Aspects of Endocrine Therapy in Primary Breast Cancer. Risk Profiling and Adherence Perspectives for Improving Tailored Adjuvant Treatment

Sammanfattning: Abstract: Breast cancers are heterogeneous tumours. Prognostic markers are needed to better profile the patient´s risk, and predictive markers to indicate the expected benefit of systemic treatment. Using gene expression analyses, breast tumours can be divided into intrinsic subtypes. Immunohistochemical (IHC) markers (oestrogen and progesterone receptors (ER and PR), human epidermal growth factor receptor 2 (HER2), proliferation marker (Ki67)) and histological grade (HG) are used to classify the tumours into the corresponding surrogate subtypes. The ER-positive/HER2-negative (ER+/HER2−) tumours are divided into Luminal A and Luminal B, which are associated with different prognoses. Patients with Luminal B tumours are generally recommended adjuvant chemotherapy in addition to endocrine therapy. The agreement between the subtyping by gene expression and surrogate classification, is not perfect. Prosigna® test provides the tumour subtype and assigns the patient a relapse risk score (Risk of Recurrence (ROR) score) by gene expression analyses, predicting 10 years risk of distant metastases. This test is currently in clinical use for postmenopausal women only, and assumes treatment with endocrine adjuvant drugs. The adherence to these drugs is however known to be poor, mostly because of the side-effects. The immune system and its complex components, such as tumour-infiltrating lymphocytes (TILs) have so far proven to be important markers for certain subtypes of breast cancer, although their value in ER+/HER2− tumours is less known.Study I: Data on the prescribed and collected endocrine drugs from the Swedish Prescribed Drug Register for patients in Region Jönköping County, was retrived. Adherence to the therapy was calculated after 3 (n=445) and 5 years (n=248), defined as collecting over or equal to 80% of the prescribed drugs during the time periods, respectively. The results showed that adherence was over 90% after both 3 and 5 years.Study II: Patient and tumour data from over 2,000 patients included in the SCAN-B project, in which primary tumours were defined by PAM50 subtypes, was retrieved. The ER+/HER2− tumours were divided into Luminal ASurrogate Classification (SC) and Luminal BSC according to three surrogate algorithms. The agreement between luminal subtyping by gene expression and surrogate markers showed poor results. The highest agreement was 70% for the classification mainly based on HG. By combing HG and Ki67, nine subgroups were generated, and among these, six groups (51% of the cohort) were identified having >90% Luminal APAM50 tumours.Study III: Tumour blocks from primary breast cancer tissues were collected from patients that participated in the SBII:2pre study, in which premenopausal women were randomised between 2 years of adjuvant tamoxifen or no systemic treatment. Available follow-up data was over 30 years. TILs were assessed on whole tumour sections. The results showed that a high proportion of TILs (≥50%) was associated with better prognosis in all breast cancer subtypes. Furthermore, the benefit of tamoxifen was higher in patients whose tumours had low infiltration (<50%) of lymphocytes.Study IV: Gene expression analysis (by NanoString Breast Cancer 360™ assay) of the primary tumours from patients in the SBII:2pre study, was conducted. This assigned each tumour a PAM50 intrinsic subtype and the corresponding patient a relapse risk score (ROR score). Surrogate classification according to St. Gallen 2013 was also performed. Both PAM50 and ROR score were prognostic. After 10 years of follow-up, re-classification of Luminal BSC tumours into Luminal APAM50 was associated with improved prognosis as compared to those uniformly classified as Luminal B, and benefit from tamoxifen could only be demonstrated in patients with Luminal APAM50 tumours.In conclusion, the results presented in this thesis showed that risk profiling of patients with primary breast cancer can be performed using a combination of gene expression and IHC markers. These markers and tests are pieces of the puzzle to be put together for each unique patient, and the pieces should be given different weights in order to tailor adjuvant treatment. Moreover, the results indicated that good adherence to endocrine therapy is possible to achieve.