 82,434 female breast cancers ASCO Annual Meeting. J Clin Oncol 2009;27:15s (suppl; abstr 549). 11. Stemmer SM, Steiner M, Rizel S, et al. Real-life analysis evaluating 1594 N0/Nmic breast cancer patients for whom treatment decisions incorporated the 21-gene recurrence score result: 5-year KM estimate for breast cancer specific survival with recurrence score results< 30 is >98%. SABCS 2015; P Arun B, Bayraktar S, Liu DD, et al. Response to neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers: a single-institution experience. J Clin Oncol 2011; 29: Paluch-Shimon S, Friedman E, Berger R, et al. Neo-adjuvant doxorubicin and cyclophosphamide followed by paclitaxel in triple-negative breast cancer among BRCA1 mutation carriers and non-carriers. Breast Cancer Res Treat 2016;157: Gyanchandani R, Lin Y, Lin HM, et al. Intra-tumor heterogeneity affects gene expression profile test prognostic risk stratification in early breast cancer. Clin Cancer Res 2016;22:

Twenty-One Gene Recurrence Score Assay in BRCA-Associated Versus Sporadic Breast Cancers: Differences Based on Germline Mutation Status

Twenty-One Gene Recurrence Score Assay in BRCA-Associated Versus Sporadic Breast Cancers: Differences Based on Germline Mutation Status Payal D. Shah, MD 1 ; Sujata Patil, PhD 2 ; Maura N. Dickler, MD