Dana Zakalik

Study of Sexual Functioning Determinants in Breast Cancer Survivors

Abstract:u2003 Our goal was to identify the treatment, personal, interpersonal, and hormonal (testosterone) factors in breast cancer survivors (BCSs) that determine sexual dysfunction. The treatment variables studied were type of surgery, chemotherapy, radiation, and tamoxifen. The personal, interpersonal, and physiologic factors were depression, body image, age, relationship distress, and testosterone levels. A sample of 55 female breast cancer survivors seen for routine follow‐up appointments from July 2002 to September 2002 were recruited to complete the Female Sexual Functioning Index (FSFI), Hamilton Depression Inventory (HDI), Body Image Survey (BIS), Marital Satisfaction Inventory‐Revised (MSI‐R), a demographic questionnaire, and have a serum testosterone level drawn. The average time since diagnosis was 4.4 years (SD 3.4 years). No associations were found between the type of cancer treatment, hormonal levels, and sexual functioning. BCS sexual functioning was significantly poorer than published normal controls in all areas but desire. The BCSs’ level of relationship distress was the most significant variable affecting arousal, orgasm, lubrication, satisfaction, and sexual pain. Depression and having traditional role preferences were the most important determinants of lower sexual desire. BCSs on antidepressants had higher levels of arousal and orgasm dysfunction. Women who were older had significantly more concerns about vaginal lubrication and pain. Relationship concerns, depression, and age are important influences in the development of BCS sexual dysfunction. The relationship of testosterone and sexual dysfunction needs further study with larger samples and more accurate assay techniques.

Timing of oral contraceptive use and the risk of breast cancer in BRCA1 mutation carriers.

It is not clear if early oral contraceptive use increases the risk of breast cancer among young women with a breast cancer susceptibility gene 1 (BRCA1) mutation. Given the benefit of oral contraceptives for the prevention of ovarian cancer, estimating age-specific risk ratios for oral contraceptive use and breast cancer is important. We conducted a case–control study of 2,492 matched pairs of women with a deleterious BRCA1 mutation. Breast cancer cases and unaffected controls were matched on year of birth and country of residence. Detailed information about oral contraceptive use was collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate the odds ratios (OR) and 95xa0% confidence intervals (CI) for the association between oral contraceptive and breast cancer, by age at first use and by age at diagnosis. Among BRCA1 mutation carriers, oral contraceptive use was significantly associated with an increased risk of breast cancer for women who started the pill prior to age 20 (OR 1.45; 95xa0% CI 1.20–1.75; Pxa0=xa00.0001) and possibly between ages 20 and 25 as well (OR 1.19; 95xa0% CI 0.99–1.42; Pxa0=xa00.06). The effect was limited to breast cancers diagnosed before age 40 (OR 1.40; 95xa0% CI 1.14–1.70; Pxa0=xa00.001); the risk of early-onset breast cancer increased by 11xa0% with each additional year of pill use when initiated prior to age 20 (OR 1.11; 95xa0% CI 1.03–1.20; Pxa0=xa00.008). There was no observed increase for women diagnosed at or after the age of 40 (OR 0.97; 95xa0% CI 0.79–1.20; Pxa0=xa00.81). Oral contraceptive use before age 25 increases the risk of early-onset breast cancer among women with a BRCA1 mutation and the risk increases with duration of use. Caution should be taken when advising women with a BRCA1 mutation to take an oral contraceptive prior to age 25.

Oophorectomy after Menopause and the Risk of Breast Cancer in BRCA1 and BRCA2 Mutation Carriers

Background: To evaluate the effect of the cumulative number of ovulatory cycles and its contributing components on the risk of breast cancer among BRCA mutation carriers. Methods: We conducted a matched case–control study on 2,854 pairs of women with a BRCA1 or BRCA2 mutation. Conditional logistic regression was used to estimate the association between the number of ovulatory cycles and various exposures and the risk of breast cancer. Information from a subset of these women enrolled in a prospective cohort study was used to calculate age-specific breast cancer rates. Results: The annual risk of breast cancer decreased with the number of ovulatory cycles experienced (ρ = −0.69; P = 0.03). Age at menarche and duration of breastfeeding were inversely related with risk of breast cancer among BRCA1 (Ptrend < 0.0001) but not among BRCA2 (Ptrend ≥ 0.28) mutation carriers. The reduction in breast cancer risk associated with surgical menopause [OR, 0.52; 95% confidence interval (CI), 0.40–0.66; Ptrend < 0.0001] was greater than that associated with natural menopause (OR, 0.81; 95% CI, 0.62–1.07; Ptrend = 0.14). There was a highly significant reduction in breast cancer risk among women who had an oophorectomy after natural menopause (OR, 0.13; 95% CI, 0.02–0.54; P = 0.006). Conclusions: These data challenge the hypothesis that breast cancer risk can be predicted by the lifetime number of ovulatory cycles in women with a BRCA mutation. Both pre- and postmenopausal oophorectomy protect against breast cancer. Impact: Understanding the basis for the protective effect of oophorectomy has important implications for chemoprevention. Cancer Epidemiol Biomarkers Prev; 21(7); 1089–96. ©2012 AACR.

The impact of pregnancy on breast cancer survival in women who carry a BRCA1 or BRCA2 mutation

Physicians are often approached by young women with a BRCA mutation and a recent history of breast cancer who wish to have a baby. They wish to know if pregnancy impacts upon their future risks of cancer recurrence and survival. To date, there is little information on the survival experience of women who carry a mutation in one of the BRCA genes and who become pregnant. From an international multi-center cohort study of 12,084 women with a BRCA1 or BRCA2 mutation, we identified 128 case subjects who were diagnosed with breast cancer while pregnant or who became pregnant after a diagnosis of breast cancer. These women were age-matched to 269 mutation carriers with breast cancer who did not become pregnant (controls). Subjects were followed from the date of breast cancer diagnosis until the date of last follow-up or death from breast cancer. The Kaplan–Meier method was used to estimate 15-year survival rates. The hazard ratio for survival associated with pregnancy was calculated using a left-truncated Cox proportional hazard model, adjusting for other prognostic factors. Among women who were diagnosed with breast cancer when pregnant or who became pregnant thereafter, the 15-year survival rate was 91.5xa0%, compared to a survival of 88.6xa0% for women who did not become pregnant (adjusted hazard ratioxa0=xa00.76; 95xa0% CI 0.31–1.91; pxa0=xa00.56). Pregnancy concurrent with or after a diagnosis of breast cancer does not appear to adversely affect survival among BRCA1/2 mutation carriers.

Venous limb gangrene and fatal hemorrhage: Adverse consequences of hit “overdiagnosis” in a patient with antiphospholipid syndrome

This unfortunate patient case highlights the problems with overdiagnosis of HIT. Despite positive tests for HIT antibodies, the low pretest probability for HIT and the known propensity of patients with APS to yield false-positive HIT antibody results suggests that the patient did not have a true diagnosis of HIT. Moreover, the early administration of warfarin and the choice of argatroban for parenteral anticoagulation when monitoring was hindered by a prolonged baseline aPTT likely play a key factor in the progression of UE DVT to VLG. Ironically, the problems of anticoagulant monitoring posed by the prolonged baseline aPTT likely contributed to the subsequent overanticoagulation and fatal pulmonary hemorrhage. With benefit of hindsight, avoiding the temptation to test for HIT in a low pretest probability situation, and treatment with either heparin using anti-factor Xa monitoring or with non-aPTT-monitored therapy such as LMWH or fondaparinux would likely have resulted in a more favorable clinical course.

Duration of tamoxifen use and the risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers.

Women with a mutation in BRCA1 or BRCA2 face a lifetime risk of breast cancer of approximately 80xa0%. Tamoxifen treatment of the first cancer has been associated with a reduction in the risk of a subsequent contralateral cancer. We studied 1,504 women with a known BRCA1 or BRCA2 mutation, 411 women with bilateral breast cancer (cases) and 1,093 women with unilateral breast cancer (controls) in a matched case–control study. Control women were of similar age and had a similar age of diagnosis of first breast cancer as the cases. For each woman who used tamoxifen, the starting and stopping dates were abstracted and the duration of tamoxifen use was calculated. Three hundred and thirty-one women had used tamoxifen (22xa0%); of these 84 (25xa0%) had completed four or more years of tamoxifen, the remainder stopped prematurely or were current users. For women with up to 1xa0year of tamoxifen use, the odds ratio for contralateral breast cancer was 0.37 (95xa0% CI 0.20–0.69; pxa0=xa00.001) compared to women with no tamoxifen use. Among women with 1–4xa0years of tamoxifen use the odds ratio was 0.53 (95xa0% CI 0.32–0.87; pxa0=xa00.01). Among women with four or more years of tamoxifen use the odds ratio was 0.83 (95xa0% CI 0.44–1.55; pxa0=xa00.55). Short-term use of tamoxifen for chemoprevention in BRCA1 and BRCA2 mutation carriers may be as effective as a conventional 5-year course of treatment.

Investigating the Existence of Quantum Metabolic Values in Non-Hodgkin’s Lymphoma by 2-Deoxy-2-[F-18]fluoro- d -glucose Positron Emission Tomography

ObjectivesTo investigate the existence of quantum metabolic values in various subtypes of non-Hodgkin’s lymphoma (NHL).MethodsFifty-eight patients with newly diagnosed NHL and positron emission tomography (PET) performed within three months of biopsy were included. The standardized uptake value (SUV) from PET over the area of biopsy and serum glucose [Glc] were recorded. The group glucose sensitivity(G) for indolent and aggressive NHL was obtained by linear regression with ln(SUV)u2009=u2009G·ln[Glc]u2009+u2009C, where C is a constant for the group. Finally, the individual’s glucose sensitivity (g) was obtained by gu2009=u2009{ln(SUV)-C}/ln[Glc], along with their means in various subtypes of NHL. To further investigate the influence of extreme [Glc] conditions, the SUVs corrected by the individually calculated g at various glucose levels, [Glc′] using SUV′u2009=SUV·{[Glc′]/[Glc]}g, were compared to the original SUVs for both indolent and aggressive NHL.ResultsThe averaged g (=G) for aggressive was significant different from that for indolent NHL (−0.94u2009±u20090.51 vs. +0.13u2009±u20090.10, respectively, pu2009<u20090.00005). There were significant differences in SUV for [Glc]u2009<u200980 or >110xa0mg/dl for both types of NHL. Unlike overlap among SUVs between NHL subtypes, the g value clearly categorized them into two distinct groups with positive (near-zero) and negative g values (around −1) for the indolent and aggressive NHLs, respectively.ConclusionsDistinct quantum metabolic values of −1 and 0 were noted in NHL. Aggressive NHL has a more negative value (or higher glucose sensitivity) than that of indolent and, thus, is more susceptible to extreme glucose variation.

Myelodysplastic syndrome at a large tertiary care community hospital: analysis according to the international prognostic scoring system ☆

The outcome of patients diagnosed myelodysplastic syndromes (MDS) between 1990 and 1997 from William Beaumont Hospital (WBH) was analyzed according to the International Prognostic Scoring System (IPSS) risk categorization. A retrospective study of 195 MDS patients wa s performed. Seventy-nine patients with MDS, in whom a karyotype was obtained and with an adequate follow-up were included in the final analysis. Cases of proliferative CMML (WBC > 12x10(9)/l) were excluded from the study. The overall median survival was 3.1 years, and median survival stratified by IPSS was 3.4, 4.1 and 0.5 years for the INT-1, INT-2 and high risk group and not yet reached for the low risk group. The overall survival by IPSS subcategorization were 6.88, 5.29, 5.30 and 2.12 years for the low, INT-1, INT-2, and high risk groups respectively. Cytogenetics were significant in predicting the overall survival. The IPSS score stratified patients into risk categories for development of AML. The risk of development into AML was 8, 8, 33 and 54% for the low, INT-1, INT-2 and high risk groups, respectively. We conclude that IPSS score can be useful in predicting survival and AML evolution in some MDS patients.

Treatment of infertility does not increase the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation

OBJECTIVEnTo evaluate the relationship between use of fertility medication (i.e., selective estrogen receptor [ER] modulator, gonadotropin, or other) or infertility treatment (i.e., IVF or IUI) and the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation.nnnDESIGNnA matched case-control study of 941 pairs of BRCA1 or BRCA2 mutation carriers with and without a diagnosis of ovarian cancer.nnnSETTINGnGenetic clinics.nnnPATIENT(S)nDetailed information regarding treatment of infertility was collected from a routinely administered questionnaire.nnnINTERVENTION(S)nNone.nnnMAIN OUTCOME MEASURE(S)nConditional logistic regression was used to estimate odds ratios and 95% confidence intervals associated with fertility treatment.nnnRESULT(S)nThere was no significant relationship between the use of any fertility medication or IVF treatment (odds ratio, 0.66; 95% confidence interval 0.18-2.33) and the subsequent risk of ovarian cancer.nnnCONCLUSION(S)nOur findings suggest that treatment for infertility does not significantly increase the risk of ovarian cancer among women with a BRCA mutation.

Outcomes of retesting BRCA-negative patients using multigene panels.

23 Background: New technologies for identifying hereditary predisposition to breast cancer have led to the discovery of novel genes associated with cancer risk. This has prompted re-evaluation of patients who previously tested negative for BRCA1/2 gene mutations, with a possibility of discovering new genes which may impact management. This study reports on the results of retesting patients who previously were negative for BRCA1/2.nnnMETHODSnPatients who tested negative for BRCA1/2 mutations who had significant personal and family history were referred back to the Cancer Genetics Center between February 1, 2012 and May 30, 2105 for discussion of additional testing. A detailed personal and family history was reviewed, and patients were counseled about the genetics and clinical implications of panel testing for multiple breast cancer genes. Panel testing using next generation sequencing technologies was ordered. Patients were seen in follow up for discussion of results and management.nnnRESULTSnA total of 12 pathogenic mutations were identified during the study period. The genes and frequencies of these mutations were: CHEK2(3), PALB2(3), ATM(2), APC(1), BARD(1), CDH(1), MUTYH(1). There were 33 variants of undetermined significance(VUS) in 27 patients. 5 of these were seen in patients with a known pathogenic mutation; 3 others were later classified as benign. The frequencies of these VUSs were: ATM (9), PALB2(3), BARD1 (3), PTEN(3), PMS2(3), MSH6(2), CHEK2 (1), MYH(1), RAD51(1), BRIP1(2), NF1(1), BMPR1A(1). Of the 46 patients who had their initial BRCA testing and repeat panel testing between February 1, 2012 and May 30, 2015, 6 (13%) tested positive for a pathogenic mutation.nnnCONCLUSIONSnThis study demonstrates the feasibility and potential clinical benefit of retesting individuals who previously tested negative for BRCA1/2 mutation. This approach had a significant management impact on patients and their families, with a 13% detection rate of pathogenic mutations. The success of retesting is predicated upon an infrastructure of provider and patient education, pre and post genetic counseling and serves as a model for other centers.