CYP2D6 genotype predicts tamoxifen discontinuation and drug response: a secondary analysis of the KARISMA trial.

BACKGROUND: Guidelines regarding whether tamoxifen should be prescribed based on women's cytochrome P450 2D6 (CYP2D6) genotypes are conflicting and have caused confusion. This study aims to investigate if CYP2D6 metabolizer status is associated with tamoxifen-related endocrine symptoms, tamoxifen discontinuation, and mammographic density change. PATIENTS AND METHODS: We used data from 1440 healthy women who participated the KARISMA dose determination trial. Endocrine symptoms were measured using a modified Functional Assessment of Cancer Therapy - Endocrine Symptoms (FACT-ES) questionnaire. Change in mammographic density was measured and used as a proxy for tamoxifen response. Participants were genotyped and categorized as poor, intermediate, normal, or ultrarapid CYP2D6 metabolizers. RESULTS: The median endoxifen level per mg oral tamoxifen among poor, intermediate, normal and ultrarapid CYP2D6 metabolizers were 0.18 ng/ml, 0.38 ng/ml, 0.56 ng/ml and 0.67 ng/ml, respectively. Ultrarapid CYP2D6 metabolizers were more likely than other groups to report a clinically relevant change in cold sweats, hot flash, mood swings, being irritable, as well as the overall modified FACT-ES score, after taking tamoxifen. The 6-month tamoxifen discontinuation rates among poor, intermediate, normal, and ultrarapid CYP2D6 metabolizers were 25.7%, 23.6%, 28.6%, and 44.4%, respectively. Among those who continued and finished the 6-month tamoxifen intervention, the mean change in dense area among poor, intermediate, normal, and ultrarapid CYP2D6 metabolizers were -0.8 cm2, -4.5 cm2, -4.1 cm2, and -8.0 cm2 respectively. CONCLUSIONS: Poor CYP2D6 metabolizers are likely to experience an impaired response to tamoxifen, measured through mammographic density reduction. In contrast, ultrarapid CYP2D6 metabolizers are at risk for exaggerated response with pronounced adverse effects that may lead to treatment discontinuation.

Statins: a role in breast cancer therapy?

Statin drugs have been used for more than two decades to treat hypercholesterolemia and as cardio-preventive drugs, resulting in a marked decrease in cardiovascular morbidity and mortality worldwide. Statins halt hepatic cholesterol biosynthesis by inhibiting the rate-limiting enzyme in the mevalonate pathway, hydroxymethylglutaryl-coenzyme A reductase (HMGCR). The mevalonate pathway regulates a host of biochemical processes in addition to cholesterol production. Attenuation of these pathways is likely responsible for the myriad benefits of statin therapy beyond cholesterol reduction - the so-called pleiotropic effects of statins. Chief amongst these purported effects is anti-cancer activity. A considerable body of preclinical, epidemiologic and clinical evidence shows that statins impair proliferation of breast cancer cells and reduce the risk of breast cancer recurrence. Potential mechanisms for this effect have been explored in laboratory models, but remain poorly understood and require further investigation. The number of clinical trials assessing the putative clinical benefit of statins in breast cancer is increasing. Currently, a total of 30 breast cancer/statin trials are listed at the global trial identifier website clinicaltrials.gov. Given the compelling evidence from performed trials in a variety of clinical settings, there have been calls for a clinical trial of statins in the adjuvant breast cancer setting. It would be imperative for such a trial to incorporate tumour biomarkers predictive of statin response in its design and analysis plan. Ongoing translational clinical trials aimed at biomarker discovery will help identify, which breast cancer patients are most likely to benefit from adjuvant statin therapy, and will add valuable clinical knowledge to the field.

Thyroid function and survival following breast cancer.

BACKGROUND: Thyroid function has been associated with breast cancer risk, and breast cancer cell growth and proliferation. It is not clear whether thyroid function affects prognosis following breast cancer but, if so, this could have an important clinical impact. The present study analysed prospectively collected measurements of free tri-iodothyronine (T3), free thyroxine (T4), thyroid-stimulating hormone (TSH) and thyroid peroxidase antibodies (TPO-Ab) in relation to breast cancer survival. METHODS: The Malmö Diet and Cancer Study is a prospective cohort study of 17 035 women in Sweden. Study enrolment was conducted between 1991 and 1996. Patients with incident breast cancer were identified through record linkage with cancer registries until 31 December 2006. Information on vital status was collected from the Swedish Cause of Death Registry, with the endpoint breast cancer mortality (31 December 2013). Hazard ratios (HRs) with 95 per cent confidence intervals (c.i.) were obtained by Cox proportional hazards analysis. RESULTS: Some 766 patients with incident breast cancer were identified, of whom 551 were eligible for analysis. Compared with patients in the first free T4 tertile, breast cancer mortality was lower among those in the second tertile (HR 0·49, 95 per cent c.i. 0·28 to 0·84). There was an indication, although non-significant, of lower breast cancer mortality among patients in the second TSH tertile (HR 0·63, 0·37 to 1·09) and in those with positive TPO-Ab status (HR 0·61, 0·30 to 1·23). Free T3 showed no clear association with mortality. CONCLUSION: In the present study, there was a positive association between free T4 levels and improved breast cancer survival.

Circulating C-reactive protein levels as a prognostic biomarker in breast cancer across body mass index groups.

Obesity and systemic inflammation are associated with breast cancer (BC) outcomes. Systemic inflammation is increased in obesity. We examined the association between C-reactive protein (CRP) and disease-free survival (DFS) and overall survival (OS) overall, and according to body mass index (BMI). We assembled a cohort of women with BC (stage I-III) seen at Aarhus University Hospital between 2010 and 2020 who donated blood at BC diagnosis (N = 2673). CRP levels were measured and divided into quartiles. We followed patients from surgery to recurrence, contralateral BC, other malignancy, death, emigration, or end-of-follow-up. We used Cox regression to estimate hazard ratios (HRs) with 95% confidence intervals (95% CIs) to compare outcomes across CRP quartiles, overall and stratified by BMI (normal-weight (18.5 ≤ BMI < 25 kg/m2), overweight (25 ≤ BMI < 30 kg/m2), and obesity (BMI ≥ 30 kg/m2)). During follow-up, 368 events (212 recurrences, 38 contralateral BCs, and 118 deaths) occurred (median follow-up 5.55 years). For DFS, high CRP (CRP ≥ 3.19 mg/L) was associated with an increased risk of events (HRadj:1.62 [95% CI = 1.14-2.28]). In BMI-stratified analyses, high CRP was associated with elevated risk of events in normal-weight and overweight (HRadj:1.70 [95% CI = 1.09-2.66]; HRadj:1.75 [95% CI = 1.08-2.86]), but in obesity, the estimate was less precise (HRadj:1.73 [95% CI = 0.78-3.83]). For OS, high CRP was associated with increased risk of death (HRadj:2.47 [95% CI = 1.62-3.76]). The association was strong in normal-weight and overweight (HRadj:3.66 [95% CI = 1.95-6.87]; HRadj:1.92 [95% CI = 1.06-3.46]), but less clear in obesity (HRadj:1.40 [95% CI = 0.64-3.09]). To sum up, high CRP levels at BC diagnosis were associated with inferior prognosis in early BC irrespective of BMI, although less clear in patients with obesity.

Tumour-related factors and prognosis in breast cancer detected by screening.

BACKGROUND: Breast cancer detected by screening has an unexplained prognostic advantage beyond stage shift compared with cancers detected clinically. The aim was to investigate biological factors in invasive breast cancer, with reference to mode of detection and rate of death from breast cancer. METHODS: Histology, oestrogen receptor α and ß, progesterone receptor, human epidermal growth factor receptor (HER) 2, cyclin D1, p27, Ki-67 and perinodal growth were analysed in 466 tumours from a prospective cohort, the Malmö Diet and Cancer Study. Using logistic regression, odds ratios were calculated to investigate the relationship between tumour characteristics and mode of detection. The same tumour factors were analysed in relation to standard prognostic features. Death from breast cancer was analysed using Cox regression with adjustments for standard tumour factors; differences following adjustment were analysed by means of Freedman statistics. RESULTS: None of the biological tumour characteristics varied with mode of detection of breast cancer. After adjustment for age, tumour size, axillary lymph node involvement (ALNI) and grade, women with cancer detected clinically had an increased risk of death from breast cancer (hazard ratio 2·48, 95 per cent confidence interval 1·34 to 4·59), corresponding to a 37·2 per cent difference compared with the unadjusted model. Additional adjustment for biological tumour factors studied caused only minor changes. CONCLUSION: None of the biological tumour markers investigated explained the improved prognosis in breast cancer detected by screening. None of the factors was related to ALNI, suggesting that other mechanisms may be responsible for tumour spread.

Primary brain tumours and specific serum immunoglobulin E: a case-control study nested in the European Prospective Investigation into Cancer and Nutrition cohort.

BACKGROUND: Case-control studies suggest that patients with allergic diseases have a lower risk of developing glioma but not meningioma or schwannoma. However, those data can be differentially biased. Prospective studies with objective measurements of immunologic biomarkers, like immunoglobulin E (IgE), in blood obtained before cancer diagnosis could help to clarify whether an aetiological association exists. METHODS: The present case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) measured specific serum IgE as a biomarker for the most common inhalant allergens in 275 glioma, 175 meningioma and 49 schwannoma cases and 963 matched controls using the ImmunoCAP specific IgE test. Subjects with an IgE level ≥0.35 kUA/l (kilo antibody units per litre) were classified as sensitized by allergens. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by adjusted conditional logistic regression models for each tumour subtype. The effect of dose-response relationship was assessed in five increasing IgE level categories to estimate P-values for trend. RESULTS: The risk of glioma was inversely related to allergic sensitization (OR = 0.73; 95% CI 0.51-1.06), especially pronounced in women (OR = 0.53; 95% CI 0.30-0.95). In dose-response analyses, for high-grade glioma, the lowest OR was observed in sera with the highest IgE levels (P for trend = 0.04). No association was seen for meningioma and schwannoma. CONCLUSION: The results, based on serum samples prospectively collected in a cohort study, provide some support for the hypothesis that individuals with allergic sensitization are at reduced risk of glioma and confirm results from previous case-control studies.

Oral contraceptives, reproductive history and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Oral contraceptive use and reproductive factors may initiate long-term changes to the hormonal milieu and thereby, possibly influence colorectal cancer risk. METHODS: We examined the association of hormonal and reproductive factors with risk of colorectal cancer among 337,802 women in the European Prospective Investigation into Cancer and Nutrition, of whom 1878 developed colorectal cancer. RESULTS: After stratification for center and age, and adjustment for body mass index, smoking, diabetes mellitus, physical activity and alcohol consumption, ever use of oral contraceptives was marginally inversely associated with colorectal cancer risk (hazard ratio (HR), 0.92; 95% confidence interval (CI), 0.83-1.02), although this association was stronger among post-menopausal women (HR, 0.84; 95% CI: 0.74-0.95). Duration of oral contraceptive use and reproductive factors, including age at menarche, age at menopause, type of menopause, ever having an abortion, parity, age at first full-term pregnancy and breastfeeding, were not associated with colorectal cancer risk. CONCLUSION: Our findings provide limited support for a potential inverse association between oral contraceptives and colorectal cancer risk.

Serum vitamin D (25OHD3) levels and the risk of different subtypes of breast cancer: A nested case-control study.

BACKGROUND: Previous studies regarding the association between serum 25-hydroxyvitamin D (25OHD3) and breast cancer risk have not been conclusive. The aim of this study was to investigate the potential association between pre-diagnostic serum 25OHD3 levels and the risk of different subtypes of breast cancer. MATERIALS AND METHODS: The study was based on The Malmö Diet and Cancer Study recruiting 17,035 women from 1991 to 1996. A total of 764 incident breast cancers with matched controls were analysed for 25OHD3 in samples collected at baseline, before diagnosis. A logistic regression analysis was used to calculate odds ratios with 95% confidence intervals for tertiles of 25OHD3 in relation to different subtypes of breast cancer, i.e. defined according to tumour type, tumour size, lymph node involvement, histological grade, oestrogen receptor (ER) status, progesterone receptor (PgR) status, Ki67, cyclin D1 and p27. RESULTS: As compared to the 1st tertile of 25OHD3, the second tertile had a statistically significantly lower risk of ER negative tumours, PgR negative tumours and tumours with a high expression of Ki67, A similar pattern was seen in relation to large tumours (≥21 mm), grade III tumours, and tumours with low p27 expression, but these associations did not reach statistical significance. The third tertile had a similar risk as the first tertile. CONCLUSIONS: We found that women with low levels of 25OHD3, as compare to women in the middle tertile, had a high risk of breast tumours with an unfavourable prognosis.

ESTIMATES OF BREAST CANCER GROWTH RATE FROM MAMMOGRAMS AND ITS RELATION TO TUMOUR CHARACTERISTICS.

This study aimed to investigate the growth rate of 31 consecutive invasive breast cancers based on volume measures on at least two serial mammograms and its relation to histopathological findings. The average tumour volume-doubling time in all invasive breast cancer subtypes was 282 d (range 46-749 d). Grade III breast cancers had a significantly shorter average tumour volume-doubling time of 105 d (range 46-157 d) compared with Grade I and II tumours (average of 296 d, range 147-531 d and average of 353 d, range 139-749 d, respectively) (p = 0.002). Multiple linear regression identified that tumour volume-doubling time was positively associated with patient age, histological grade and progesterone receptor expression and inversely associated with axillary lymph node involvement, human epidermal growth factor receptor 2 and Ki-67 expression (p < 0.001). In conclusion, tumour volume-doubling time as estimated on serial mammography may provide important prognostic information relevant for clinical decision-making.

Parity in relation to survival following breast cancer.

AIM: The present study examines the association between parity and survival following breast cancer diagnosis. METHODS: Medical records of 4453 women diagnosed with breast cancer in Malmö, Sweden, between 1961 and 1991 were analysed. All women were followed until 31 December 2003, using the Swedish Cause-of-Death Registry. Breast cancer specific mortality rate was calculated in different levels of parity. Corresponding relative risks, with 95% confidence intervals (CI), were obtained using Cox's proportional hazards analysis. All analyses were adjusted for potential prognostic factors and stratified for age, menopausal status and diagnostic period. RESULTS: As compared to women with one child, nulliparity (RR 1.27: 95% CI 1.09-1.47), and high parity (four or more children) (1.49: 1.20-1.85) were positively associated with a high mortality from breast cancer. When adjusted for potential confounders, the association was only statistically significant for high parity (1.33: 1.07-1.66). In the analyses stratified on age and menopausal status, there was a similar positive association between high parity and breast cancer death in all strata, although only statistically significant among women older than 45 years of age or postmenopausal. Nulliparity was associated with breast cancer death in women that were younger than 45 years of age (1.28: 0.79-2.09) or premenopausal (1.30: 0.95-1.80), but these associations did not reach statistical significance. There was no association between nulliparity and breast cancer death in women older than 45 years of age or postmenopausal. All associations were similar in analyses stratified for diagnostic period. CONCLUSION: Women with four or more children have a poor breast cancer survival as compared to women with one child.

Oestrogen receptors alpha and beta show different associations to clinicopathological parameters and their co-expression might predict a better response to endocrine treatment in breast cancer.

AIMS: The majority of all breast cancers are hormone responsive, traditionally defined by the expression of oestrogen receptor (ER) alpha and/or progesterone receptors. In contrast to ERalpha, the clinical significance of the relatively recently identified ERbeta is still unclear. This study aimed to define the relationship between ERbeta and clinicopathological parameters in a mixed cohort of breast cancer and, furthermore, to investigate the impact of ERbeta expression on disease outcome. METHODS: The immunohistochemical expression of ERalpha and ERbeta was analysed in tissue microarrays containing a total number of 512 tumours with all incident breast cancers diagnosed at the Malmö University Hospital between 1988 and 1992. RESULTS: 78% of the tumours were ERalpha positive and 50% were ERbeta positive. ERbeta correlated positively with ERalpha (p = 0.001). In contrast to ERalpha, ERbeta was not associated with any important clinicopathological variables. Furthermore, no overall prognostic significance could be demonstrated for ERbeta. In the ERalpha-positive subgroup, however, a low expression of ERbeta correlated with a decreased disease-free survival in patients receiving endocrine treatment (p = 0.003). CONCLUSIONS: Although interrelated, ERalpha and ERbeta seem to be differentially associated to clinicopathological parameters, and this would support the fact that they might have different functions in vivo. Furthermore, ERbeta might be a predictive marker of response to endocrine therapy, although this needs to be confirmed in additional studies, preferably randomised trials.