GRACE :: Breast Cancer

Molecular Subtypes of Breast Cancer

Breast cancer is a remarkably diverse disease.  In terms of gene expression there are multiple different molecular subtypes of breast cancer.  Dr. Chuck Perou and his colleagues demonstrated that the way an individual breast cancer behaved was associated with differences in the expression of various genes in the tumor. From the genes in the tissue samples, they selected a subset of 456 genes which they named the “intrinsic” gene subset. This subset contained genes that were significantly different among different breast cancers. Using this subset, they were then able to identify 5 very different molecular subtypes of breast cancer:

  • ER-positive/luminal A
  • ER-positive/luminal B
  • Basal-like
  • HER2-positive
  • Normal breast

These five molecular subtypes have been confirmed in independent data sets, and importantly, the individual gene expression subtype appears to remain consistent between the original tumor and subsequent metastatic lesions occurring years later.  Furthermore, these subtypes are associated with differences in clinical outcome. Sorlie and his colleagues examined a subset of 49 locally advanced breast cancers that had been treated with adriamycin and found that both relapse-free (RFS) and overall survival (OS) differed significantly among the breast cancer subtypes.  Luminal A tumors had the longest survival times, the basal-like and HER2+/ER- subtypes had the shortest survival times and the luminal B tumors had intermediate survival times

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New Targeted Therapy approved for ER-positive, HER2-negative Breast Cancer: Afinitor with Aromasin

On July 20, 2012, the U.S. Food and Drug Administration (FDA) gave us another option for treating postmenopausal patients with metastatic, ER-positive, HER2-negative breast cancer whose disease has progressed on Arimidex or Femara by approving Afinitor (everolimus) in combination with Aromasin (exemestane). This new approval was based on the BOLERO-2 trial which was a randomized, double-blind, multicenter trial conducted in 724 postmenopausal women.  Patients were randomized to receive either Afinitor 10 mg/day plus Aromasin 25 mg/day or to placebo plus Aromasin 25 mg/day. Both Aromasin and Afinitor are oral drugs.

Aromasin is an aromatase inhibitor which works by lowering estrogen levels in postmenopausal women. This trial was based on the observation that resistance (either not responding or stopping responding) to hormonal therapy is associated with a tumor being able to use pathways other than the estrogen pathway to survive and grow. One example of this is activation of the mammalian target of rapamycin (mTOR) signaling pathway in cells. Afinitor targets the mTOR pathway and is classified as an mTOR inhibitor. 

On the BOLERO-2 trial, the median progression-free survival (PFS) was longer for the patients receiving Afinitor (7.8 vs 3.2 months). These results were consistent regardless of age, race, presence or extent of visceral metastases (such as liver metastases), and response to prior hormonal therapy.  The response rate was also better for the patients receiving Afinitor (12.6% vs 1.7%).  The analysis of overall survival (OS) was not significant however this was an interim analysis.  The final OS analysis isn’t expected to become available until June, 2014.

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Perjeta (Pertuzumab) Approved by FDA for HER2-Positive Advanced Breast Cancer

On June 8, The U.S. Food and Drug Administration (FDA) approved Perjeta (pertuzumab) to treat patients with metastatic, HER2-positive breast cancer who have not received previous treatment with either chemotherapy or HER2-targeted therapy. Approximately 20-30% of breast cancer is HER2-positive.

Herceptin is a monoclonal antibody that works by blocking HER2. While Perjeta also targets HER2, it binds to a different area of the HER2 protein and prevents the HER2 protein from combining with other HER receptors (HER1, HER3, and HER4). This prevents tumor growth and survival. Perjeta’s mechanism of action is therefore believed to be complimentary to that of Herceptin. In fact, Perjeta by itself has very little activity; its real use is in combination with Herceptin.

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Antibody-Drug Conjugate T-DM1 Offers New Mechanism and Significant Benefit in HER2-Positive Breast Cancer

Right at the top of the list of the most exciting news from the 2012 American Society of Clinical Oncology (ASCO) meeting in Chicago this week involved using T-DM1 to treat metastatic, HER2-positive breast cancer.  T-DM1 is an “antibody-drug conjugate” (ADC).

ADCs combine a tumor-specific antibody with a chemotherapy drug. They are therefore specifically designed to be able to deliver chemotherapy drugs directly to tumor cells (like a “smart bomb”), potentially increasing efficacy and decreasing damage to normal cells. T-DM1 combines the anti-HER2 antibody Herceptin (trastuzumab), a stable linker and a chemotherapy agent, DM1, also known as emtansine.

Befitting its importance, the EMILIA trial was presented at the high profile Plenary Session. In this study almost 1000 patients with metastatic, HER2-positive breast cancer whose disease had progressed after treatment with a taxane and Herceptin were randomized to receive Xeloda (capecitable) plus Tykerb (HER2-inhibiting tyrosine kinase inhibitor lapatinib) or T-DM1. Xeloda and Tykerb are oral drugs; the T-DM1 was given intravenously every 3 weeks. There was no “cross-over”, meaning that patients whose disease progressed on Xeloda and Tykerb did not have access to T-DM1.

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Drugs for Breast Cancer Prevention

Large trials testing drugs to prevent breast cancer (chemoprevention) date back to the 1990s, when tamoxifen was first evaluated in this setting. Tamoxifen is a selective estrogen receptor modulator (SERM). SERMs block the effects of estrogen in breast tissue by binding to the estrogen receptors in breast cancer cells leaving no room for estrogen to attach to the receptor. If estrogen can’t attach, it is unable to signal the cell to grow and multiply. The initial, large-scale breast cancer chemoprevention trial was the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (P-1), initiated in 1992. P-1 randomized approximately 14,000 women who had a risk of at least 1.66% of developing breast cancer in the upcoming 5 years to 5 years of tamoxifen or placebo. Risk was assessed using the Gail model, which is a tool designed by scientists at the National Cancer Institute (NCI) and the NSABP to estimate a woman’s risk of developing invasive breast cancer, both in the next 5 years and in her lifetime (assuming she lives to age 90). Factors included in this tool include current age, age of menarche (first menstrual period) and first live birth, number of first degree relatives with breast cancer, and whether or not a woman has had breast biopsies in the past with or without atypical cells.  In the P-1 trial, 5 years of tamoxifen reduced the risk of breast cancer by almost 50%. Tamoxifen also led to a 32% reduction in the risk of fractures due to osteoporosis however the risk of strokes, blood clots, uterine cancer and cataracts were increased in the tamoxifen group. As a result of this trial, the FDA approved tamoxifen for breast cancer chemoprevention in women aged 35 and older with a 5-year breast cancer risk of 1.67% or higher.

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