Masteronderzoek Oncologie borstkanker

Title 
Optimal adjuvant endocrine therapy for primary lobular breast cancer 

Contact details 
Dr. Annette Heemskerk-Gerritsen, cancer epidemiologist and  prof. dr. Agnes Jager, medical oncologist 
Dept. of Medical Oncology, Breast Cancer group  
Erasmus MC Cancer Institute 
E-mail: b.heemskerk-gerritsen@erasmusmc.nl, a.jager@erasmusmc.nl

Background 
Adjuvant endocrine therapy in patients with ER+/HER2- breast cancer leads to a significant reduction in the risk of  recurrent disease activity. Until recently, no clear distinction was made between tumor histology and the choice of  endocrine therapy. In recent years, however, oncologists have increasingly tended to use upfront aromatase inhibitors in  postmenopausal patients with ER+ breast carcinoma of the lobular subtype (ILC). This is based on a retrospective analysis  of the randomized Breast International Group (BIG) 1-98 study which showed that postmenopausal patients with ER+  breast cancer with classic ILC clearly benefited more from treatment for 5 years with an aromatase inhibitor than from  treatment for 5 years with tamoxifen (1). With regard to premenopausal women, there is no knowledge about the effect  of tamoxifen on lobular histology compared to ductal/IC-NST type. Preclinical effectiveness of tamoxifen compared to  aromatase inhibitors in ILC cell lines has never been properly investigated due to a lack of good ex vivo/in vitro lobular  breast cancer models. Therefore, (inter)national guidelines still do not definitively recommend the use aromatase  inhibitors only in patients with ILC (4,5). If the results from the BIG 1-98 study could be confirmed, this would be a reason  to adjust the (inter)national guidelines.  

Problem description 
Until now, no study has investigated whether aromatase inhibitors are more effective than tamoxifen in ILC patients as  the primary research question. Randomized clinical trials to answer this important question will no longer take place due  to the large number of patients required and the long duration of median follow-up required to obtain the final results  (>10 years). Retrospective studies using real world data (RWD) could provide a solution here. 

Solution/research direction 
Primary research questions 
Is the long-term outcome of postmenopausal women with primary pN0 classical lobular breast carcinoma (grade 2, ER  ≥50%, PR ≥50%, HER2- and if known a Ki67 <14%) significantly better when treated for five years with an aromatase  inhibitor than when treated with 2-3 years with tamoxifen followed by 3-2 years of an aromatase inhibitor? 

Secondary research questions: 
Is the long-term outcome of postmenopausal women treated with upfront AI significantly better for patients with primary  pN0 classical lobular breast carcinoma than for women with primary pN0 ER+/PR+/Her2- ductal/IC-NST breast carcinoma 

Purpose of the current study 
To investigate the effectiveness of adjuvant tamoxifen treatment in patients with invasive lobular breast cancer 

Type of research 
This is a large retrospective cohort study using real world data (RWD) of de Dutch National Cancer Registry (NKR). 

Before 2003, postmenopausal patients with ER+/Her2- pN0 breast cancer were adjuvantly treated with tamoxifen for 5  years. Since the 2004 guidelines, these patients have increasingly been treated with 2.5 years of tamoxifen followed by  2.5 years of AI (sequential) and since 2008 patients are only treated with 2.5 years of tamoxifen followed by 2.5 years AI  (sequential) or 5 years AI (upfront). Patients with a (relative) contraindication to treatment with an AI underwent  tamoxifen for 5 years. Premenopausal patients with ER+/Her2- pN0 breast carcinoma receive adjuvant treatment with  tamoxifen with or without a GnRH agonist, regardless of stage and histology.  

In more than 50% of ER+/Her2- breast carcinoma patients who develop a recurrence of the disease, this is more than 5 years after diagnosis. It is therefore important that, when investigating the effect of endocrine therapy on long-term outcome, the median follow-up should be at least 10 years. 

We would therefore like to investigate the above research questions in two populations. 

1. The population of ER+ pre- and postmenopausal breast cancer patients with incidence years 2004 to 2008 and Q1 2012  where data on local, regional and distant metastases is also known 
2. The population of ER+ pre- and postmenopausal breast cancer patients with incidence years from 2004 to 2020 where  data on overall survival are known. 

Expected results  
It is expected that detailed data from a large number of breast cancer patients will be available. This will allow us to  answer the two main research questions and probably also some secondary research questions. 

This project will be supervised by prof. dr. Agnes Jager, medical oncologist, and dr. Annette Heemskerk-Gerritsen, Cancer  epidemiologist. 

Other people involved in this project: dr. Maartje Hooning, cancer epidemiologist and Mandy van Rosmalen