Original Article
Improved Survival for BRCA2-Associated Serous Ovarian Cancer Compared With Both BRCA-Negative and BRCA1-Associated Serous Ovarian Cancer David M. Hyman, MD1; Qin Zhou, MA2; Alexia Iasonos, PhD2; Rachel N. Grisham, MD1; Angela G. Arnold, MS, CGC3; Mary F. Phillips1,4; Jasmine Bhatia, BS3; Douglas A. Levine, MD4; Carol Aghajanian, MD1; Kenneth Offit, MD3; Richard R. Barakat, MD4; David R. Spriggs, MD1; and Noah D. Kauff, MD3,4
BACKGROUND: Multiple observational studies have suggested that breast cancer gene (BRCA)-associated ovarian cancers have improved survival compared with BRCA-negative ovarian cancers. However, most of those studies combined BRCA1 and BRCA2 patients or evaluated only BRCA1 patients. The objective of the current study was to examine whether BRCA1-associated and BRCA2-associated ovarian cancers were associated with different outcomes. METHODS: This was a single-institution, retrospective analysis of patients who had a new diagnosis of histologically confirmed stage III or IV serous ovarian, fallopian tube, or primary peritoneal cancer between January 1, 1996 and February 1, 2011 and who underwent BRCA mutation testing on 1 of 2 institutional review board-approved follow-up studies. Patients who had been tested for BRCA mutations beyond 24 months of diagnosis were excluded from analysis to minimize selection bias from including patients who were referred for genetic testing because of long survival. RESULTS: Data from 190 patients (143 BRCA-negative patients, 30 BRCA1-positive patients, and 17 BRCA2-positive patients) were analyzed. During the study period, 73 deaths were observed (60 BRCA-negative patients, 10 BRCA1-positive patients, 3 BRCA2-positive patients). The median follow-up for the remaining 117 survivors was 2.5 years. At 3 years, 69.4%, 90.7%, and 100% of BRCA-negative patients, BRCA1-positive patients, and BRCA2-positive patients were alive, respectively. On univariate analysis, age, BRCA2 mutations, debulking status, and type of first-line therapy (intravenous or intraperitoneal) were significant predictors of overall survival. On multivariate analysis, BRCA2 mutations (hazard ratio, 0.20; 95% confidence interval, 0.06-0.65; P ¼ .007), but not BRCA1 mutations (hazard ratio, 0.70; 95% confidence interval, 0.36-1.38; P ¼ .31), predicted for improved overall survival compared with BRCA-negative patients. When carriers of BRCA2 mutations were directly compared with carriers of BRCA1 mutations, BRCA2 mutations appeared to confer improved overall survival (hazard ratio, 0.29; 95% confidence interval, 0.08-1.05; P ¼ .060), although this finding did not reach significance. CONCLUSIONS: The current data suggests that BRCA2 mutations confer an overall survival advantage compared with either being BRCA-negative or having a BRCA1 mutation in high-grade serous ovarian cancer. This finding may have important implications for cliniC 2011 American Cancer Society. cal trial design. Cancer 2012;118:3703-9. V KEYWORDS: ovarian cancer, BRCA1, BRCA2, poly(ADP-ribose), polymerase inhibitors.
INTRODUCTION Ovarian cancer is the leading cause of death from gynecologic malignancies in the United States and is the fourth most common cause of cancer death in women.1 An estimated 21,000 cases are diagnosed in the United States each year, resulting in 15,000 deaths. It is now recognized that approximately 10% of unselected cases and 16% to 21% of the highgrade serous subtype are caused by a hereditary susceptibility, of which breast cancer gene 1 (BRCA1) and breast cancer gene 2 (BRCA2) mutations account for the majority.2-4 Although BRCA1 and BRCA2 mutations both are implicated in the development of hereditary ovarian cancers, each represents a clinically distinct entity in several important ways. The penetrance of ovarian cancer differs in these 2 Corresponding author: Noah D. Kauff, MD, Clinical Genetics and Gynecology Services, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 295, New York, NY 10065; Fax: (646) 888-4075 1 Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; 2Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York; 3Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; 4Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York
DOI: 10.1002/cncr.26655, Received: August 11, 2011; Revised: September 20, 2011; Accepted: October 4, 2011, Published online December 2, 2011 in Wiley Online Library (wileyonlinelibrary.com)
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populations, with a lifetime risk of 36% to 60% in BRCA1 mutation carriers and 16% to 27% in BRCA2 mutation carriers.5-7 BRCA1 mutation carriers also develop ovarian cancers approximately 10 years earlier than BRCA2 mutation carriers (median age at diagnosis, 53 years and 62 years, respectively).8,9 The distinct underlying biology of BRCA1 and BRCA2-associated ovarian cancers also has been characterized in comparative gene array profiles, which demonstrated >100 nonredundant genes with significantly different expression levels.10 Despite these clear biologic and clinical differences, investigators typically have grouped together BRCA1 and BRCA2 mutation carriers when investigating the prognosis and survival of this subset of women with ovarian cancer. In several observational studies, BRCA-associated ovarian cancers have been associated with improved overall survival (OS).9,11-19 The majority of those studies, including the 3 largest to date, combined BRCA1 and BRCA2 mutation carriers in their survival analyses.9,14,19 Only 1 report independently evaluated the survival of BRCA1 and BRCA2 mutation carriers, but the power of that analysis was limited because of the inclusion of only 6 BRCA2-associated serous ovarian cancers.16 Given these issues, we investigated survival with BRCA1-associated and BRCA2-associated ovarian cancers independently in patients who received primary therapy at our institution. Our objective was to determine whether these 2 ovarian cancer syndromes were associated with different prognoses.
MATERIALS AND METHODS Patients Institutional Review Board/Privacy Board (IRB/PB) approval was obtained for this retrospective analysis. Eligible patients were seen at Memorial Sloan-Kettering Cancer Center (MSKCC) between January 1, 1996 and February 1, 2011 for a new diagnosis of histologically confirmed, stage III or IV, serous ovarian, fallopian tube, or primary peritoneal cancer and underwent germline BRCA mutation testing on 1 of 2 IRB/PB-approved follow-up studies that were being conducted by the Clinical Genetics Service to investigate the clinical significance of germline BRCA mutations. Details of these 2 follow-up studies have been published previously.20 For the current study, patients with nonhigh-grade histology (low malignant potential or International Federation of Gynecology and Obstetrics grade 1) and/or recurrent disease were excluded. Diagnoses were confirmed by a full-time gynecologic pathologist at a highvolume comprehensive cancer center. In the event there
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was uncertainty regarding the diagnosis, the case was reviewed at a gynecologic pathology consensus conference. Patients who were tested for BRCA mutations beyond 24 months from diagnosis were excluded from the analysis to minimize the selection bias that could result from including patients who were referred for genetic testing because of long survival. Patients were considered to have a BRCAassociated cancer if their BRCA1 or BRCA2 mutation was predicted to be deleterious. Patients with variants of unknown significance were considered to be BRCA negative. All patients received cytotoxic chemotherapy according to the appropriate institutional protocol at the time of diagnosis. This therapy could be intravenous alone (IV) or combined intravenous and intraperitoneal (IP). Because the standard regimen for IP chemotherapy changed over the time studied, patients were considered to have received IP chemotherapy if they received any IP cisplatin as part of first-line therapy. Statistical Methods This was a single-institution, retrospective analysis with the primary objective of determining OS of patients by BRCA mutation status (BRCA1-positive, BRCA2-positive, and BRCA-negative). The associations between clinical factors and BRCA mutation status were tested by either using the Wilcoxon rank-sum test or the Kruskal-Wallis test for continuous variables or the Fisher exact test for categorical variables. OS was calculated from the date of diagnosis to the date of either death or last follow-up. Univariate OS analyses for BRCA mutation status, age, and disease stage were performed using the log-rank test for categorical variables or the Wald test based on Cox proportional hazards model for continuous variable. A landmark survival analysis was used to evaluate time-dependent covariates, such as timing of chemotherapy initiation or an attempt at surgical debulking.21 That analysis was conditional on being at risk at the landmark; therefore, patients who had a follow-up time shorter than the landmark time were excluded. Variables were regarded significant at a significance level of .05. A forward-selection technique was used to build multivariate model using a significance level of .05 for the variable to remain in the model.22 Analyses were conducted using the SAS statistical software package (version 9.2; SAS Institute, Cary, NC). BRCA Testing During the study period, patients who presented for the treatment of newly diagnosed pelvic serous cancer at MSKCC were not required to undergo genetic
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Improved Survival in BRCA2Ăž Ovarian Ca/Hyman et al
Table 1. Patient Demographics
No. of Patients (%)
P
Variable
All
BRCA Negative
BRCA1 Positive
BRCA2 Positive
Test for Group
Test for BRCA1 vs BRCA2
All patients
190
143
30
17
59 [58.45] 32-78
61 [59.72] 37-78
55 [53.7] 32-73
56 [56.12] 40-74
.008
.41
148 (77.9) 42 (22.1)
110 (76.9) 33 (23.1)
23 (76.7) 7 (23.3)
15 (88.2) 2 (11.8)
.63
.46
45 (23.7) 145 (76.3)
41 (28.7) 102 (71.3)
2 (6.7) 28 (93.3)
2 (11.8) 15 (88.2)
.012
.61
95 (50.5) 93 (49.5)
82 (57.7) 60 (42.3)
10 (33.3) 20 (66.7)
3 (18.8) 13 (81.3)
.001
.49
Age at diagnosis, y Median [mean] Range
Stage III IV
Optimal debulking No Yes
IP/IVa IV IP
Abbreviations: BRCA1/BRCA2, breast cancer genes 1 and 2, respectively; BRCA negative, negative for mutations in both BRCA genes; IP, combined intravenous and intraperitoneal therapy; IV, intravenous therapy alone. a Two patients were missing information.
counseling or testing. Between 1996 and 2008, patients typically were referred based on at least 1 of the following: 1) family history of breast cancer before age 50 years or ovarian cancer at any age in a first-degree or second-degree relative, 2) Eastern European (Ashkenazi) Jewish heritage, 3) patient request, or 4) physician request. Since July 2008, genetic counseling has been offered to (but not required of) all patients diagnosed with high-grade serous ovarian cancer irrespective of family history. For patients whose 4 grandparents all were of Ashkenazi Jewish heritage, germline DNA was screened for the 3 Ashkenazi founder mutations (BRCA1*185delAG, BRCA1*5382insC, and BRCA2*6174delT). If these were wild-type and there was a strong family history of ovarian or early onset breast cancer, then sequencing of the entire coding and flanking intronic regions of both BRCA1 and BRCA2 was performed by Myriad Genetics (Salt Lake City, Utah). For participants who were not of exclusive Ashkenazi ancestry, sequencing of BRCA1 and BRCA2 was performed in all cases. Testing for structural rearrangements was obtained based on individual patient characteristics and testing coverage.
RESULTS In total, 190 patients (143 BRCA-negative patients, 30 BRCA1-positive patients, and 17 BRCA2-positive patients) were eligible for analysis. No patient had mutations in both BRCA1 and BRCA2. Sixty-eight (36%) patients reported 4 Ashkenazi Jewish (AJ) grandparents,
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18 (9%) reported at least 1 AJ grandparent, and the remaining 104 (55%) were of entirely non-AJ decent. Baseline demographic and treatment data are listed in Table 1. There were no significant differences between the BRCA1-positive patients and the BRCA2-positive patients in distribution according to age, disease stage, debulking outcomes (optimal vs suboptimal), or first-line therapy (IV vs IP). Comparing across all 3 groups, the BRCA-positive patients were more likely to be younger, to have undergone optimal debulking and to have received IPbased first-line chemotherapy. Survival data and univariate OS analysis are presented in Table 2. During the period of follow-up, there were 73 deaths (10 deaths in BRCA1-positive patients, 3 deaths in BRCA2-positive patients, and 60 deaths in BRCA-negative patients). The OS rate at 3 years for the BRCA-negative, BRCA1-positive, and BRCA2-positive patients was 69.4%, 90.7%, and 100%, respectively. The median survival for BRCA-negative and BRCA1positive patients was 4.3 years and 5.6 years, respectively. At median follow-up of 5.3 years for the surviving BRCA2-positive patients, the median survival had not yet been reached. The median follow-up for the remaining 117 surviving patients was 2.5 years (range, 0.47-13.1 years). The impact of age, disease stage, debulking status, and type of first-line therapy (IV or IP) on OS was analyzed using univariate analyses. Of these variables, only age (10-year hazard ratio [HR], 1.38; 95% confidence
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Original Article Table 2. Univariate Overall Survival Analyses
Variable
No. of Patients
No. of Deaths
3-Year OS rate (95% CI), %
Median Survival (95% CI), y
All
190
73
75.8 (67.7-82.1)
5.4 (4.2-5.9)
143 30 17
60 10 3
69.4 (59.4-77.3) 90.7 (67.6-97.6) 100
4.3 (3.6-5.5) 5.6 (3.5-Not estimable) Not reached
HR (95% CI)
LogRank P
Ref 0.61 (0.31-1.2) 0.19 (0.06-0.62)
.005a
1.38 (1.08-1.77)
.01
BRCA mutation status BRCA negative BRCA1 positive BRCA2 positive Age at diagnosis; 10-y HR
Stage III IV
148 42
58 15
79.7 (70.9-86.1) 60.3 (39.4-76.1)
5.4 (4.3-6.0) 3.5 (2.7-Not estimable)
Ref 1.29 (0.73-2.29)
.38
44 144
23 50
45.6 (27.2-62.3) 70.6 (60-78.9)
3.0 (1.7-4.0) 4.9 (3.7-5.8)
Ref 0.5 (0.31-0.82)
.005
94 93
47 26
58.1 (45.3-69) 74.2 (60.3-83.9)
3.7 (2.7-5.0) 5.0 (3.8-Not Estimable)
Ref 0.51 (0.32-0.83)
.005
Optimal debulkingb No Yes
IP/IVc IV IP
Abbreviations: BRCA1/BRCA2, breast cancer genes 1 and 2, respectively; BRCA negative, negative for mutations in both BRCA genes; CI, confidence interval; HR, hazard ratio; IP, combined intravenous and intraperitoneal therapy; IV, intravenous therapy alone; OS, overall survival; Ref, reference level. a The log-rank P value was .150 for BRCA1 positive vs BRCA negative, .003 for BRCA2 positive vs BRCA-negative, and .050 for BRCA1 positive vs BRCA2 positive. b Two patients were excluded from the landmark analysis. c Two patients were missing information, and 1 patient was excluded from the landmark analysis.
Table 3. Multivariate Overall Survivala
Variable
HR (95% CI)
Age at diagnosis; 10-y HR BRCA1 positive vs BRCA negative BRCA2 positive vs BRCA negative Optimal vs suboptimal debulking
1.32 0.70 0.20 0.60
(1.02-1.71) (0.36-1.38) (0.06-0.65) (0.36-1.00)
P .035 .31 .007 .050
Abbreviations: BRCA1/BRCA2, breast cancer genes 1 and 2, respectively; BRCA negative, negative for mutations in both BRCA genes; CI, confidence interval; HR, hazard ratio. a Landmark analysis was used to build this multivariate model.
Figure 1. Kaplan-Meier curves illustrating overall survival for patients with breast cancer gene (BRCA)-negative, BRCA1-positive, and BRCA2-positive high-grade serous ovarian cancer.
interval [CI], 1.08-1.77), optimal debulking status (HR, 0.50; 95% CI, 0.31-0.82), and IP therapy (HR, 0.51; 95% CI, 0.32-0.83) were statistically significant predictors of survival. Surgical stage (III vs IV) was not associated significantly with survival, although the majority of
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patients had stage III disease (78%; 148 of 190 patients). When BRCA mutation status (BRCA1-positive, BRCA2positive, and BRCA-negative) was examined in univariate fashion, BRCA2 mutations (HR, 0.19; 95% CI, 0.060.62), but not BRCA1 mutations (HR, 0.61; 95% CI, 0.31-1.20), were a significant predictor of OS (Figure 1). The effect of BRCA mutation status on OS also was evaluated in a multivariate analysis. The results are presented in Table 3. By using a forward-selection technique, the covariates age, optimal versus suboptimal debulking, and BRCA mutation status were selected for inclusion in the final multivariate model. The type of first-line therapy was not included, because it did not reach statistical significance in the final model. This probably was because of the substantial correlation between debulking status and
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receipt of IP chemotherapy. In the final multivariate model, only BRCA2 mutation status (HR, 0.20; 95% CI, 0.06-0.65; P ¼ .007) and age (10-year HR, 1.32; 95% CI, 1.02-1.71; P ¼ .035) remained significant predictors of OS. Optimal debulking status had borderline significance, and BRCA1 mutation status was not a significant predictor of survival (HR, 0.70; 95% CI, 0.36-1.38; P ¼ .31). When carriers of BRCA2 mutations were compared directly with carriers of BRCA1 mutations in our multivariate model setting, BRCA2 mutations appeared to predict for substantially improved survival (HR, 0.29; 95% CI, 0.08-1.05; P ¼ .06), although this finding did not quite reach statistical significance.
DISCUSSION Our data suggest that women who have BRCA2-associated serous ovarian cancer may have a meaningfully different outcome compared not only with women who have BRCA-negative disease but also compared with those who have BRCA1-associated, high-grade serous ovarian cancer. This finding, if confirmed, will have an important impact on clinical trial design given the 16% to 21% prevalence of germline BRCA mutations in unselected patients with serous ovarian cancer. The ongoing and upcoming trials of poly(ADP-ribose) polymerase (PARP) inhibitors in high-grade epithelial ovarian cancer, many of which will specifically enrich for BRCA1 and BRCA2 carriers, may be at particular risk for confounded results if stratification of these 2 groups is not considered. Our analysis has several strengths. Unlike several other survival analyses of BRCA-associated ovarian cancers, we restricted our analysis to only advanced-stage (III/ IV), high-grade serous tumors, the ovarian cancer subtype that accounts for the majority of the morbidity and mortality related to ovarian cancer.23 We also chose to limit or cohort to patients who presented to our institution at the time of diagnosis, because the likelihood of recurrence after initial therapy may be linked to BRCA status. Further, the patients in the present analysis were treated almost exclusively at a single institution with common surgical and medical standards over the study period, minimizing the possibility that our analysis was confounded by subtle differences in surgical or chemotherapeutic management styles across institutions or time. Our analysis also was limited to patients who had been tested for BRCA mutations within 2 years of their initial diagnosis of ovarian cancer. This restriction, which caused us to remove 43 patients from the analysis, eliminated patients who may have undergone BRCA testing because of unexpected lon-
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gevity or persistent sensitivity to chemotherapy. Finally, all control (BRCA-negative) patients in our analysis were confirmed noncarriers rather then untested, matched controls, which was the case in some previously published reports.11,17 This analysis does have several limitations. Our findings are based on a convenience sample of patients who were tested for BRCA mutations. During the period included in this report, our institution treated approximately 1200 unique cases of newly diagnosed and recurrent, stage III/IV, high-grade serous ovarian cancers, which means that only approximately 15% of potential cases were captured for our analysis. This relatively low capture rate reflects several factors, including the lack of universal BRCA mutation testing and the use of strict inclusion and exclusion criteria in the study design to minimize bias. In addition, only patients who were tested for BRCA mutations on 1 of 2 IRB-approved follow-up protocols were included because of unique patient issues and privacy concerns related to germline genetic testing. It is not possible to speculate how a higher rate of capture would have affected our results. Differences in the BRCA1-associated, BRCA2-associated, and BRCA-negative cohorts are also worth addressing. The BRCA2-associated cohort included only 11.8% of stage IV patients compared with 23.3% and 23.1% in the BRCA1-associated and BRCA-negative cohorts. Although neither difference was statistically significant, a repeat analysis limited to stage III patients did not change the conclusions presented here (data not shown). Patients with BRCA1 or BRCA2 mutations also were more likely to have undergone optimal debulking and to have received IP-based first-line chemotherapy. Because IP chemotherapy traditionally has been restricted to patients who undergo optimal debulking, it is likely that these 2 findings were correlated. Our analysis revealed a trend toward improved survival in BRCA1 mutation carriers compared with BRCAnegative patients, although this finding did not reach significance (HR, 0.70; 95% CI, 0.36-1.38; P ¼ .31). This is consistent with other published data. In the large, multivariate analysis reported by Chetrit et al, BRCA1 mutations demonstrated a similar impact on survival (HR, 0.82; 95% CI, 0.63-1.05; P ¼ .10).14 It is unclear whether this result would reach statistical significance in an even larger cohort. Finally, the data presented here do not provide insight into the reason for improved survival in BRCA2 mutation carriers compared with BRCA1 mutation
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carriers and BRCA-negative patients. The relative contributions of improved chemotherapy sensitivity versus underlying differences in tumor biology are unclear. A case-control study by Tan and colleagues revealed higher rates of platinum sensitivity across first-line, second-line, and third-line therapy for patients with BRCA1/BRCA2 mutation-positive ovarian cancer compared with matched controls.18 However, their report included only 22 BRCA mutation carriers (17 BRCA1 mutation carriers and 5 BRCA2 mutation carriers) and did not attempt to compare BRCA1-associated and BRCA2-associated outcomes. More recently, our group examined predictors of survival in a subset of the patients included in the current report.15 In that previous work, both the presence of a BRCA mutation and platinum sensitivity were independent predictors of survival, suggesting that both tumor biology and chemotherapy sensitivity may contribute to prolonged survival. However, that earlier study also was not powered to examine at differences between carriers of BRCA1 mutations and BRCA2 mutations. Ultimately, the mechanisms through which BRCA1 and BRCA2 mutations may result in different tumor biology are poorly understood and require further research. Until recently, all ovarian cancers have been managed similarly regardless of germline BRCA mutation status. Although it has been suggested for more than a decade that BRCA1/BRCA2-associated ovarian cancers have a more favorable prognosis compared with BRCAnegative tumors, there have been no targeted therapies available to exploit the underlying biologic differences between these tumors. Since the development of PARP inhibitors, which may be specifically active in BRCA-deficient tumors, the molecular subclassification of ovarian cancers has become increasingly important.24 BRCA-deficient tumors have alterations in homologous recombination, the DNA repair pathway responsible for highfidelity resolution of double-stranded DNA breaks and cross-links.25 PARP inhibitors block base excision repair, a lower fidelity salvage DNA repair pathway necessary to maintain genomic stability in tumors deficient in homologous recombination, and are an extremely promising class of agents for treating BRCA-deficient ovarian cancer.26 However, the mechanism of BRCA inactivation, and the associated loss of homologous recombination function, may be important. Hennessy et al reported on a cohort of 44 ovarian cancer specimens that were tested for BRCA1/ BRCA2 mutations.27 Thirty-three (75%) of the mutations were germline, and the remaining 11 (25%) were somatic. In that analysis, patients who had loss of BRCA function through either mechanism had improved progression-free
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survival compared with patients who had intact BRCA function. However, those authors did not report the outcomes of germline and somatically mutated tumors separately. Finally, their analysis did not examine specimens for epigenetic BRCA inactivation. Recent data generated by The Cancer Genome Atlas Ovarian Project demonstrate that, although approximately 50% of high-grade serous ovarian tumors have alterations in the homologous recombination pathway by BRCA1/BRCA2 germline mutation, somatic mutation, epigenetic silencing, or other putative homologous recombination defects, patients who have tumors with epigenetically silenced BRCA1 have significantly worse outcomes than patients who had tumors with germline and somatic BRCA1/BRCA2 mutations.19 Like our current findings, these results strongly suggest that the methods and types of BRCA inactivation may have different prognostic implications. Although our analysis indicates that presence of a BRCA2 mutation is an important predictor of survival compared with both being BRCA-negative or having a BRCA1 mutation, it seems appropriate to consider this report hypothesis generating rather then definitive given the relatively small number of patients and events (only 3 deaths in the BRCA2-associated cohort). These conclusions certainly will need to be validated in prospective data sets. However, our findings indicate that, in the emerging era of targeted therapies for molecularly characterized subtypes of ovarian cancer, the grouping of BRCA1 and BRCA2 mutations, which cause two related but distinct cancer susceptibility syndromes, may not be appropriate, and strong consideration should be given to stratifying future studies in ovarian cancer according to BRCA1 and BRCA2 mutation status.
FUNDING SOURCES This work was supported by Project Hope for Ovarian Cancer Research and Education, the Kaleidoscope of Hope Foundation, the Genet Fund, and by NIH Grant # P01-CA52477-17.
CONFLICT OF INTEREST DISCLOSURES N.D.K. has received consulting fees and has been an expert witness for Pfizer.
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