The third day of the San Antonio Breast Cancer Symposium began with a plenary session on tumor heterogeneity – a term that refers to the extensive genetic variability of breast cancers. Not only is each breast cancer unique with its own profile of gene mutations and alterations, but even within a single tumor, there are individual or groups of cells (called clones) with distinct genetic profiles– a property referred to as intratumor heterogeneity.
Understanding the mechanisms that contribute to this genetic diversity is critical to the development of effective targeted therapies and to achieving the promise of precision medicine. Getting there requires the efforts of multidisciplinary teams of experts in oncology and tumor biology, and technologies such as gene sequencing, bioinformatics, mathematical and computational modeling and liquid biopsy. But first and foremost, none of this could be done without patients.
Many of these studies are conducted within clinical trials using tissue and blood that is collected before, during or after therapy to connect changes in genes (DNA and RNA), proteins or other cellular components to a patient’s response to the treatment. Thus, many clinical trials today not only test a new drug or regimen against the current standard, but also probe patient samples for biomarkers that can be used to identify future patients who are most likely to benefit – or not– from the therapy. Biomarkers may also be able to identify which patients are most likely to have a recurrence, or patients who may not need aggressive therapy.
Here are a few highlights from studies reported.
Predictive markers for recurrence and treatment
BCRF investigator Dr. Mitch Dowsett reported results from a translational study conducted within the Arimidex, tamoxifen, Alone or in Combination (ATAC) clinical trial. His group compared two recurrence predictive assays in estrogen receptor (ER)-positive and HER2- negative breast cancer patients treated with the aromatase inhibitor, anastrozole (Arimidex), alone or in combination with tamoxifen for five years.
Previously, the TransATAC team, including BCRF investigators Drs. Jack Cuzick and John Forbes, had reported that the OncoTypeDx-21 gene recurrence score (RS), a test result that determines the likelihood of distant breast cancer recurrence in early stage breast cancer, was a valid prognostic assay in patients receiving aromatase inhibitors. OncoTypeDx-21 RS, was derived from patients receiving tamoxifen alone. However, in the current study they compared a new predictive algorithm called EPclin. This prognostic test combines the expression of eight genes associated with risk of recurrence with the clinical parameters of tumor size and lymph node status, to create a dichotomous score of high or low risk of recurrence.
Researchers found that in many cases the EPclin performed better than the OncoTypeDx RS, particularly in patients whose disease had spread to their lymph nodes. The EPclin assay was also able to identify a group of very low risk patients without lymph node involvement, though some patients with negative lymph nodes did fall into the high risk group.
Dr. Dowsett concluded his presentation by saying, “These data highlight the importance of the inclusion of clinicopathological features and the type of endocrine treatment for prediction of risk of recurrence.”
Following Dr. Dowsett’s presentation, BCRF investigator Dr. Kathy Albain reported on results from SWOG-8814, a randomized phase III trial in postmenopausal women with hormone receptor-positive, node-positive breast cancer to test the survival benefit of adding a chemotherapy regimen referred to as CAF (cyclophosphamide, doxorubicin [AdriamycinR], and 5-fluorouracil) to five years of tamoxifen, compared to treatment with tamoxifen alone.
In 2009 the group reported that patients treated with CAF followed by the tamoxifen regimen had the best 10 year survival. In the current study, the SWOG team set out to identify novel genes and/or gene networks that could predict early relapse and to identify patients most likely to benefit from adding the CAF regimen. The research team found that distinct gene clusters called metagenes were informative in predicting good versus poor outcome with tamoxifen alone, as well as in identifying patients who would most likely benefit from the addition of chemotherapy.
Identifying early versus late drivers of metastasis
Molecular characterization of breast cancer has shown that subtypes of breast cancer tend to metastasize to specific organs (bone, liver, lung, brain), but the underlying biology of these events is poorly understood. In an afternoon session, Marni Siegel of the University of North Carolina, Chapel Hill, discussed findings from a study conducted in collaboration with BCRF investigators, Drs. Lisa Carey and Charles Perou. The group examined both early and late metastases to determine whether there are features in the primary cancer that can predict future metastasis and whether the process of metastasis is driven by single or multiple clones (groups of cells derived from a single cell lineage with the same genetic makeup).
To do so, the group utilized a rapid autopsy program in which terminally ill patients and their families provided advanced consent to immediate autopsy after death for the collection of metastatic lesions arising from the patient’s breast cancer. Using these samples, the research team was able to study multiple metastases from a single patient and compare the gene profiles across metastases and to the primary tumor, creating a phylogenetic tree showing the evolutionary relationship of the metastases to the primary tumor. Using novel computational methods combining results from DNA and RNA analyses, the group reported that most genetic drivers of metastasis are present in the primary tumor and maintained through metastasis, while additional mutations are acquired later in the process of metastasis.
“The rapid autopsy donation represents the ultimate gift a patient can give to future breast cancer patients and this study demonstrates how valuable autopsy tissue can be in understanding the process of metastasis,” BCRF investigator Dr. Hyman Muss said about the study, noting the uniqueness of the rapid autopsy program.
Androgen receptor in breast cancer – an alternative target for endocrine therapy for triple negative breast cancer.
While typically associated with prostate cancer, the androgen receptor (AR) is also highly expressed in breast cancer cells – found in nearly 95 percent of estrogen receptor positive (ER+) breast cancers and up to 50 percent of ER- breast cancers. Anti-androgen drugs currently used to treat prostate cancer may provide options for endocrine therapy in some triple negative breast cancers, which are not candidates for anti-estrogen therapies such as tamoxifen or aromatase inhibitors.
“In triple negative breast cancer, more people have the androgen receptor than previously predicted. This means hormone therapy targeting the AR may be available to a new class of patients whom we never thought of before,” Chairman of the BCRF Scientific Advisory Board Dr. Clifford Hudis said about the findings.
Several clinical trials are ongoing to test anti-androgen therapies in advanced and triple negative breast cancer. For more information on these trials, visit BreastCancerTrials.org.
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