Noah Kauff

Positions:

Instructor, Temporary in the Obstetrics and Gynecology

Obstetrics and Gynecology, Gynecologic Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1993

University of Pennsylvania

Grants:

Publications:

Mortality reduction and cost-effectiveness of performing hysterectomy at the time of risk-reducing salpingo-oophorectomy for prophylaxis against serous/serous-like uterine cancers in BRCA1 mutation carriers.

OBJECTIVE: To estimate the survival benefit and cost-effectiveness of performing hysterectomy during risk-reducing salpingo-oophorectomy (RRSO) for BRCA1 mutation carriers. METHODS: Based on a recent prospective cohort study indicating an elevated incidence of serous/serous-like uterine cancers among BRCA1 mutation carriers, we constructed a modified Markov decision model from a payer perspective to inform decisions about performance of hysterectomy during RRSO at age 40. We assumed patients had previously undergone a risk-reducing mastectomy and had a residual risk of death from breast or ovarian cancer. Disease-specific survival, age-adjusted competing hysterectomy rates, and deaths from other causes were incorporated. Costs of risk-reducing surgery, competing hysterectomy, and care for serous/serous-like uterine cancer were included. RESULTS: A 40year old woman who undergoes RRSO+Hysterectomy gains 4.9 additional months of overall survival (40.38 versus 39.97 undiscounted years) compared to RRSO alone. The lifetime probabilities of developing or dying from serous/serous-like uterine cancer in the RRSO group are 3.5% and 2%, respectively. The RRSO alone strategy has an average cost of $9013 compared to $8803 for RRSO+Hysterectomy, and is dominated (less effective and more costly) when compared to RRSO+Hysterectomy. In an alternative analysis, delayed hysterectomy remains a cost-effective prevention strategy with an ICER of less than $100,000/year for up to 25years following RRSO at age 40. CONCLUSIONS: The addition of hysterectomy to RRSO in a 40year old BRCA1 mutation carrier results in a mean gain of 4.9 additional months of life and is cost-effective.
MLA Citation
URI
https://scholars.duke.edu/individual/pub1244382
PMID
28390820
Source
pubmed
Published In
Gynecol Oncol
Volume
145
Published Date
Start Page
549
End Page
554
DOI
10.1016/j.ygyno.2017.03.025

The performance of BRCA1 immunohistochemistry for detecting germline, somatic, and epigenetic BRCA1 loss in high-grade serous ovarian cancer.

BACKGROUND: BRCA1 expression can be lost by a variety of mechanisms including germline or somatic mutation and promotor hypermethylation. Given the potential importance of BRCA1 loss as a predictive and prognostic biomarker in high-grade serous ovarian cancer, we sought to evaluate the utility of BRCA1 immunohistochemistry (IHC) in screening for BRCA1 loss by germline, somatic, and epigenetic mechanisms. PATIENTS AND METHODS: Patients with advanced high-grade serous ovarian cancer who had previously undergone germline BRCA1 testing were identified. Samples from each tumor were stained for BRCA1 and reviewed independently by two pathologists blinded to BRCA status. Tumors with abnormal BRCA1 IHC and wild-type germline testing underwent further evaluation for somatic BRCA1 mutations and promoter hypermethylation. McNemar's test was used to determine the association of BRCA1 IHC with germline BRCA1 mutations and BRCA1 loss through any mechanism. Kaplan-Meier methods were used to estimate overall survival (OS), and the log-rank test was used to assess differences between groups. RESULTS: Inter-rater reliability between the two pathologists on BRCA IHC interpretation was very good (kappa coefficient 0.865, P = 0.16; McNemar's test). BRCA1 IHC was abnormal in 36% (48/135) of cases. When compared with germline BRCA1 status, BRCA1 IHC had a high negative predictive value (95.4%) but a low positive predictive value (PPV, 52.1%). When accounting for promoter hypermethylation and somatic mutations as alternative methods of BRCA1 loss, the PPV rose to 87.5%. Five-year OS rate was 49.6% [95% confidence interval (CI) 26.3% to 69.3%] for patients with germline BRCA1 mutations, 50.4% (95% CI 27.5% to 69.5%) for germline wild-type BRCA1 and abnormal IHC, and 52.1% (95% CI 38.4% to 64.2%) for germline wild-type BRCA1 and normal IHC (P = 0.92). CONCLUSIONS: BRCA1 IHC interpretation was a highly reproducible and accurate modality for detecting germline, somatic, or epigenetic mechanisms of BRCA1 loss. These results support further development of BRCA1 IHC as a potential biomarker for BRCA1 loss in high-grade serous ovarian cancer.
Authors
Meisel, JL; Hyman, DM; Garg, K; Zhou, Q; Dao, F; Bisogna, M; Gao, J; Schultz, ND; Grisham, RN; Phillips, M; Iasonos, A; Kauff, ND; Levine, DA; Soslow, RA; Spriggs, DR
MLA Citation
Meisel, J. L., et al. “The performance of BRCA1 immunohistochemistry for detecting germline, somatic, and epigenetic BRCA1 loss in high-grade serous ovarian cancer..” Ann Oncol, vol. 25, no. 12, Dec. 2014, pp. 2372–78. Pubmed, doi:10.1093/annonc/mdu461.
URI
https://scholars.duke.edu/individual/pub1327349
PMID
25281711
Source
pubmed
Published In
Ann Oncol
Volume
25
Published Date
Start Page
2372
End Page
2378
DOI
10.1093/annonc/mdu461

Morphologic patterns associated with BRCA1 and BRCA2 genotype in ovarian carcinoma.

This study was undertaken with the hypothesis that certain common morphologic features of ovarian carcinomas are predictably associated with BRCA1 and BRCA2 deficiencies. We selected 43 high-grade serous carcinomas diagnosed at Memorial Sloan-Kettering Cancer Center that were studied as part of The Cancer Genome Atlas pilot project. In addition to 12 randomly selected nonfamilial BRCA-unassociated cases, all 31 Memorial Sloan-Kettering Cancer Center cases with BRCA1 or BRCA2 abnormality were included (n=43). Slides were examined to assess tumor architecture, mitotic index, tumor-infiltrating lymphocytes (TILs), nuclear pleomorphism, necrosis, and involvement of fallopian tube epithelium. Comparing BRCA1-associated cases (BRCA1 germline mutation, n=4, BRCA1 somatic mutation, n=6, BRCA1 promoter methylation, n=13) with unassociated cases (n=12) identified statistically significant differences in morphology. BRCA1-associated high-grade serous carcinomas had more frequent Solid, pseudoEndometrioid, and Transitional cell carcinoma-like morphology (SET features) (P=0.0045), higher mitotic indexes (P=0.012), more TILs (P=0.034), and either geographic or comedo necrosis (P=0.034). BRCA2-associated cases (germline mutation, n=4 and somatic mutation, n=4) tended to show SET features, but they were relatively deficient in TILs and necrosis. Two algorithms incorporating tumor architecture, necrosis, and either mitotic indexes or TILs separated cases that showed 2 of 3 features (BRCA1 associated) from those with 0 of 3 features (BRCA unassociated; P=0.0016 and P=0.0033). A test set comprising 9 BRCA1 germline mutants and 14 high-grade serous carcinoma controls lacking BRCA1 and BRCA2 germline mutation was used to validate the algorithms, with specific emphasis on the ability to detect cases with BRCA1 germline mutation. Best results were obtained with the algorithm that incorporated SET features, necrosis, and mitotic index (P=0.0072; sensitivity of 1.0 (95% CI, 0.66-1.0); specificity of 0.57 (95% CI, 0.29-0.82); positive predictive value of 0.60 (95% CI, 0.32-0.84) and a negative predictive value of 1.0 (95% CI, 0.63-1.0)). These preliminary data indicate potential strong associations between morphology and genotype in high-grade serous carcinomas.
Authors
Soslow, RA; Han, G; Park, KJ; Garg, K; Olvera, N; Spriggs, DR; Kauff, ND; Levine, DA
MLA Citation
Soslow, Robert A., et al. “Morphologic patterns associated with BRCA1 and BRCA2 genotype in ovarian carcinoma..” Mod Pathol, vol. 25, no. 4, Apr. 2012, pp. 625–36. Pubmed, doi:10.1038/modpathol.2011.183.
URI
https://scholars.duke.edu/individual/pub1327366
PMID
22193042
Source
pubmed
Published In
Modern Pathology
Volume
25
Published Date
Start Page
625
End Page
636
DOI
10.1038/modpathol.2011.183

Absence of genomic BRCA1 and BRCA2 rearrangements in Ashkenazi breast and ovarian cancer families.

A substantial proportion of Ashkenazi Jewish (AJ) breast and ovarian cancer families carry one of three founder mutations in BRCA1 (185delAG, 5382InsC) and BRCA2 (6174delT). Non-founder mutations are identified in another 2-4% of such families. The extent to which major genomic rearrangements in BRCA contribute to breast and ovarian cancer in the Ashkenazim is not well understood. We identified AJ individuals with breast and/or ovarian cancer undergoing hereditary breast/ovarian cancer risk assessment since 2006 without evidence of a deleterious mutation on BRCA gene sequencing who were screened for major gene rearrangements in BRCA1 and BRCA2. For each proband, the pre-test probability of identifying a deleterious BRCA mutation was estimated using the Myriad II model. We identified 108 affected individuals who underwent large rearrangement testing (80 breast cancer, 19 ovarian cancer, nine both breast and ovarian cancer). The mean estimated AJ specific pre-test probability of a deleterious mutation in BRCA1 and BRCA2 was 24.7% (range: 4.4-88.9%). No genomic rearrangements were identified in either the entire group or in the 26 subjects with pre-test mutation prevalence estimates exceeding 30%. Major gene rearrangements involving the BRCA1 and BRCA2 genes appear to contribute little to the burden of inherited predisposition to breast and ovarian cancer in the Ashkenazim.
Authors
Stadler, ZK; Saloustros, E; Hansen, NAL; Schluger, AE; Kauff, ND; Offit, K; Robson, ME
MLA Citation
Stadler, Zsofia K., et al. “Absence of genomic BRCA1 and BRCA2 rearrangements in Ashkenazi breast and ovarian cancer families..” Breast Cancer Res Treat, vol. 123, no. 2, Sept. 2010, pp. 581–85. Pubmed, doi:10.1007/s10549-010-0818-y.
URI
https://scholars.duke.edu/individual/pub1327407
PMID
20221693
Source
pubmed
Published In
Breast Cancer Res Treat
Volume
123
Published Date
Start Page
581
End Page
585
DOI
10.1007/s10549-010-0818-y

Risk-reducing salpingo-oophorectomy in patients with germline mutations in BRCA1 or BRCA2.

Women with mutations in BRCA1 or BRCA2 are at tremendously increased lifetime risk of both breast and BRCA-associated gynecologic (ovarian, fallopian tube, and primary peritoneal) cancer. Because of limitations in the efficacy of available screening and chemopreventive approaches for women with a mutation in one of these genes, surgical risk reduction, particularly risk-reducing salpingo-oophorectomy (RRSO), has become an important component of the management options in hereditary breast-ovarian cancer syndrome. This article will review the rationale and efficacy of RRSO for prevention of breast and BRCA-associated gynecologic cancer. Surgical technique and methods of pathologic evaluation will be presented. Controversies regarding uterine preservation and post-RRSO hormone replacement therapy will be addressed. Considerations that may impact the appropriate timing of the procedure will be reviewed, and the potential role of RRSO in BRCA-negative hereditary breast cancer families will also be discussed.
Authors
Kauff, ND; Barakat, RR
MLA Citation
Kauff, Noah D., and Richard R. Barakat. “Risk-reducing salpingo-oophorectomy in patients with germline mutations in BRCA1 or BRCA2..” J Clin Oncol, vol. 25, no. 20, July 2007, pp. 2921–27. Pubmed, doi:10.1200/JCO.2007.11.3449.
URI
https://scholars.duke.edu/individual/pub1327395
PMID
17617523
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
25
Published Date
Start Page
2921
End Page
2927
DOI
10.1200/JCO.2007.11.3449