Hormone Replacement Therapy does not Increase Risk of Breast Cancer in Women with BRCA Mutation after BSO Treatment

By Anthony M Magliocco MD

In a large multicenter international prospective study reported in JAMA Oncology, Kotsopoulos et al found that use of hormone replacement therapy overall did not appear to increase risk the of breast cancer among women with BRCA1-mutation after prophylactic bilateral salpingo-oophorectomy; however, use of estrogen-progesterone hormone replacement therapy appeared to be associated with increased risk vs estrogen alone.

Study Specifics

The study was a prospective, longitudinal cohort study of BRCA1- and BRCA2-mutation carriers from 80 centers in 17 countries which was conducted between 1995 and 2017. There was a mean follow-up of 7.6 years. The study participants had undergone BRCA1 or BRCA2 testing for familial or other reasions.

The current study included a total of 872 BRCA1-mutation carriers with no personal history of cancer with a mean postoophorectomy follow-up of 7.6 years. Patients had a mean age of 43.4 years. the questionnaires were administered every 2 years for information on hormone replacement therapy use.

The investigators concluded,

“These findings suggest that use of estrogen after oophorectomy does not increase the risk of breast cancer among women with a BRCA1 mutation and should reassure BRCA1 mutation carriers considering preventive surgery that [hormone replacement therapy] is safe. The possible adverse effect of progesterone-containing [hormone replacement therapy] warrants further study.”

However the study also revealed that use of estrogen plus progesterone was associated with higher risk vs use of estrogen-alone hormone replacement therapy.

HER2/HER3 and PIK3CA Mutations in Colorectal Cancer are Associated with Microsatellite Instability

By Anthony M Magliocco MD

 

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A recent study by Loree reported in the  Journal of the National Cancer Institute, found that ERBB2/ERBB3 mutations in colorectal cancer are associated with the presence of MSI microsatellite instability and PIK3CA mutation.

Study Details- Retrospective analysis of Colorectal Cancer Cases from two Cohorts

The study involved retrospective analysis of 419 patients from The University of Texas MD Anderson Cancer Center (MDACC) and 619 patients from the Nurses’ Health Study (NHS)/Health Professionals Follow-Up Study (HPFS) with stage I to IV disease, with tissue sequencing, clinicopathologic, mutational, and colorectal cancer consensus molecular subtype (CMS) profiles of patients with ERBB2/ERBB3 mutations. The circulating tumor DNA profile associated with ERBB2mutation was also investigated in an additional cohort of 1,623 patients with circulating tumor DNA assay results.

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Factors Associated With ERBB2/ERBB3 Mutation

Mutations were found in over 5% of cases and were not associated with age, location or stage of tumor. ERBB2 mutations were associated with shortend survival HR 1.82 but not ERBB3

The investigators concluded, “[Microsatellite instability] and PIK3CA mutations are associated with ERBB2/ERBB3 mutations. Co-occurring PIK3CA mutations may represent a second hit to oncogenic signaling that needs consideration when targeting ERBB2/ERBB3.”

 

The findings are interesting in that mutated ERBB2 is potentially an actionable target.

Moffitt Cancer Center Morsani Molecular Lab Researchers Create New Laboratory Test to Better Diagnose Metastatic Bladder Cancer

Moffitt researchers reported the discovery of a new 19 gene expression signature that appears to have value in improving the accuracy of urothelial cancer diagnosis at the USCAP 2018 meeting in Vancouver.

The correct diagnosis of urothelial cancer, especially when metastatic can be very challenging for the surgical pathologist Urothelial carcinoma (UC) can mimic a poorly squamous cell carcinoma (SCC) and it may be difficult to distinguish the two especially in metastatic sites.

Metastatic cancer imaged with PET scan

 

It is important to distinguish the two cancers for proper patient management. These two cancers have an overlapping immunohistochemical profile (both positive for CK5/6, CK7, p63 and p40). GATA3 although relatively specific for UC, can also be expressed in SCC.

It is important to distinguish urothelial carcinoma from other epithelial cancers to ensure proper diagnosis and patient managment

Gene expression analysis is a powerful method that can measure the expression level of thousands of mRNA messages simultaneously in a tissue biopsy specimen. Analysis of data from this technique, when coupled with bioinformatics analysis can produce powerful classification algorithms which could be used in a CLIA laboratory to improve the accuracy of current diagnostic approaches.

Affymetrix chips for rapid gene expression

The Moffitt researchers analyzed 161 UC, 38 head and neck cases, and 268 lung cancer SCC cases from Moffitts Total Cancer Care (TCC) database to create the initial algorithm. The data was collected on the a specially modified HuRSTA chip containing 60607 probe sets covering 26356 genes. An algorithm was developed from the 19 top most differentially expressed genes using principal component analysis (PCA). The PCA model performed at above 98% sensitivity and specificity correctly identifying the histological origin of the specimens on self validation.

PCA analysis separating tumor types using 19 gene signature

The signature was further validated on publicly available external datasets at GEO datasets, with 96 cases of H&N SCC from GSE31056, 18 lung SCCs from GSE10245 and 93 UC from GSE31684, total of 207 cases.This signature correctly identified 112 of the 114 publicly available SCCs with gene data (96 H&N and 16 lung) as SCC and all of 93 publicly available UCs with gene data as UC

The identification of a gene classification algorithm will enable improved classification of these challenging lesions, particularly in the metastatic setting.

The Moffitt investigators will continue to evaluate this new signature and propose to develop it into a routine diagnostic assay. In addition, deeper understanding of the molecular basis of urothelial cancer and how it differs at the molecular level potentially opens new approaches to therapy.

An assay like this could be far superior than classical IHC as the complexity of gene expression will give multiple insights into not only tissue of orign but also other aspects of the cancer biology such as immune status.

Understanding the molecular basis of urothelial cancer will provide insights into novel treatment opportunity

The work was supported by the Moffitt Morsani Molecular Laboratories

Presented at the 2018 USCAP meeting in Vancouver Canada

Gene Biomarker Signature for Distinguishing Urothelial Carcinoma from Squamous Cell Carcinoma. Jasreman Dhillon, MD Yin Xiong, Ph.D. Anthony Magliocco, MD, Soner Altiok, MD, PhD, H. Lee Moffitt Cancer Center, Tampa FL