Milestones of Lynch syndrome: 1895-2015 Lynch, Henry T; Snyder, Carrie L; Shaw, Trudy G ...
Nature reviews. Cancer,
03/2015, Letnik:
15, Številka:
3
Journal Article
Recenzirano
Lynch syndrome, which is now recognized as the most common hereditary colorectal cancer condition, is characterized by the predisposition to a spectrum of cancers, primarily colorectal cancer and ...endometrial cancer. We chronicle over a century of discoveries that revolutionized the diagnosis and clinical management of Lynch syndrome, beginning in 1895 with Warthin's observations of familial cancer clusters, through the clinical era led by Lynch and the genetic era heralded by the discovery of causative mutations in mismatch repair (MMR) genes, to ongoing challenges.
Purpose
Unaffected women who carry
BRCA1
or
BRCA2
mutations face difficult choices about reducing their breast cancer risk. Understanding their treatment preferences could help us improve patient ...counseling and inform drug trials. The objective was to explore preferences for various risk-reducing options among women with germline
BRCA1/2
mutations using a discrete-choice experiment survey and to compare expressed preferences with actual behaviors.
Methods
A discrete-choice experiment survey was designed wherein women choose between hypothetical treatments to reduce breast cancer risk. The hypothetical treatments were characterized by the extent of breast cancer risk reduction, treatment duration, impact on fertility, hormone levels, risk of uterine cancer, and ease and mode of administration. Data were analyzed using a random-parameters logit model. Women were also asked to express their preference between surgical and chemoprevention options and to report on their actual risk-reduction actions. Women aged 25–55 years with germline
BRCA1/2
mutations who were unaffected with breast or ovarian cancer were recruited through research registries at five clinics and a patient advocacy group.
Results
Between January 2015 and March 2016, 622 women completed the survey. Breast cancer risk reduction was the most important consideration expressed, followed by maintaining fertility. Among the subset of women who wished to have children in future, the ability to maintain fertility was the most important factor, followed by the extent of risk reduction. Many more women said they would take a chemoprevention drug than had actually taken chemoprevention.
Conclusions
Women with
BRCA1/2
mutations indicated strong preferences for breast cancer risk reduction and maintaining fertility. The expressed desire to have a safe chemoprevention drug available to them was not met by current chemoprevention options.
This study analyzes the occurrence of colorectal cancer (CRC) in Lynch syndrome (LS) mutation carriers, interval until diagnosis of metachronous CRC, and survival after proximal colectomy (PC) ...compared with total (TC) and subtotal colectomy (STC) for right-sided first CRC in LS mutation carriers.
Sixty-four LS mutation carriers with right-sided first CRC treated with PC or TC + STC were confirmed by clinical records. Bivariate analyses were examined for significance and life tables were generated for risk of metachronous CRC and survival estimates following surgery.
One of 16 (6.3%) mutation carriers treated with TC + STC developed subsequent CRC compared with 13/48 (27%) treated by PC. There was no significant difference in survival estimates between PC compared with TC + STC through 25 years after surgery.
Risk of subsequent CRC and survival estimates following PC and TC + STC should be considered in surgical management of right-sided first CRC in LS mutation carriers.
•Lynch syndrome (LS) mutation carriers at high risk for proximal first colorectal cancer (CRC).•Metachronous CRC diagnosed in 27% LS patients after proximal colectomy (PC) for proximal first CRC.•Compared with metachronous CRC diagnosed in 6% LS patients after total & subtotal colectomy (TC + STC).•No significant difference in estimated survival after PC compared with TC + STC through 25 years.•Extra-colonic abdominal-pelvic cancers diagnosed in 30% of LS patients after proximal first CRC.
Hereditary ovarian cancer accounts for at least 5% of the estimated 22,000 new cases of this disease during 2009. During this same time, over 15,000 will die from malignancy ascribed to ovarian ...origin. The bulk of these hereditary cases fits the hereditary breast–ovarian cancer syndrome, while virtually all of the remainder will be consonant with the Lynch syndrome, disorders which are autosomal dominantly inherited. Advances in molecular genetics have led to the identification of
BRCA1 and
BRCA2 gene mutations which predispose to the hereditary breast–ovarian cancer syndrome, and mutations in mismatch repair genes, the most common of which are
MSH2 and
MLH1, which predispose to Lynch syndrome. These discoveries enable relatively certain diagnosis, limited only by their variable penetrance, so that identification of mutation carriers through a comprehensive cancer family history might be possible. This paper reviews the subject of hereditary ovarian cancer, with particular attention to its molecular genetic basis, its pathology, and its phenotypic/genotypic heterogeneity.
The aim of this study was to categorize and report endometrial cancers in mutation carriers from hereditary breast ovarian cancer families.
Our Hereditary Cancer Registry was searched for gynecologic ...and peritoneal cancers linked to mutations in BRCA1 or BRCA2. Invasive cancers were registered in 101 mutation carriers with complete pathology reports. Efforts were made to secure diagnostic surgical pathology tissues for review. All records and available diagnostic slides were meticulously studied, and primary cancers were classified.
Eight malignancies were classified as primary endometrial cancers. Five of these were low- or intermediate-grade endometrioid carcinomas, and 3 were pure serous carcinomas or contained serous carcinoma elements mixed with high-grade endometrioid carcinoma. Breast cancers were diagnosed in 5 patients before and in 1 patient after endometrial carcinoma. Three endometrioid carcinomas were preceded by estrogen treatment, 2 for many years and the other for only 2 months, and 2 of the patients with serous carcinoma had been treated with tamoxifen.
The finding that 8 of gynecologic and peritoneal cancers in 101 mutation carriers were endometrial cancers with a smaller proportion of endometrioid carcinomas than reported in general populations is added to the current controversial literature on endometrial cancer, particularly regarding serous carcinomas, in hereditary breast ovarian cancer syndrome. Well-designed prospective programs for standardized surgical and pathologic handling, processing, and reporting are essential for working out the pathogenesis, true risks, and best management of this disease in carriers of deleterious BRCA1 and BRCA2 germline mutations.
Women with a
or
mutation have high lifetime risks of developing breast and ovarian cancer. The decision to embark on risk reduction strategies is a difficult and personal one. We surveyed an ...international group of women with
mutations and measured choices and sequence of breast cancer risk reduction strategies.
Women with a
mutation and no previous cancer diagnosis were recruited from the US, Canada, the UK, Australia, and from a national advocacy group. Using an online survey, we asked about cancer-risk reduction preferences including for one of two hypothetical medicines, randomly assigned, and women's recommendations for a hypothetical woman (Susan, either a 25- or 36-year-old). Sunburst diagrams were generated to illustrate hierarchy of choices.
Among 598 respondents, mean age was 40.9 years (range 25-55 years). Timing of the survey was 4.8 years (mean) after learning their positive test result and 33% had risk-reducing bilateral salpingo-oophorectomy (RRBSO) and bilateral mastectomy (RRBM), while 19% had RRBSO only and 16% had RRBM only. Although 30% said they would take a hypothetical medicine, 6% reported taking a medicine resembling tamoxifen. Respondents were 1.5 times more likely to select a hypothetical medicine for risk reduction when Susan was 25 than when Susan was 36. Women assigned to 36-year-old Susan were more likely to choose a medicine if they had a family member diagnosed with breast cancer and personal experience taking tamoxifen.
Women revealed a willingness to undergo surgeries to achieve largest reduction in breast cancer risk, although this would not be recommended for a younger woman in her 20s. The goal of achieving the highest degree of cancer risk reduction is the primary driver for women with
or
mutations in selecting an intervention and a sequence of interventions, regardless of whether it is non-surgical or surgical.
Mutations in BRCA1/2 dramatically increase the risk of both breast and ovarian cancers. Three mutations in these genes (185delAG, 5382insC, and 6174delT) occur at high frequency in Ashkenazi Jews. We ...evaluated how these common Jewish mutations (CJMs) affect cancer risks and risk reduction.
Our cohort comprised 4,649 women with disease-associated BRCA1/2 mutations from 22 centers in the Prevention and Observation of Surgical End Points Consortium. Of these women, 969 were self-identified Jewish women. Cox proportional hazards models were used to estimate breast and ovarian cancer risks, as well as risk reduction from risk-reducing salpingo-oophorectomy (RRSO), by CJM and self-identified Jewish status.
Ninety-one percent of Jewish BRCA1/2-positive women carried a CJM. Jewish women were significantly more likely to undergo RRSO than non-Jewish women (54% v 41%, respectively; odds ratio, 1.87; 95% CI, 1.44 to 2.42). Relative risks of cancer varied by CJM, with the relative risk of breast cancer being significantly lower in 6174delT mutation carriers than in non-CJM BRCA2 carriers (hazard ratio, 0.35; 95% CI, 0.18 to 0.69). No significant difference was seen in cancer risk reduction after RRSO among subgroups.
Consistent with previous results, risks for breast and ovarian cancer varied by CJM in BRCA1/2 carriers. In particular, 6174delT carriers had a lower risk of breast cancer. This finding requires additional confirmation in larger prospective and population-based cohort studies before being integrated into clinical care.
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