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Beth Karlan

Publications and source records attributed to Beth Karlan.

11 recordsLinked to original sources
PubMed2007

Reproductive risk factors for ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study.

BACKGROUND: Several of the known risk factors for ovarian cancer are thought to act through their effects on ovulation and the menstrual cycle, such as parity, breastfeeding, and use of oral contraceptives. We aimed to assess the effect of these three risk factors, and of tubal ligation, on the risk of ovarian cancer in women who carry a mutation in the BRCA1 or BRCA2 genes. METHODS: We did a matched case-control study in women who were found to carry a pathogenetic mutation in BRCA1 or BRCA2. Participants were derived from a population-based study of ovarian cancer in Ontario, Canada, and from an international registry of mutation carriers based in Toronto, ON, Canada. All participants completed a written questionnaire that detailed their reproductive history. Women with invasive ovarian cancer and controls were matched on year of birth, country of residence, mutation (BRCA1 or BRCA2), and history of breast cancer. The odds ratios and 95% CI for ovarian cancer were estimated with respect to use of oral contraceptives, parity, breastfeeding, and tubal ligation. FINDINGS: Questionnaires were completed by 799 women with a history of invasive ovarian cancer (670 with BRCA1 mutations, 128 with BRCA2 mutations, and one with a mutation in both genes), and controls were 2424 women without ovarian cancer (2043 with BRCA1 mutations, 380 with BRCA2 mutations, and one with a mutation in both genes). Use of oral contraceptives reduced the risk of ovarian cancer in carriers of BRCA1 mutations (odds ratio 0.56 [95% CI 0.45-0.71]; p<0.0001) and carriers of BRCA2 mutations (0.39 [0.23-0.66]; p=0.0004). Parity was associated with a reduced risk for carriers of BRCA1 mutations (0.67 [0.46-0.96]; p=0.03), but with an increased risk for those with BRCA2 mutations (2.74 [1.18-6.41]; p=0.02). Breastfeeding was associated with a reduced risk for carriers of BRCA1 mutations (0.74 [0.56-0.97]; p=0.03). An effect of similar magnitude was seen for carriers of BRCA2 mutations (0.72 [0.41-1.29]; p=0.27), but this was not statistically significant. The association with tubal ligation was not significant for carriers of BRCA1 mutations (0.80 [0.59-1.08]; p=0.15), or for carriers of BRCA2 mutations (0.63 [0.34-1.15]; p=0.13). INTERPRETATION: Oral contraceptives could be used as a means to prevent ovarian cancer in carriers of BRCA1 and BRCA2 mutations. The possible adverse effect of parity on ovarian-cancer risk in women with a BRCA2 mutation needs further study.

Adult↗
PubMed2006

Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 Mutation.

CONTEXT: Women with BRCA1 or BRCA2 mutation are often advised to undergo preventive oophorectomy. The effectiveness of this intervention has not been prospectively evaluated in a large cohort. OBJECTIVES: To estimate the incidence of ovarian, fallopian tube, and primary peritoneal cancer in women who carry a deleterious mutation in BRCA1 or BRCA2. To estimate the reduction in risk of these cancers associated with a bilateral prophylactic salpingo-oophorectomy. DESIGN, SETTING, AND PARTICIPANTS: Women known to carry a BRCA1 or BRCA2 mutation were identified from an international registry between 1992 and 2003. A total of 1828 carriers at 1 of 32 centers in Canada, the United States, Europe, and Israel completed questionnaires at baseline and follow-up. Participants were observed from the date of study entry until: diagnosis of ovarian, fallopian tube, or peritoneal cancer; death; or the date of the most recent follow-up. INTERVENTION: Participants were divided into women who had undergone bilateral prophylactic oophorectomy and those who had not. MAIN OUTCOME MEASURE: The incidence of ovarian, peritoneal, and fallopian tube cancer was determined by survival analysis. The risk reduction associated with prophylactic salpingo-oophorectomy was evaluated by a time-dependent survival analysis, adjusting for covariates. RESULTS: After a mean follow-up of 3.5 years, 50 incident ovarian, fallopian tube, and peritoneal cancer cases were reported in the cohort. Of the 1828 women, 555 (30%) underwent a bilateral prophylactic salpingo-oophorectomy prior to study entry, 490 (27%) underwent the procedure after entering the study, and 783 (43%) did not undergo the procedure. There were 32 incident cancers diagnosed in women with intact ovaries (1015/100,000 per year). Eleven cancer cases were identified at the time of prophylactic oophorectomy and 7 were diagnosed following prophylactic oophorectomy (217/100,000 per year). The estimated cumulative incidence of peritoneal cancer is 4.3% at 20 years after oophorectomy. The overall (adjusted) reduction in cancer risk associated with bilateral oophorectomy is 80% (multivariate hazard ratio = 0.20; 95% confidence interval, 0.07-0.58; P = .003). CONCLUSION: Oophorectomy is associated with reduced risk of ovarian and fallopian tube cancer in high-risk women, although there is a substantial residual risk for peritoneal cancer in BRCA1 and BRCA2 mutation carriers following prophylactic salpingo-oophorectomy.

Adult↗
PubMed2006

Spontaneous and therapeutic abortions and the risk of breast cancer among BRCA mutation carriers.

INTRODUCTION: BRCA1 and BRCA2 mutation carriers are at increased risk for developing both breast and ovarian cancer. It has been suggested that carriers of BRCA1/2 mutations may also be at increased risk of having recurrent (three or more) miscarriages. Several reproductive factors have been shown to influence the risk of breast cancer in mutation carriers, but the effects of spontaneous and therapeutic abortions on the risk of hereditary breast cancer risk have not been well studied to date. METHODS: In a matched case-control study, the frequencies of spontaneous abortions were compared among 1,878 BRCA1 mutation carriers, 950 BRCA2 mutation carriers and 657 related non-carrier controls. The rates of spontaneous and therapeutic abortions were compared for carriers with and without breast cancer. RESULTS: There was no difference in the rate of spontaneous abortions between carriers of BRCA1 or BRCA2 mutations and non-carriers. The number of spontaneous abortions was not associated with breast cancer risk among BRCA1 or BRCA2 mutation carriers. However, BRCA2 carriers who had two or more therapeutic abortions faced a 64% decrease in the risk of breast cancer (odds ratio = 0.36; 95% confidence interval 0.16-0.83; p = 0.02). CONCLUSION: Carrying a BRCA1 or BRCA2 mutation is not a risk factor for spontaneous abortions and spontaneous abortions do not appear to influence the risk of breast cancer in carriers of BRCA1 or BRCA2 mutations. However, having two or more therapeutic abortions may be associated with a lowered risk of breast cancer among BRCA2 carriers.

Abortion, Spontaneous↗
PubMed2005

Hormone replacement therapy and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers.

OBJECTIVE: Hormone replacement therapy (HRT) is commonly prescribed to alleviate the climacteric symptoms of menopause. Recent findings from the Women's Health Initiative has raised questions about the routine use of HRT due to the increased observed incidence of cardiovascular disease and of breast and ovarian cancers in the treatment arm of the trial. In the general population, the association between HRT use and risk of ovarian cancer has not yet been resolved. This association has not been evaluated in BRCA1 or BRCA2 mutation carriers who face very high lifetime risks of both breast and ovarian cancers. METHODS: We conducted a matched case-control study on 162 matched sets of women who carry a deleterious mutation in either the BRCA1 or BRCA2 gene. Women who had been diagnosed with ovarian cancer were matched to control subjects by mutation, year of birth, and age at menopause. Information on HRT use was derived from a questionnaire routinely administered to women who were found to be carriers of a mutation in either gene. Conditional logistic regression was used to estimate the association between HRT use and the risk of ovarian cancer, stratified by mutation status and type of HRT. RESULTS: Compared with those who had never used HRT, the odds ratio associated with ever use of HRT was 0.93 (95% CI = 0.56-1.56). There was no significant relationship with increasing duration of HRT use. There was a suggestion that progestin-based HRT regimens might protect against ovarian cancer (odds ratio = 0.57) but this association was not statistically significant (P = 0.20). CONCLUSION: HRT use does not appear to adversely influence the risk of ovarian cancer in BRCA mutation carriers.

Aged↗
PubMed2005

Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer.

PURPOSE: Pertuzumab, a recombinant humanized monoclonal antibody (2C4), binds to extracellular domain II of the HER-2 receptor and blocks its ability to dimerize with other HER receptors. Pertuzumab represents a new class of targeted therapeutics known as HER dimerization inhibitors. A clinical study was conducted to investigate safety and pharmacokinetics of pertuzumab and to perform a preliminary assessment of HER dimerization inhibition as a treatment strategy. PATIENTS AND METHODS: Patients with incurable, locally advanced, recurrent or metastatic solid tumors that had progressed during or after standard therapy were recruited to a dose-escalation study of pertuzumab (0.5 to 15 mg/kg) given intravenously every 3 weeks. RESULTS: Twenty-one patients received pertuzumab and 19 completed at least two cycles. Pertuzumab was well tolerated. Overall, 365 adverse events were reported and 122 considered to be possibly drug related. Of these, 116 were of grade 1 to 2 intensity. The pharmacokinetics of pertuzumab were similar to other humanized immunoglobulin G antibodies, supporting a 3-week dosing regimen. Trough plasma concentrations were in excess of target concentrations at doses greater than 5 mg/kg. Two patients, one with ovarian cancer (5.0 mg/kg) and one with pancreatic islet cell carcinoma (15.0 mg/kg), achieved a partial response. Responses were documented by Response Evaluation Criteria in Solid Tumors after 1.5 and 6 months of pertuzumab therapy, and lasted for 11 and 10 months, respectively. Stable disease lasting for more than 2.5 months (range, 2.6 to 5.5 months) was observed in six patients. CONCLUSION: These results demonstrate that pertuzumab is well tolerated, has a pharmacokinetic profile which supports 3-week dosing, and is clinically active, suggesting that inhibition of dimerization may be an effective anticancer strategy.

Adult↗
PubMed2005

Age at menarche and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers.

Age at menarche is a strong and consistent predictor of breast cancer risk in the general population, but has not been well studied in women with a family history of breast cancer. We conducted this study to examine whether the presence of a deleterious BRCA1 or BRCA2 mutation influences age at menarche and to investigate whether or not there is an association between age at menarche and the risk of breast cancer in BRCA1 or BRCA2 mutation carriers. The presence of a deleterious BRCA1 or BRCA2 mutation did not appear to influence a woman's age at menarche. A matched case-control study was conducted on 1311 pairs of women who have been identified to be carriers of a deleterious mutation in either the BRCA1 (n = 945 pairs) or the BRCA2 gene (n = 366 pairs). Information about age at menarche was derived from a questionnaire routinely administered to carriers of a mutation in either gene. Among women who carried a deleterious BRCA1 mutation, age at menarche was inversely associated with the risk of breast cancer (p trend = 0.0002). This association was not observed among BRCA2 mutation carriers (p trend = 0.49). Compared with BRCA1 carriers whose age at menarche was < or =11 years, women with a menarcheal age between 14 and 15 years old had a 54% reduction in risk (OR = 0.46; 95% CI 0.30-0.69). This study implicates early age at menarche as a determinant of breast cancer among women with a BRCA1 mutation.

Adolescent↗
PubMed2005

Coexisting ovarian malignancy in young women with endometrial cancer.

OBJECTIVE: In premenopausal women with endometrial cancer, ovarian preservation may be a consideration. Our objective was to examine the occurrence of coexisting ovarian malignancy and to identify predictors of adnexal involvement. METHODS: With institutional review board approval, a retrospective chart review was conducted of young women with endometrial cancer identified at 4 affiliated institutions from 1996 to 2004. RESULTS: Among 102 young women (aged 24-45 years) who underwent hysterectomy for endometrial cancer, 26 (25%) were found to have coexisting epithelial ovarian tumors: 23 were classified as synchronous primaries, and 3 as metastases. Ovarian cancer histology was endometrioid in 92% of cases. Among the 26 cases of coexisting ovarian involvement, 12 (46%) had grade 1 endometrial cancer on preoperative biopsy, 4 (15%) had normal preoperative imaging of the adnexa, and 4 (15%) had benign-appearing ovaries at the time of intraoperative assessment. On final pathology, 18 of 26 cases (69%) occurred in patients with grade 1 endometrial cancers, and 15 (58%) occurred with inner myometrial invasion. Our study further highlights the risk of conservative management with 1 case of ovarian cancer diagnosed 9 months after hysterectomy with ovarian conservation for a stage IA, grade 1 endometrial cancer and a case of advanced endometrial cancer metastatic to the ovaries developing 3 years after successful resolution of a grade 1 endometrial cancer treated with megestrol acetate (Megace). CONCLUSION: Careful preoperative and intraoperative assessment of the adnexa is mandatory in young women with endometrial cancer. Those who desire ovarian preservation should be counseled regarding the high rate of coexisting ovarian malignancy.

Adult↗
PubMed2003

Reproductive factors and ovarian cancer risk in Jewish BRCA1 and BRCA2 mutation carriers (United States).

OBJECTIVE: To determine whether oral contraceptive (OC) use, childbearing, breastfeeding and tubal ligation differ between ovarian cancer cases with and without a BRCA1/2 mutation. METHODS: A case-only study of 242 Jewish women with invasive epithelial ovarian cancer. Women were genotyped for three Ashkenazi founder mutations (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2). We obtained data on OC use, childbearing, breastfeeding, gynecologic surgeries and other reproductive factors from each woman. We compared the frequencies of these risk factors in carriers and non-carriers using unconditional logistic-regression, controlling for other covariates. RESULTS: Among the 242 cases, 64 (26.4%) carried one of the BRCA1 founder mutations, and 31 (12.8%) carried the BRCA2 mutation. Although there were no differences in the percent of nulliparous women between carriers and non-carriers, parous BRCA1 carriers reported fewer live births than non-carriers (average of 2.1 versus 2.5 live births, OR = 0.61, 95% CI = 0.39-0.95, adjusted for age at diagnosis, tubal ligation and duration of OC use). Carriers and non-carriers did not differ in their history of breastfeeding, or in their lifetime use of OCs. BRCA1 carriers were more likely than non-carriers to have had a tubal ligation (25.0 versus 10.2%, OR = 3.67, 95% CI = 1.55-8.70, adjusted for age at diagnosis, number of live births and OC duration). CONCLUSIONS: In general, OC use, childbearing and breastfeeding do not differ between BRCA1/2 carriers and non-carriers with ovarian cancer. However, the effects of tubal ligation may differ between BRCA1 carriers and non-carriers.

Adult↗
PubMed2002

Long term follow-up of patients with recurrent ovarian cancer after Ad p53 gene replacement with SCH 58500.

OBJECTIVE: We have previously reported the safety, efficient gene transfer, and favorable CA125 responses of individuals with recurrent ovarian cancer treated by p53 gene replacement with the adenoviral vector SCH 58500. The purpose of the present investigation was to evaluate the long-term follow-up of these heavily pretreated patients subsequent to SCH 58500 dosing. METHODS: Patients (n=36) were treated with either single-dose SCH 58500 in the phase I study or with multiple doses (MD) of SCH 58500 over multiple cycles in combination of platinum-based chemotherapy in the phase I/II portion of the study. Five patients were initially treated in the single-dose group and re-enrolled in the MD group. The MD group was evaluated both without the re-enrolled patients as MD1 (n=19), and as MD2 (n=24), which included them. Patients who were only treated on the single-dose arm were designated as SD (n=12). Most patients received additional chemotherapy at the discretion of their physicians on completion of the trial. The current analysis is a retrospective sequential cohort survival analysis. RESULTS: The first patient was treated in March 1997 and the last patient completed SCH 58500 in September 1998. There was no difference in age at diagnosis, Karnofsky performance status, interval between diagnosis to SCH 58500, prior cycles or regimen of chemotherapy, platinum-free interval, percent platinum refractory patients, pretreatment CA125, or largest tumor volume between groups. Both MD groups had a slightly longer chemotherapy-free interval before SCH 58500 than the SD group. Median survival of individuals who received MD SCH 58500 with chemotherapy was 12-13.0 months, compared to only 5 months for those treated with SD SCH 58500. There are 10 long-term survivors more than 20 months after MD treatment for recurrent disease compared to only 2 long-term survivors after SD SCH 58500. CONCLUSION: The 12- to 13.0-month median survival in a heavily pretreated population with recurrent ovarian cancer compares favorably to the 16-month median survival for individuals treated with paclitaxel at the time of initial recurrence of this disease and is more than double the 5-month survival seen with palliative radiotherapy or paclitaxel failure. These data suggest that further study of SCH58500 is clearly indicated.

Adenoviridae↗
PubMed2002

Generating longitudinal screening algorithms using novel biomarkers for disease.

Recent advances in molecular technology are leading to the discovery of new tumor biomarkers that may be useful for cancer screening and early diagnosis. Translating a potential screening biomarker from the laboratory to its use in patient care may require an algorithm or screening rule for its application. An algorithm that can detect the smallest deviation from a defined norm is likely to achieve the highest sensitivity, but any practical screening algorithm must do so with strict controls on test specificity to avoid false-positive results, and unnecessary patient alarm and risk. Longitudinal algorithms that make use of previous tumor marker values and trends are likely to obtain improvements over single threshold rules. Thus far, a few longitudinal screening algorithms have been proposed (e.g., using serial prostate-specific antigen values for the detection of prostate cancer and serial CA125 values for the detection of ovarian cancer), but these algorithms are not appropriate for novel tumor marker discoveries, because they rely on unverifiable assumptions that may not translate to the behavior of the new marker. The algorithm presented here is motivated by: (a) the need to develop an algorithm for early detection using novel markers; (b) the practical demands on data and specimen availability; and (c) the need to be robust enough to accommodate a wide range of tumor growth behavior. We use Parametric Empirical Bayes statistical theory to model the trajectory of markers over time in a cohort of asymptomatic healthy subjects, and use the estimated trajectory to produce person-specific thresholds that depend on the screening history of each person. The thresholds are chosen to give the person (or population) a specified false-positive rate. The resulting algorithm is simple and can be represented in a simple graph or a chart. The statistical analysis needed to generate the algorithm can be found in nearly every basic statistical package. The algorithm is highly robust and can detect a wide range of tumor behaviors. The Parametric Empirical Bayes screening algorithm should take a central role when evaluating marker discoveries for use in screening. The algorithm is particularly useful when screening with a new marker of which the behavior in the preclinical period is not well known.

Algorithms↗