October is Breast Cancer Awareness Month, and this year it is marked by the release of new findings that might represent a research breakthrough for this disease.
Investigators with the Cancer Genome Atlas Network analyzed the genetic characteristics of primary breast tumor cells from 825 patients using 6 different technology platforms. Most previous studies have used only 1 or 2 platforms. From these data, the researchers determined that a diverse array of genetic mutations converge to produce 4 classes, or intrinsic subtypes, of breast cancer, each with its own biology, prognosis, and response to treatment.
These 4 types, called intrinsic subtypes of breast cancer, are HER2-enriched (HER2E), luminal A, luminal B, and basal-like. A fifth type, called Normal-type, appeared in only 8 patients, too few to provide meaningful data. HER2E, luminal A, and luminal B tumors are HER2-positive, whereas basal-like cancers are not.
The luminal subtypes had both the lowest overall mutation rate and the highest number of genes with significant mutations, suggesting that each significantly mutated gene is more likely to promote cancer progression and therefore may be an important target for therapy. The highest number of significantly mutated genes was found in the luminal A subtype. By contrast, mutations of a single gene, TP53, occurred in 80% of basal-like cancers. The HER2E subtype showed a high frequency of TP53 and PIK3CA mutations and a much lower frequency of other gene mutations. Whereas luminal tumors had primarily missense mutations (which result in codons that code for a different amino acid) of TP53, mutations in basal-like tumors were mostly nonsense (codons coding for a nonfunctional protein) and frame-shift (insertion or deletion of nucleotides into a DNA sequence).
Nearly all genes with significant mutations previously implicated in breast cancer were identified in this study, as well as at least 10 new ones. Several of these mutations are also seen in other cancers, including acute myeloid leukemia, glioma, endometrial cancer, myelodysplastic syndromes, chronic lymphocytic leukemia, and lung adenocarcinoma.
The most unexpected finding from the Cancer Genome Atlas study is that basal-like subgroup tumors share numerous genetic features with high-grade serous ovarian cancer, which is highly resistant to treatment. The 2 cancers appear to be of similar molecular origin, suggesting that they may respond to the same chemotherapeutic agents. For example, both might respond to angiogenesis inhibitors or compounds such as cisplatin that target DNA repair.
The basal-like subgroup has also been called triple-negative breast cancer because many cancers in this subgroup lack estrogen, progesterone, and HER2 receptors and therefore do not respond to treatments that target these receptors.
The high frequency of PIK3CA mutations in luminal/ER+ cancers suggests that agents that inhibit this activated kinase or its signaling pathway might be effective for this form of breast cancer. Numerous mutations in HER2+ cancers also appeared to be likely targets of drug therapy.
The Cancer Genome Atlas Network study will be the subject of an upcoming feature article on ChemotherapyAdvisor.com.
Readers, we want to hear from you!
- What do you consider the most important finding from the Cancer Genome Atlas Network study?
- Do you think that the Cancer Genome Atlas Network study will have a significant impact on the treatment of breast cancer within the next 5 years?