Epidemiological studies on breast cancer risk factors and screening

This thesis aims to enhance cancer prevention by investigating the factors and outcomes associated with false-positive (FP) mammography recalls, as well as understanding the association between breast cancer risk factors of women and cancer risk among their relatives. Specifically, four studies were conducted using data from Swedish national registers, the Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) cohort, and the Linné-Bröst1 (Libro-1) cohort. In Study I, we characterized factors associated with FP mammography recalls, comparing women with a FP recall to those who were not recalled and to those who had a true-positive recall (screen-detected cancer). We found that several mammographic and non-mammographic factors, as well as high breast cancer risk scores, were associated with having a FP recall. However, these factors were either equally or more strongly associated with having a truepositive recall. In Study II, using a matched-cohort design, we examined the risk of subsequent breast cancer among women with a FP mammography recall. We observed a long-term increased breast cancer risk after a FP recall, compared with women who were not recalled. The elevated breast cancer risk differed by age and mammographic density at the matching mammography. In addition, the increased risk for breast cancer diagnosed on the ipsilateral side to the FP recall decreased over time and was highest within the first four years of follow-up. In Study III, we investigated whether specific breast cancer risk factors in women were associated with their sisters' breast cancer incidence. We found that for women with high breast cancer risk prediction scores, benign breast disease (BBD), and high mammographic density, there was an increased risk of breast cancer for their sisters. In Study IV, we investigated the associations of both carriership of protein-truncating variants (PTV) in eight genes and breast cancer polygenic risk scores (PRS) in women, with the risk of cancers in their first-degree relatives. We observed an elevated breast cancer risk among female relatives of women with PTVs, and among those with high breast cancer PRS. Additionally, we found a slightly elevated risk of cancers related to hereditary breast and ovarian cancer syndrome (HBOC)—other than breast cancer—among relatives of women with either high PRS or PTVs in the studied genes. In summary, this thesis provides valuable information for both screening processes and genetic counseling. Although none of the studied factors are viable for interventions aimed at reducing FP recalls—due to the risk of simultaneously missing tumors—our results may aid in tailoring individualized surveillance plans for women with a FP recall. Additionally, our results suggest that women’s breast density and breast cancer risk scores—information that will be available at screening—may be useful for estimating the breast cancer risk in their sisters. Furthermore, PTVs in non-BRCA genes might offer insights into cancer aggregation in families. Overall, this thesis advances evidence-based cancer prevention in the era of precision medicine

CYP2D6-polymorphism and effect of adjuvant tamoxifen in breast cancer patients

Adjuvant tamoxifen at the standard dose of 20 mg daily for five to ten years reduces the risk for relapse and mortality in hormone sensitive breast cancer. The effect however varies and no early marker of poor response is yet available. Varying activation of tamoxifen due to polymorphism in the CYP2D6 gene has been suggested to influence the effect of the treatment, but data are inconsistent. Our previous study in a smaller cohort of tamoxifen treated early breast cancer diagnosed 1998-2000 indicated a poorer prognosis in premenopausal patients with reduced CYP2D6 activity. The overall aim of this thesis was to investigate various aspects of tamoxifen treatment to facilitate improved personalized endocrine treatment strategies in early breast cancer, with individualized tamoxifen dosing, to improve quality of life, adherence and prognosis. In study I we investigated the correlation between CYP2D6 genotype and tamoxifen metabolite levels in plasma, focusing on reduced function CYP2D6 variants (n=118). We also explored the relationship between endoxifen levels and adverse effects to tamoxifen. The degree of side effects to tamoxifen appeared to be dependent on endoxifen concentration. We found a distinct correlation between CYP2D6 activity and plasma concentrations of endoxifen. The effect of reduced function variants, in particular CYP2D6*41, on endoxifen formation was greater than anticipated. Markedly reduced endoxifen concentrations were seen in all homozygous carriers of CYP2D6 no function variants and in those with two reduced activity alleles. The fraction of patients with poor tamoxifen activation might thus be larger than expected. This may be important information for future genotype-based tamoxifen dosing. Although the clinical relevance of the proposed target level of endoxifen at around 5.9 ng/mL needs to be evaluated, it is concerning that a third of our study patients had endoxifen concentrations below this level with tamoxifen at the current standard dose. This underlines the importance of further work to define a target concentration of endoxifen for clinical benefit. In study II we investigated the effect of CYP2D6 activity and other systemic adjuvant therapy on mammographic density (MD) change (n=699) in tamoxifen treated patients. As expected, MD declined during follow up, with a more prominent decrease in the premenopausal subgroup. Other systemic adjuvant treatment did not further extend density decline in this tamoxifen treated cohort. Density reduction appeared to persist after tamoxifen was stopped. Importantly, the previously proposed correlation between CYP2D6 activity and density change in patients with adjuvant tamoxifen could not be confirmed in this cohort with modern complex systemic adjuvant treatment. More data is needed to ascertain whether mammographic density change may be used as a marker of the desired effect of adjuvant tamoxifen. In study III we compared information from patient records to data from the National Prescribed Drug Register in Sweden on adherence to adjuvant endocrine treatment (n=1235). We also investigated the association between CYP2D6-activity, menopausal status, the patients’ risk for relapse and adherence. Consistency, i.e. agreement, between the two sources of adherence data was good, 86%, when including medication with an aromatase inhibitor (AI) after tamoxifen. In those with at least 4.5 years follow up, adherence to adjuvant tamoxifen was reasonable, 72% and increased to 82%, when including subsequent AIs, based on prescription refill data. Adherence was not found to vary by menopausal status or recurrence risk. Unexpectedly, adherence to tamoxifen was lower in CYP2D6 poor metabolizers, despite data proposing a reduced risk of adverse effects in this group. In study IV we aimed to validate our previous findings in a larger material in a more modern setting (n=1105), with tamoxifen treated patients operated between 2006-2014, who could also be subject to improved multimodal adjuvant therapy compared to the patients in our older study and to determine if the effect of CYP2D6 genotype is affected by menopausal status. Compared with our previous study, fewer patients, 12%, had a relapse and only 4% died from breast cancer under the 11-year follow-up. In summary, no obvious correlation between poor CYP2D6 activity and a worse prognosis was found in this material, accounting for adherence to tamoxifen and CYP2D6 inhibitors. A correlation between low CYP2D6 activity and a poorer prognosis in premenopausal tamoxifen treated early breast cancer was thus not confirmed. Breast cancer treatment has steadily improved over time. A possible negative effect of poor CYP2D6 activity on clinical outcome in tamoxifen treated patients is therefore likely marginal in a clinical setting with access to multimodal postoperative breast cancer treatment. Although our results do not support CYP2D6 testing for patients with adjuvant tamoxifen in a multimodal clinical setting, we cannot exclude that CYP2D6 genotyping might still be of value in selected groups, such as in in a low resource setting, where many patients, including those at higher risk of relapse, receive tamoxifen monotherapy. Therapeutic drug monitoring of tamoxifen to secure sufficient plasma levels of endoxifen for clinical efficacy and to avoid excess drug exposure associated with severe side effects might also be relevant in the future. In conclusion, this thesis contributes to the knowledge on CYP2D6 polymorphism and the effect of postoperative tamoxifen in a multimodal setting, the correlation between CYP2D6 genotype and tamoxifen metabolites, which is important for future dose titration studies of tamoxifen, the effect of systemic adjuvant treatment on density change in tamoxifen treated patients as well as adherence to adjuvant endocrine treatment, with focus on tamoxifen. There is a need for improved management of side effects to tamoxifen treatment, to optimize quality of life and adherence. Therapeutic drug monitoring of tamoxifen might be an approach. More work on predictive markers and early evaluation of response to tamoxifen is warranted

Range of Body Mass Index and the risk of breast cancer

Introduction. Obesity leads to an increased incidence of many diseases. The research subject of scientists is the impact of obesity on breast cancer as one of the most commonly diagnosed cancers among women. Aim of the study. Analysis of the relationship between overweight and obesity with the risk of invasive breast cancer. Material and method. Review of studies on the association of obesity with the incidence of breast cancer published in the last 10 years. Results. The study conducted in 67142 women who were measured at baseline weight is noteworthy. Overweight and obese women showed an increased risk of invasive breast cancer with a positive estrogen and progesterone receptor (HR 1.86; CI 1.60-2.17). The presented analysis of 1017 cases of women suffering from breast cancer showed that the BMI above 25kg/m2 in both the period before and after menopause was associated with a larger tumor size, shorter period of disease (DFS), overall survival (OS) (