Presurgery chemo in breast cancer: Benefits of molecular subtyping

June 29, 2013 | by Roberta Nichols

Breast cancer specialists know that neoadjuvant, or presurgical, chemotherapy can allow for breast preservation and better surgical outcome for women with newly diagnosed early-stage and locally advanced breast cancer. Such therapy frequently leads to complete resolution – complete response – of the breast mass, especially in those women who present with triple negative (or basal subtype)  and HER2 positive disease.

Breast cancer can often be treated with chemotherapy before surgery. Now researchers are trying to identify who will best benefit from this approach. Breast cancer can often be treated with chemotherapy before surgery. Now researchers are trying to identify who will best benefit from this approach.

Those subtypes represent about 40 percent of all newly diagnosed breast cancers. And, as doctors point out, achievement of  pathologic complete response (pCR) has been implied to predict for longer survival.

Yet, which women really fare best with this approach?

In a new study examining a method of molecular subtyping, researchers begin to provide answers. Their goal is to personalize medicine even further, prevent women from undergoing unnecessary neoadjuvant chemotherapy and guide selection of those who may benefit most.

The study, appearing in the June 12 online edition of the journal Breast Cancer Research and Treatment, was co-led by senior and co-corresponding  author George Somlo, M.D., a professor in the departments of Medical Oncology & Therapeutics Research and Hematology & Hematopoietic Cell Transplantation at City of Hope.

To predict how to select therapies, physicians normally apply pathologic subtyping using immunohistochemistry and, if needed, fluorescence in situ hybridization (IHC/FISH). The tests reveal which tumors are positive for the estrogen receptor, progesterone receptor and HER2 (human epidermal growth factor receptor-2) and help determine which treatment will work best.

In this study, researchers compared IHC/FISH with molecular subtyping. They found that BluePrint with MammaPrint molecular subtyping helps to improve doctors’ ability to predict prognoses and select the superlative therapy. Data were pooled and analyzed from 437 patients (between the ages of 26 and 79) in four neoadjuvant chemotherapy trials.

Below, Somlo explains the significance of the research:

What is the main finding of this study?

Neoadjuvant chemotherapy  is used to kill most, if not all, cancer cells in the breast, draining lymph nodes and undetectable systemic sites, and allow for less extensive breast conservation-type surgery in a higher proportion of patients than what may be feasible if surgery is performed first.

Through a variety of methods, we have assessed the molecular characteristics so we can personalize such therapy for those who would benefit most.

In this study, pretreatment biopsy specimens from breast tumors were tested and results were pooled from several centers, applying gene expression analysis using Mammaprint and Blueprint as part of a scientific collaboration with Stefan Gluck of the University of Miami and investigators from Agendia Inc.

The findings suggest that breast cancers subtyped as Luminal A and B are less likely to respond to neoadjuvant chemotherapy  than subtypes HER2+ and basal with the variable neoadjuvant chemotherapies applied, and the Luminal A cases may not need neoadjuvant therapies.

What kind of impact do you believe this study will have?

Compared with IHC/FISH, molecular subtyping (e.g., using BluePrint and MammaPrint) leads to a more precise classification of patients with early-stage and locally advanced breast cancer and a better correlation with long-term clinical treatment outcomes. Molecular subtyping leads to the identification of a substantial group of patients with Luminal A-type disease for whom the pCR as an endpoint provides little prognostic information, who have excellent survival irrespective of chemotherapy and may therefore not need chemotherapy treatment.

What comes next for this avenue of research?

At City of Hope, we are currently redefining molecular predictors of tumor shrinkage and recurrence and identifying targets for specific therapies in patients who present with HER2+ and triple negative/basal subtypes, the types that clearly respond to neoadjuvant therapies.

In addition to continuing our scientific collaboration with Agendia Inc., we are conducting or are in the process of beginning City of Hope-investigator initiated trials focusing on novel neoadjuvant therapies.

Through collaborations with scientists from City of Hope and other academic centers, we are assessing the potential predictive roles of microRNAs, DNA and RNA markers, circulating tumor cells and proteins procured from breast tumors and blood samples of patients who are candidates for neoadjuvant therapy.

City of Hope colleagues who are involved in these ongoing or planned collaborations include Heehyoung Lee, Ph.D., Hua Yu, PhD., Emily Wang, Ph.D., Min Li, Ph.D., Xiwei Wu, M.D. Ph.D., Susan Kane, Ph.D., Yun Wu, Sushma Yadav and Paul Frankel, Ph.D. Outside collaborations include researchers at Caltech, the University of Texas MD Anderson, Stanford University and Stanford Research Institute. 

Somlo’s colleagues on the current study were Stefan Gluck from the Sylvester Comprehensive Cancer Center at the University of Miami and Femke de Snoo, Justine Peeters and Lisette Stork-Sloots from Agendia in Amsterdam, The Netherlands.

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