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

90s Cancer Prevention/Epidemiology
1516 Poster Discussion Session (Board #5), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
PTEN germline mutations in patients first tested for other hereditary cancer
syndromes: Would use of risk assessment tools have reduced health care
costs? Presenting Author: Jessica Mester, Genomic Medicine Institute,
Cleveland Clinic, Cleveland, OH
Background: PTEN Hamartoma Tumor Syndrome (PHTS) includes patients
with Cowden (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) with
germline PTEN mutation. Breast, colon, endometrial cancer and GI
polyposis are associated, creating overlap with Hereditary Breast and
Ovarian Cancer (HBOC), Lynch (LS) and adenomatous polyposis syndromes
(APS). We reviewed our PHTS patient series to find how often testing
criteria for these syndromes were met or testing was pursued before PTEN.
Methods: Patients were prospectively recruited by relaxed International
Cowden Consortium criteria or presence of known germline PTEN mutation;
mutations were identified by mutation scanning or MLPA analysis and
confirmed by sequencing or quantitative PCR, respectively. Families were
excluded if diagnosed with CS or BRRS before 1998, family history was
unavailable, or proband was �18 yrs. Pedigree, genetic testing reports, and
medical records were reviewed to determine if patients met HBOC testing
criteria, Amsterdam II or Bethesda 2004 criteria, or had adenomatous
polyps. Risk assessment was conducted for BRCA1/2 via the BRCAPRO,
Myriad II, and Penn II models; for MLH1/MSH2/MSH6 via the PREMM1,2,6
and MMRPro models; and for PTEN via the Cleveland Clinic (CC) PTEN
Risk Calculator. Results: 115 PTEN mutation-positive adult probands were
identified among 3,405 patients. 53 (46.1%) met testing criteria for HBOC
or LS and 34 (29.6%) underwent previous testing for HBOC, LS or APS.
Average risk for BRCA1/2 and MLH1/MSH2/MSH6 mutations in tested
patients were 7.5-16.9% and 33.1-41.4%, respectively; whereas PTEN
mutation risks were 35.9% and 79.7%. No patient tested for APS (average
PTEN mutation risk 73%) had �5 adenomas. An estimated $89,700 was
spent on negative analyses for HBOC, LS and APS among patients
ultimately found to have germline PTEN mutations. Conclusions: PHTS
should be part of the differential diagnosis for patients referred for question
of HBOC, LS or APS. Pathology review is key for patients with polyposis.
Using the CC PTEN risk calculator enables clinicians to understand when
PTEN mutation risk is high, allowing testing to proceed in a step-wise and
cost-saving manner.
1519 Poster Discussion Session (Board #8), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Pathologic findings at risk-reducing salpingo-oophorectomy among women
at increased ovarian cancer risk: Results from GOG-199. Presenting
Author: Phuong L. Mai, National Cancer Institute, Rockville, MD
Background: Although risk-reducing salpingo-oophorectomy (RRSO) is a
standard management option for women with BRCA1/2 mutations, the lack
of large, prospective cohort studies makes estimating the prevalence of
cancer at RRSO problematic. Methods: GOG-199 is a large, nonrandomized
multi-center trial which enrolled women at high-risk (due to
BRCA mutations or strong family history) of ovarian cancer, comparing
surgery at enrollment with serial transvaginal ultrasound and CA-125
screening. RRSO specimens were processed according to a standardized
tissue processing protocol including 2-3mm sectioning of both ovaries and
tubes. Results: 2,605 participants were accrued to GOG-199. Of the 1 030
enrolled in the baseline RRSO cohort, 28 were ineligible and 36 declined
surgery after enrollment, resulting in 966 baseline RRSO. Pathology review
demonstrated 4 tubal intraepithelial carcinoma and 20 serous pelvic
cancers, of which 12 were identified only microscopically. Among the 20
serous cancers, the predominant or exclusive site of involvement was ovary
in 10, fallopian tube in 5, and peritoneum in 5 cases. In addition, 6
endometrial cancers (among the 515 undergoing concomitant hysterectomy)
and 3 adenocarcinomas suggestive of metastasis were identified. The
serous pelvic cancer prevalence was: entire cohort�2.1% (20/966), all
BRCA mutation carriers�3.2 (18/558), BRCA1 mutation carriers�3.7%
(12/325), BRCA2 mutation carriers�2.6% (6/231), and mutationnegative�0.5%
(2/402). Compared to those without cancer, women with
serous pelvic cancer were older at surgery (p� .001), and more often
menopausal (vs pre-menopausal, p� .002), nulliparous (vs parous, p�.04)
and never users of tamoxifen (vs ever users, p� .04). Serous pelvic cancers
were more frequent in BRCA mutation carriers (vs no mutation, p� .004),
and among carriers, more common in those with BRCA1 mutations (vs
BRCA2 mutation, p� .02). Conclusions: The prevalence of serous pelvic
cancers in this cohort was 3.2% among carriers vs 0.5% among the
mutation-negative but with a strong family history. Our data will be useful
when counseling women at increased ovarian cancer risk who are contemplating
risk-reducing surgery.
1518 Poster Discussion Session (Board #7), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Risk-reducing salpingo-oophorectomy and prophylactic mastectomy among
BRCA mutation “previvors.” Presenting Author: Laura L. Holman, University
of Texas M. D. Anderson Cancer Center, Houston, TX
Background: We prospectively evaluated the timing and uptake of riskreducing
surgery in a cohort of female BRCA mutation carriers that have no
personal cancer history (“previvors”). Methods: Patients at high risk of
breast and ovarian cancer were enrolled between 2007 and 2011 and
followed in a high-risk ovarian cancer screening clinic. Women were offered
risk-reducing salpingo-oophorectomy (RRSO) and/or prophylactic mastectomy
(PM) per guidelines. Their clinical data were recorded and analyzed
using descriptive statistics. Results: Of 260 BRCA mutation carriers
enrolled, 73 have no personal history of cancer and are “previvors.”
Patients have been followed for a median of 26.5 months (1-50 months).
The median age is 38 years, 81.1% are white, 16.2% are Ashkenazi
Jewish, and 79.7% are premenopausal. BRCA1 carriers account for 43.2%
of participants and 55.4% have a BRCA2 mutation. The majority of
patients (77.6%) presented for ovarian cancer screening �1 year after
their BRCA testing. In all, 60.8% of women underwent prophylactic
surgery: 28.4% chose RRSO, 18.9% chose PM, and 13.5% chose both
procedures. Postmenopausal women were more likely to choose RRSO,
while uptake for both procedures was common for premenopausal women
(Table, p�0.04). RRSO was also more likely in parous than nulliparous
premenopausal women (35.2% vs 9% p�0.001). PM was not associated
with parity (p�0.79). Of women that had both surgeries, 20% had them
concurrently and 20% had PM first. Of the 60% that underwent RRSO first,
all had their second surgery within 14 months. Conclusions: BRCA mutation
“previvors” have a high overall uptake of prophylactic surgery. Premenopausal
women are more likely to choose PM than postmenopausal women;
reasons for this are unclear. “Previvors” that choose RRSO and PM typically
have both surgeries within a fairly short timeframe. With the growing
population of “previvors” in the US, further study of patient preferences
regarding preventative surgery and long-term consequences is needed.
Surgery choices of pre- versus postmenopausal women.
None RRSO PM RRSO�PM
Premenopausal 35.6% 23.7% 22% 16.9%
Postmenopausal 20% 46.7% 0% 6.7%
1520 Poster Discussion Session (Board #9), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
A multi-institution study of the accuracy of BRCAPRO in predicting
BRCA1/BRCA2 mutations in women with ovarian cancer. Presenting
Author: Molly S. Daniels, University of Texas M. D. Anderson Cancer
Center, Houston, TX
Background: 10-15% of ovarian cancer patients have a germline BRCA1 or
BRCA2 mutation, with significant management implications for both
patients and relatives. Genetic testing decisions are guided in part by the
estimated likelihood of identifying a mutation. The BRCAPRO model uses
personal and family history of breast and ovarian cancer to calculate the
likelihood of a BRCA1/2 mutation. This study’s purpose was to assess the
ability of BRCAPRO to accurately determine this likelihood. Methods:
BRCAPRO scores were calculated using CancerGene v5.1 for 589 ovarian
cancer patients referred for genetic counseling at three institutions. The
study population was divided into quintiles by BRCAPRO score, with
cutpoints chosen such that each quintile represented 20% of the sample.
Chi-square goodness-of-fit test was used to compare observed BRCA1/2
mutations to the number predicted. ANOVA models were used to assess
factors impacting BRCAPRO accuracy. Results: 180/589 (31%) ovarian
cancer patients tested positive for a BRCA1/2 mutation. At BRCAPRO
scores under 40%, more mutations were observed than expected (93
observed vs. 34.1 expected, p�0.001). If patients with BRCAPRO scores
�10% had not been offered genetic testing, almost one-third of mutations
(51/180, 28%) would have been missed. Multivariate analysis demonstrated
that BRCAPRO underestimated risk for high grade serous ovarian
cancers but overestimated risk for other histologies (p�0.0001), underestimation
increased as age at diagnosis decreased (p�0.02), and model
performance varied by institution (p�0.02). Conclusions: Ovarian cancer
patients classified as low risk by BRCAPRO are more likely to test positive
than predicted, therefore the BRCAPRO prediction could falsely reassure
patients considering genetic testing. BRCAPRO performance could be
improved by incorporating factors such as ovarian cancer histology.
Alternatively, given the high prevalence of BRCA1/2 mutations in high
grade serous ovarian cancer and the apparent limitations of using family
history to predict mutation probability, BRCA1/2 genetic testing could be
offered to high grade serous ovarian cancer patients regardless of family
history.
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