Endocrine therapy for breast cancer may affect cognition. The purpose of this study was to examine whether cognitive function improves after cessation of adjuvant endocrine therapy. Change in cognitive function was assessed in 100 postmenopausal breast cancer patients in the BIG 1-98 trial, who were randomized to receive 5 years of adjuvant tamoxifen or letrozole alone or in sequence. Cognitive function was evaluated by computerized tests during the fifth year of trial treatment (Y5) and 1 year after treatment completion (Y6). Cognitive test scores were standardized according to age-specific norms and the change assessed using the Wilcoxon signed-rank test. There was significant improvement in the composite cognitive function score from Y5 to Y6 (median of change = 0.22, effect size = 0.53, P < 0.0001). This improvement was consistent in women taking either tamoxifen or letrozole at Y5 (P = 0.0006 and P = 0.0002, respectively). For postmenopausal patients who received either adjuvant letrozole or tamoxifen alone or in sequence, cognitive function improved after cessation of treatment.
Cognitive function; Breast cancer; Aromatase inhibitor; Tamoxifen; Letrozole; Quality of life
Cognitive function in postmenopausal women receiving letrozole or tamoxifen as adjuvant endocrine treatment was compared during the fifth year of treatment in a substudy of the BIG 1-98 trial. In BIG 1-98 patients were randomized to receive adjuvant A) 5-years tamoxifen, B) 5-years letrozole, C) 2-years tamoxifen followed by 3-years letrozole, or D) 2-years letrozole followed by 3-years tamoxifen. The primary comparison was the difference in composite score for patients taking letrozole (B+C; N=65) versus tamoxifen (A+D; N=55). The patients taking letrozole had better overall cognitive function than those taking tamoxifen (difference in mean composite z-scores =0.28, p=0.04, 95% CI:0.02, 0.54, Cohen's D = 0.40 indicating small to moderate effect). In this substudy, breast cancer patients taking adjuvant letrozole during the fifth year of treatment had better cognitive function than those taking tamoxifen, suggesting aromatase inhibitors do not adversely impact cognition compared with tamoxifen.
Cognitive function; breast cancer; aromatase inhibitor; tamoxifen; letrozole; quality of life
Familial aggregation of testicular germ cell tumor (TGCT) has been reported, but it is unclear if familial TGCT represents a unique entity with distinct clinicopathologic characteristics. Here we describe a collection of familial TGCT cases from an international consortium, in an effort to elucidate any clinical characteristics that are specific to this population.
Materials and Methods
Families with ≥2 cases of TGCT enrolled at 18 of the sites participating in the International Testicular Cancer Linkage Consortium were included. We analyzed clinicopathologic characteristics of 985 cases from 461 families.
A majority (88.5%) of families had only 2 cases of TGCT. Men with seminoma (50% of cases) had an older mean age at diagnosis than nonseminoma cases (P=0.001). Among individuals with a history of cryptorchidism, TGCT was more likely to occur in the ipsilateral testis (kappa=0.65). Cousin pairs appeared to represent a unique group, with younger age at diagnosis and a higher prevalence of cryptorchidism than other families.
Clinicopathologic characteristics in these familial TGCT cases were similar to those generally described for non-familial cases. However, we observed a unique presentation of familial TGCT among cousin pairs. Additional studies are needed to further explore this observation.
Testicular neoplasms; familial; epidemiology; clinicopathologic characteristics
Few studies have considered the joint association of body mass index (BMI) and physical activity, two modifiable factors, with all-cause mortality after breast cancer diagnosis. Women diagnosed with invasive breast cancer (n=4,153) between 1991 and 2000 were enrolled in the Breast Cancer Family Registry through population-based sampling in Northern California, USA; Ontario, Canada; and Melbourne and Sydney, Australia. During a median follow-up of 7.8 years, 725 deaths occurred. Baseline questionnaires assessed moderate and vigorous recreational physical activity and BMI prior to diagnosis. Associations with all-cause mortality were assessed using Cox proportional hazards regression, adjusting for established prognostic factors. Compared with no physical activity, any recreational activity during the three years prior to diagnosis was associated with a 34% lower risk of death (hazard ratio (HR) = 0.66, 95% confidence interval (CI): 0.51-0.85) for women with estrogen receptor (ER)-positive tumors, but not those with ER-negative tumors; this association did not appear to differ by race/ethnicity or BMI. Lifetime physical activity was not associated with all-cause mortality. BMI was positively associated with all-cause mortality for women diagnosed at age ≥50 years with ER-positive tumors (compared with normal-weight women, HR for overweight = 1.39, 95% CI: 0.90-2.15; HR for obese = 1.77, 95% CI: 1.11-2.82). BMI associations did not appear to differ by race/ethnicity. Our findings suggest that physical activity and BMI exert independent effects on overall mortality after breast cancer.
breast cancer; physical activity; body mass index; obesity; mortality
Aromatase inhibitors are an important component of treatment for most postmenopausal women with hormone receptor-positive, early-stage breast cancer. Women taking aromatase inhibitors experience very low levels of circulating estrogen. This might be expected to result in cognitive dysfunction given the important relationship between estrogen and cognition in the basic science literature. Several studies have examined the cognitive effects of aromatase inhibitors, including two within large randomized trials which were adequately powered to detect moderate (but not small) effects. With this caveat, the available data do not support the hypothesis that aromatase inhibitors adversely affect cognitive function or that aromatase inhibitors might have a more adverse effect on cognitive function in comparison with tamoxifen. Further research is needed for confirmation.
A base substitution in the mouse Dnd1 gene resulting in a truncated Dnd protein has been shown to be responsible for germ cell loss and the development of testicular germ cell tumors (TGCT) in the 129 strain of mice. We investigated the human orthologue of this gene in 263 patients (165 with a family history of TGCT and 98 without) and found a rare heterozygous variant, p. Glu86Ala, in a single case. This variant was not present in control chromosomes (0/4,132). Analysis of the variant in an additional 842 index TGCT cases (269 with a family history of TGCT and 573 without) did not reveal any additional instances. The variant, p. Glu86Ala, is within a known functional domain of DND1 and is highly conserved through evolution. Although the variant may be a rare polymorphism, a change at such a highly conserved residue is characteristic of a disease-causing variant. Whether it is disease-causing or not, mutations in DND1 make, at most, a very small contribution to TGCT susceptibility in adults and adolescents.
Women with BRCA1 and BRCA2 mutations have an elevated risk of breast cancer and ovarian cancer, but also of developing second primary breast cancer. BRCA1/2 mutation carriers with breast cancer must choose between breast conservation (BCT) and mastectomy (M) yet data on outcomes are limited. The purpose of this study is to compare BCT to M in BRCA1/2 carriers.
655 women with BRCA1/2 mutations diagnosed with breast cancer and treated with BCT (n=302) or M (n=353) were identified and underwent follow up to assess local, regional and systemic recurrence.
Local failure as first failure was significantly more likely in those treated with BCT compared to M, with a cumulative estimated risk of 23.5% vs. 5.5%, respectively, at 15 years (p<0.0001); 15-year estimates in carriers treated with BCT and chemotherapy was 11.9% (p=0.08 when compared to M). Most events appeared to be second primary cancers rather than failure to control the primary tumor. The risk of contralateral breast cancer was high in all groups, exceeding 40%, but was not statistically significantly different by use of adjuvant radiotherapy (RT) or not, suggesting no added risk from scatter RT at 10 and 15 years. There were no differences seen in regional or systemic recurrences between the BCT and M groups, and no difference in overall survival.
BRCA1/2 mutation carriers with breast cancer have similar survivals whether treated with M or BCT. However, women undergoing BCT have an elevated risk of a second in-breast event that is significantly reduced in the presence of chemotherapy. Contralateral breast cancer events are very common.
hereditary breast cancer; BRCA1/2; breast conservation; mastectomy; radiotherapy
Although having a family history of breast cancer is a well established breast cancer risk factor, it is not known whether it influences mortality after breast cancer diagnosis.
Subjects were 4,153 women with first primary incident invasive breast cancer diagnosed between 1991 and 2000, and enrolled in the Breast Cancer Family Registry through population-based sampling in Northern California, USA; Ontario, Canada; and Melbourne and Sydney, Australia. Cases were oversampled for younger age at diagnosis and/or family history of breast cancer. Carriers of germline mutations in BRCA1 or BRCA2 were excluded. Cases and their relatives completed structured questionnaires assessing breast cancer risk factors and family history of cancer. Cases were followed for a median of 6.5 years, during which 725 deaths occurred. Cox proportional hazards regression was used to evaluate associations between family history of breast cancer at the time of diagnosis and risk of all-cause mortality after breast cancer diagnosis, adjusting for established prognostic factors.
The hazard ratios for all-cause mortality were 0.98 (95% confidence interval [CI]=0.84-1.15) for having at least one first- or second-degree relative with breast cancer, and 0.85 (95% CI=0.70-1.02) for having at least one first-degree relative with breast cancer, compared with having no such family history. Estimates did not vary appreciably when stratified by case or tumor characteristics.
Family history of breast cancer is not associated with all-cause mortality after breast cancer diagnosis for women without a known germline mutation in BRCA1 or BRCA2. Therefore, clinical management should not depend on family history of breast cancer.
breast cancer; survival; mortality; family history
One of the clinical hallmarks of hereditary cancer susceptibility disorders is a younger-than-usual age at diagnosis. Familial aggregation of testicular germ cell tumor (TGCT) has been reported, but data on whether familial TGCT cases are diagnosed at an earlier age are inconclusive. Here we compared the age at diagnosis of familial TGCT cases with that of population cases in several countries. Familial TGCT is defined as affected individuals from families with ≥2 cases of TGCT. Age at diagnosis of familial cases from the United States, Canada, United Kingdom, Australia and New Zealand, Norway, and Hungary was compared to cases identified in population-based cancer registries from the respective country, using the Generalized Estimation Equation (GEE) method. Age at diagnosis was statistically significantly younger for familial TGCT cases from North America (p=0.024), the United Kingdom (p<0.0001), and Australia and New Zealand (p=0.0033) compared with population cases. When stratified by histology, the difference in age at diagnosis distribution between familial and population cases was observed for seminoma cases from North America (p=0.002) and the United Kingdom (p<0.0001) and nonseminoma cases from the United Kingdom (p=0.029) and Australia and New Zealand (p=0.0023). In summary, we found that the age at diagnosis for familial TGCT cases is, on the average, 2–3 years younger than that for the population cases in North America, United Kingdom, and Australia and New Zealand. The younger age at diagnosis might be suggestive of a genetic basis for familial TGCT.
age at diagnosis; familial; non-seminoma; population-based testicular cancer; seminoma; testicular germ cell tumor
Studies have examined the prognostic relevance of reproductive factors prior to breast cancer (BC) diagnosis, but most have been small and overall their findings inconclusive. Associations between reproductive risk factors and all-cause mortality after BC diagnosis were assessed using a population-based cohort of 3,107 women of white European ancestry with invasive BC (1,130 from Melbourne and Sydney, Australia; 1,441 from Ontario, Canada; and 536 from Northern California, USA). During follow-up with a median of 8.5 years, 567 deaths occurred. At recruitment, questionnaire data were collected on oral contraceptive use, number of full-term pregnancies, age at first full-term pregnancy, time from last full-term pregnancy to BC diagnosis, breastfeeding, age at menarche and menopause and menopausal status at BC diagnosis. Hazard ratios (HR) for all-cause mortality were estimated using Cox proportional hazards models with and without adjustment for age at diagnosis, study center, education and body mass index. Compared with nulliparous women, those who had a child up to 2 years, or between 2 to 5 years, prior to their BC diagnosis were more likely to die. The unadjusted HR estimates were 2.75 (95%CI=1.98–3.83, p<0.001) and 2.20 (95%CI=1.65–2.94, p<0.001), respectively, and the adjusted estimates were 2.25 (95%CI=1.59–3.18, p<0.001) and 1.82 (95%CI=1.35–2.46, p<0.001), respectively). When evaluating the prognosis of women recently diagnosed with BC, the time since last full-term pregnancy should be routinely considered along with other established host and tumor prognostic factors, but consideration of other reproductive factors may not be warranted.
Breast cancer; survival; reproductive; outcome; pregnancy
Most women with early-stage breast cancer believe that psychosocial factors are an important influence over whether their cancer will recur. Studies of the issue have produced conflicting results.
Patients and Methods
A population-based sample of 708 Australian women diagnosed before age 60 years with nonmetastatic breast cancer was observed for a median of 8.2 years. Depression and anxiety, coping style, and social support were assessed at a median of 11 months after diagnosis. Hazard ratios for distant disease-free survival (DDFS) and overall survival (OS) associated with psychosocial factors were estimated separately using Cox proportional hazards survival models, with and without adjustment for known prognostic factors.
Distant recurrence occurred in 209 (33%) of 638 assessable patients, and 170 (24%) of 708 patients died during the follow-up period. There were no statistically significant associations between any of the measured psychosocial factors and DDFS or OS from the adjusted analyses. From unadjusted analyses, associations between greater anxious preoccupation and poorer DDFS and OS were observed (P = .02). These associations were no longer evident after adjustment for established prognostic factors; greater anxious preoccupation was associated with younger age at diagnosis (P = .03), higher tumor grade (P = .02), and greater number of involved axillary nodes (P = .008).
The findings do not support the measured psychosocial factors being an important influence on breast cancer outcomes. Interventions for adverse psychosocial factors are warranted to improve quality of life but should not be expected to improve survival.
Effective chemoprevention strategies exist for women at high risk for breast cancer, yet uptake is low. Physician recommendation is an important determinant of uptake, but little is known about clinicians' attitudes to chemoprevention.
Focus groups were conducted with clinicians at five Family Cancer Centers in three Australian states. Discussions were recorded, transcribed and analyzed thematically.
Twenty three clinicians, including genetic counselors, clinical geneticists, medical oncologists, breast surgeons and gynaecologic oncologists, participated in six focus groups in 2007. The identified barriers to the discussion of the use of tamoxifen and raloxifene for chemoprevention pertained to issues of evidence (evidence for efficacy not strong enough, side-effects outweigh benefits, oophorectomy superior for mutation carriers), practice (drugs not approved for chemoprevention by regulatory authorities and not government subsidized, chemoprevention not endorsed in national guidelines and not many women ask about it), and perception (clinicians not knowledgeable about chemoprevention and women thought to be opposed to hormonal treatments).
The study demonstrated limited enthusiasm for discussing breast cancer chemoprevention as a management option for women at high familial risk. Several options for increasing the likelihood of clinicians discussing chemoprevention were identified; maintaining up to date national guidelines on management of these women and education of clinicians about the drugs themselves, the legality of "off-label" prescribing, and the actual costs of chemopreventive medications.
Men who carry mutations in BRCA1 or BRCA2 are at increased risk for prostate cancer. However the efficacy of prostate screening in this setting is uncertain and limited data exists on the uptake of prostate screening by mutation carriers. This study prospectively evaluated uptake of prostate cancer screening in a multi-institutional cohort of mutation carriers. Subjects were unaffected male BRCA1 and BRCA2 mutation carriers, aged 40–69 years, enrolled in the Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab) and who had completed a mailed, self-report follow-up questionnaire 3 yearly after study entry. Of the 75 male carriers in this study, only 26 (35%) had elected to receive their mutation result. Overall, 51 (68%) did not recall having received a recommendation to have prostate screening because of their family history, but 41 (55%) had undergone a prostate specific antigen (PSA) test and 32 (43%) a digital rectal examination (DRE) in the previous 3 years. Those who were aware of their mutation result were more likely to have received a recommendation for prostate screening (43 vs. 6%, p = 0.0001), and to have had a PSA test (77 vs. 43%, p = 0.005) and a DRE (69 vs. 29%, p = 0.001) in the previous 3 years. The majority of unaffected males enrolled in kConFab with a BRCA1/2 mutation have not sought out their mutation result. However, of those aware of their positive mutation status, most have undergone at least one round of prostate screening in the previous 3 years.
BRCA1; BRCA2; prostate; screening
To estimate the association between measures of socio-economic status (SES) and breast cancer (BC) survival for young, urban Australian women.
We used a population-based sample of 1,029 women followed prospectively for a median of 7.9 years. SES was defined by education and area of residence. Hazard ratios (HRs) associated with SES measures were estimated for (i) distant recurrence (DR) and (ii) all-cause mortality as end-points.
HRs for area of residence were not significantly different from unity, with or without adjustment for age at diagnosis and education level. The univariable HR estimate of DR for women with university education compared with women with incomplete high school education was 1.51 (95% CI = 1.08 – 2.13, p = 0.02), which reduced to 1.20 (95% CI = 0.85 – 1.72, p = 0.3) after adjusting for age at diagnosis and area of residence. Adjusting for prognostic factors differentially distributed across SES groups did not substantially alter the association between survival and SES.
Among young, urban Australian women there is no association between SES and BC survival.
This lack of estimates of association may be partly attributed to universal access to adequate breast cancer care in urban areas.
Breast cancer; socioeconomic status; Australia; survival
The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) is a multidisciplinary, collaborative framework for the investigation of familial breast cancer. Based in Australia, the primary aim of kConFab is to facilitate high-quality research by amassing a large and comprehensive resource of epidemiological and clinical data with biospecimens from individuals at high risk of breast and/or ovarian cancer, and from their close relatives.
Epidemiological, family history and lifestyle data, as well as biospecimens, are collected from multiple-case breast cancer families ascertained through family cancer clinics in Australia and New Zealand. We used the Tyrer-Cuzick algorithms to assess the prospective risk of breast cancer in women in the kConFab cohort who were unaffected with breast cancer at the time of enrolment in the study.
Of kConFab's first 822 families, 518 families had multiple cases of female breast cancer alone, 239 had cases of female breast and ovarian cancer, 37 had cases of female and male breast cancer, and 14 had both ovarian cancer as well as male and female breast cancer. Data are currently held for 11,422 people and germline DNAs for 7,389. Among the 812 families with at least one germline sample collected, the mean number of germline DNA samples collected per family is nine. Of the 747 families that have undergone some form of mutation screening, 229 (31%) carry a pathogenic or splice-site mutation in BRCA1 or BRCA2. Germline DNAs and data are stored from 773 proven carriers of BRCA1 or BRCA1 mutations. kConFab's fresh tissue bank includes 253 specimens of breast or ovarian tissue – both normal and malignant – including 126 from carriers of BRCA1 or BRCA2 mutations.
These kConFab resources are available to researchers anywhere in the world, who may apply to kConFab for biospecimens and data for use in ethically approved, peer-reviewed projects. A high calculated risk from the Tyrer-Cuzick algorithms correlated closely with the subsequent occurrence of breast cancer in BRCA1 and BRCA2 mutation positive families, but this was less evident in families in which no pathogenic BRCA1 or BRCA2 mutation has been detected.
The aim of this study was to collect serial samples of nipple aspirate (NA) and ductal lavage (DL) fluid from women with germline BRCA1/2 mutations in order to create a biorepository for use in identifying biomarkers of breast cancer risk.
Between March 2003 and February 2005, 52 women with germline BRCA1 or BRCA2 mutations (median age 43 years, range 27 to 65 years) were scheduled for six-monthly NA, DL and venesection. DL was attempted for all NA fluid-yielding (FY) and any non-FY ducts that could be located at each visit.
Twenty-seven (52%) women were postmenopausal, predominantly (19/27) from risk reducing bilateral salpingo-oophorectomy (BSO). FY ducts were identified in 60% of all women, 76% of premenopausal women versus 44% of postmenopausal (P = 0.026). Eighty-five percent of women had successful DL. Success was most likely in women with FY ducts (FY 94% versus non-FY 71% (P = 0.049). DL samples were more likely to be cellular if collected from FY ducts (FY 68% versus non-FY 43%; P = 0.037). Total cell counts were associated with FY status (FY median cell count 30,996, range 0 to >1,000,000 versus non-FY median cell count 0, range 0 to 173,577; P = 0.002). Four women (8%) had ducts with severe atypia with or without additional ducts with mild epithelial atypia; seven others had ducts with mild atypia alone (11/52 (21%) in total). Median total cell count was greater from ducts with atypia (105,870, range 1920 to >1,000,000) than those with no atypia (174, 0 to >1,000,000; P ≤ 0.001).
It is feasible to collect serial NA and DL samples from women at high genetic risk of breast cancer, and we are creating a unique, prospective collection of ductal samples that have the potential to be used for discovery of biomarkers of breast cancer risk and evaluate the ongoing effects of risk reducing BSO. DL cellular atypia was not predictive of a current breast cancer and longer follow up is needed to determine whether atypia is an additional marker of future breast cancer risk in this population already at high genetic risk of breast cancer.