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Annual Meeting Proceedings Part 1 - American Society of Clinical ...

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90s Cancer Prevention/Epidemiology<br />

1516 Poster Discussion Session (Board #5), Sun, 8:00 AM-12:00 PM and<br />

11:30 AM-12:30 PM<br />

PTEN germline mutations in patients first tested for other hereditary cancer<br />

syndromes: Would use <strong>of</strong> risk assessment tools have reduced health care<br />

costs? Presenting Author: Jessica Mester, Genomic Medicine Institute,<br />

Cleveland Clinic, Cleveland, OH<br />

Background: PTEN Hamartoma Tumor Syndrome (PHTS) includes patients<br />

with Cowden (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) with<br />

germline PTEN mutation. Breast, colon, endometrial cancer and GI<br />

polyposis are associated, creating overlap with Hereditary Breast and<br />

Ovarian Cancer (HBOC), Lynch (LS) and adenomatous polyposis syndromes<br />

(APS). We reviewed our PHTS patient series to find how <strong>of</strong>ten testing<br />

criteria for these syndromes were met or testing was pursued before PTEN.<br />

Methods: Patients were prospectively recruited by relaxed International<br />

Cowden Consortium criteria or presence <strong>of</strong> known germline PTEN mutation;<br />

mutations were identified by mutation scanning or MLPA analysis and<br />

confirmed by sequencing or quantitative PCR, respectively. Families were<br />

excluded if diagnosed with CS or BRRS before 1998, family history was<br />

unavailable, or proband was �18 yrs. Pedigree, genetic testing reports, and<br />

medical records were reviewed to determine if patients met HBOC testing<br />

criteria, Amsterdam II or Bethesda 2004 criteria, or had adenomatous<br />

polyps. Risk assessment was conducted for BRCA1/2 via the BRCAPRO,<br />

Myriad II, and Penn II models; for MLH1/MSH2/MSH6 via the PREMM1,2,6<br />

and MMRPro models; and for PTEN via the Cleveland Clinic (CC) PTEN<br />

Risk Calculator. Results: 115 PTEN mutation-positive adult probands were<br />

identified among 3,405 patients. 53 (46.1%) met testing criteria for HBOC<br />

or LS and 34 (29.6%) underwent previous testing for HBOC, LS or APS.<br />

Average risk for BRCA1/2 and MLH1/MSH2/MSH6 mutations in tested<br />

patients were 7.5-16.9% and 33.1-41.4%, respectively; whereas PTEN<br />

mutation risks were 35.9% and 79.7%. No patient tested for APS (average<br />

PTEN mutation risk 73%) had �5 adenomas. An estimated $89,700 was<br />

spent on negative analyses for HBOC, LS and APS among patients<br />

ultimately found to have germline PTEN mutations. Conclusions: PHTS<br />

should be part <strong>of</strong> the differential diagnosis for patients referred for question<br />

<strong>of</strong> HBOC, LS or APS. Pathology review is key for patients with polyposis.<br />

Using the CC PTEN risk calculator enables clinicians to understand when<br />

PTEN mutation risk is high, allowing testing to proceed in a step-wise and<br />

cost-saving manner.<br />

1519 Poster Discussion Session (Board #8), Sun, 8:00 AM-12:00 PM and<br />

11:30 AM-12:30 PM<br />

Pathologic findings at risk-reducing salpingo-oophorectomy among women<br />

at increased ovarian cancer risk: Results from GOG-199. Presenting<br />

Author: Phuong L. Mai, National Cancer Institute, Rockville, MD<br />

Background: Although risk-reducing salpingo-oophorectomy (RRSO) is a<br />

standard management option for women with BRCA1/2 mutations, the lack<br />

<strong>of</strong> large, prospective cohort studies makes estimating the prevalence <strong>of</strong><br />

cancer at RRSO problematic. Methods: GOG-199 is a large, nonrandomized<br />

multi-center trial which enrolled women at high-risk (due to<br />

BRCA mutations or strong family history) <strong>of</strong> ovarian cancer, comparing<br />

surgery at enrollment with serial transvaginal ultrasound and CA-125<br />

screening. RRSO specimens were processed according to a standardized<br />

tissue processing protocol including 2-3mm sectioning <strong>of</strong> both ovaries and<br />

tubes. Results: 2,605 participants were accrued to GOG-199. Of the 1 030<br />

enrolled in the baseline RRSO cohort, 28 were ineligible and 36 declined<br />

surgery after enrollment, resulting in 966 baseline RRSO. Pathology review<br />

demonstrated 4 tubal intraepithelial carcinoma and 20 serous pelvic<br />

cancers, <strong>of</strong> which 12 were identified only microscopically. Among the 20<br />

serous cancers, the predominant or exclusive site <strong>of</strong> involvement was ovary<br />

in 10, fallopian tube in 5, and peritoneum in 5 cases. In addition, 6<br />

endometrial cancers (among the 515 undergoing concomitant hysterectomy)<br />

and 3 adenocarcinomas suggestive <strong>of</strong> metastasis were identified. The<br />

serous pelvic cancer prevalence was: entire cohort�2.1% (20/966), all<br />

BRCA mutation carriers�3.2 (18/558), BRCA1 mutation carriers�3.7%<br />

(12/325), BRCA2 mutation carriers�2.6% (6/231), and mutationnegative�0.5%<br />

(2/402). Compared to those without cancer, women with<br />

serous pelvic cancer were older at surgery (p� .001), and more <strong>of</strong>ten<br />

menopausal (vs pre-menopausal, p� .002), nulliparous (vs parous, p�.04)<br />

and never users <strong>of</strong> tamoxifen (vs ever users, p� .04). Serous pelvic cancers<br />

were more frequent in BRCA mutation carriers (vs no mutation, p� .004),<br />

and among carriers, more common in those with BRCA1 mutations (vs<br />

BRCA2 mutation, p� .02). Conclusions: The prevalence <strong>of</strong> serous pelvic<br />

cancers in this cohort was 3.2% among carriers vs 0.5% among the<br />

mutation-negative but with a strong family history. Our data will be useful<br />

when counseling women at increased ovarian cancer risk who are contemplating<br />

risk-reducing surgery.<br />

1518 Poster Discussion Session (Board #7), Sun, 8:00 AM-12:00 PM and<br />

11:30 AM-12:30 PM<br />

Risk-reducing salpingo-oophorectomy and prophylactic mastectomy among<br />

BRCA mutation “previvors.” Presenting Author: Laura L. Holman, University<br />

<strong>of</strong> Texas M. D. Anderson Cancer Center, Houston, TX<br />

Background: We prospectively evaluated the timing and uptake <strong>of</strong> riskreducing<br />

surgery in a cohort <strong>of</strong> female BRCA mutation carriers that have no<br />

personal cancer history (“previvors”). Methods: Patients at high risk <strong>of</strong><br />

breast and ovarian cancer were enrolled between 2007 and 2011 and<br />

followed in a high-risk ovarian cancer screening clinic. Women were <strong>of</strong>fered<br />

risk-reducing salpingo-oophorectomy (RRSO) and/or prophylactic mastectomy<br />

(PM) per guidelines. Their clinical data were recorded and analyzed<br />

using descriptive statistics. Results: Of 260 BRCA mutation carriers<br />

enrolled, 73 have no personal history <strong>of</strong> cancer and are “previvors.”<br />

Patients have been followed for a median <strong>of</strong> 26.5 months (1-50 months).<br />

The median age is 38 years, 81.1% are white, 16.2% are Ashkenazi<br />

Jewish, and 79.7% are premenopausal. BRCA1 carriers account for 43.2%<br />

<strong>of</strong> participants and 55.4% have a BRCA2 mutation. The majority <strong>of</strong><br />

patients (77.6%) presented for ovarian cancer screening �1 year after<br />

their BRCA testing. In all, 60.8% <strong>of</strong> women underwent prophylactic<br />

surgery: 28.4% chose RRSO, 18.9% chose PM, and 13.5% chose both<br />

procedures. Postmenopausal women were more likely to choose RRSO,<br />

while uptake for both procedures was common for premenopausal women<br />

(Table, p�0.04). RRSO was also more likely in parous than nulliparous<br />

premenopausal women (35.2% vs 9% p�0.001). PM was not associated<br />

with parity (p�0.79). Of women that had both surgeries, 20% had them<br />

concurrently and 20% had PM first. Of the 60% that underwent RRSO first,<br />

all had their second surgery within 14 months. Conclusions: BRCA mutation<br />

“previvors” have a high overall uptake <strong>of</strong> prophylactic surgery. Premenopausal<br />

women are more likely to choose PM than postmenopausal women;<br />

reasons for this are unclear. “Previvors” that choose RRSO and PM typically<br />

have both surgeries within a fairly short timeframe. With the growing<br />

population <strong>of</strong> “previvors” in the US, further study <strong>of</strong> patient preferences<br />

regarding preventative surgery and long-term consequences is needed.<br />

Surgery choices <strong>of</strong> pre- versus postmenopausal women.<br />

None RRSO PM RRSO�PM<br />

Premenopausal 35.6% 23.7% 22% 16.9%<br />

Postmenopausal 20% 46.7% 0% 6.7%<br />

1520 Poster Discussion Session (Board #9), Sun, 8:00 AM-12:00 PM and<br />

11:30 AM-12:30 PM<br />

A multi-institution study <strong>of</strong> the accuracy <strong>of</strong> BRCAPRO in predicting<br />

BRCA1/BRCA2 mutations in women with ovarian cancer. Presenting<br />

Author: Molly S. Daniels, University <strong>of</strong> Texas M. D. Anderson Cancer<br />

Center, Houston, TX<br />

Background: 10-15% <strong>of</strong> ovarian cancer patients have a germline BRCA1 or<br />

BRCA2 mutation, with significant management implications for both<br />

patients and relatives. Genetic testing decisions are guided in part by the<br />

estimated likelihood <strong>of</strong> identifying a mutation. The BRCAPRO model uses<br />

personal and family history <strong>of</strong> breast and ovarian cancer to calculate the<br />

likelihood <strong>of</strong> a BRCA1/2 mutation. This study’s purpose was to assess the<br />

ability <strong>of</strong> BRCAPRO to accurately determine this likelihood. Methods:<br />

BRCAPRO scores were calculated using CancerGene v5.1 for 589 ovarian<br />

cancer patients referred for genetic counseling at three institutions. The<br />

study population was divided into quintiles by BRCAPRO score, with<br />

cutpoints chosen such that each quintile represented 20% <strong>of</strong> the sample.<br />

Chi-square goodness-<strong>of</strong>-fit test was used to compare observed BRCA1/2<br />

mutations to the number predicted. ANOVA models were used to assess<br />

factors impacting BRCAPRO accuracy. Results: 180/589 (31%) ovarian<br />

cancer patients tested positive for a BRCA1/2 mutation. At BRCAPRO<br />

scores under 40%, more mutations were observed than expected (93<br />

observed vs. 34.1 expected, p�0.001). If patients with BRCAPRO scores<br />

�10% had not been <strong>of</strong>fered genetic testing, almost one-third <strong>of</strong> mutations<br />

(51/180, 28%) would have been missed. Multivariate analysis demonstrated<br />

that BRCAPRO underestimated risk for high grade serous ovarian<br />

cancers but overestimated risk for other histologies (p�0.0001), underestimation<br />

increased as age at diagnosis decreased (p�0.02), and model<br />

performance varied by institution (p�0.02). Conclusions: Ovarian cancer<br />

patients classified as low risk by BRCAPRO are more likely to test positive<br />

than predicted, therefore the BRCAPRO prediction could falsely reassure<br />

patients considering genetic testing. BRCAPRO performance could be<br />

improved by incorporating factors such as ovarian cancer histology.<br />

Alternatively, given the high prevalence <strong>of</strong> BRCA1/2 mutations in high<br />

grade serous ovarian cancer and the apparent limitations <strong>of</strong> using family<br />

history to predict mutation probability, BRCA1/2 genetic testing could be<br />

<strong>of</strong>fered to high grade serous ovarian cancer patients regardless <strong>of</strong> family<br />

history.<br />

Visit abstract.asco.org and search by abstract for the full list <strong>of</strong> abstract authors and their disclosure information.

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