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JAMA Network | JAMA | Genetic Studies Provide New Insights Into Breast Cancer Biology and Treatment

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JAMA Network | JAMA | Genetic Studies Provide New Insights Into Breast Cancer Biology and Treatment

Medical News and Perspectives |

Genetic Studies Provide New Insights Into Breast Cancer Biology and Treatment FREE

Tracy Hampton, PhD

JAMA. 2013;309(5):427-429. doi:10.1001/jama.2012.196394.

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Knowing that genetic alterations lie at the heart of cancer development and progression, researchers in the breast cancer field have been successfully using genetics to determine risk, make cancer diagnoses, characterize tumors, predict prognoses, and tailor treatment. Some of the latest findings were presented at the recent2012 CTRC-AACR (Cancer Therapy and Research Center–American Association for Cancer Research) San Antonio Breast Cancer Symposium.

Assessing epigenetic changes (alterations in gene expression that do not involve changes in DNA sequence), such as the addition of methyl groups to DNA, may aid in the accurate diagnosis and monitoring of patients with metastatic breast cancer, according to researchers at the Johns Hopkins University School of Medicine in Baltimore.

Image not available.

Assessing methyl groups attached to DNA (which affect gene expression) may aid in the accurate diagnosis and monitoring of patients with metastatic breast cancer.

After developing a polymerase chain reaction (PCR) test that directly measures the number of copies of methylated DNA markers in a small amount of blood, the investigators conducted a genome-wide “methylome” analysis to identify key markers that are preferentially methylated in serum from women with breast cancer.

When they used this newly developed panel of markers and the PCR test to analyze blood from 43 women with metastatic breast cancer and 55 women without disease, they detected methylation markers in sera of 39 of 43 patients with metastatic breast cancer with varying tumor burdens (91% sensitive); no methylation markers were found in sera of any of the 55 women without cancer (100% specific).

Among the 43 cancer patients in the study, 28 had sampling repeated 3 to 5 weeks after initiating therapy. Blood from those whose tumors regressed and from those who had stable disease showed a quantitative reduction in methylation, while those with progressive disease showed an increase in methylation levels of several genes.

In addition to suggesting that certain methylated DNA markers in the blood accurately discriminate between women with metastatic breast cancer and those without disease, the findings indicate that early changes in methylation after therapy for metastatic disease may correlate with subsequent clinical outcome.

Another study looked at how epigenetic silencing of tumor suppressor genes by methylation contributes to tumor metastasis. The PRKD1 gene, which encodes a protein expressed in epithelial cells of the normal mammary gland (protein kinase D1, or PKD1), is a critical suppressor of tumor cell invasion and is silenced during breast tumor progression.

Researchers found that aberrant methylation of the PRKD1 gene (specifically in the promoter, a region that initiates transcription of the gene) correlates with the silencing of the gene's expression and is associated with invasiveness of breast cancer cell lines as well as aggressiveness of in vivo breast tumors. Inhibiting PRKD1 promoter methylation with a drug called decitabine restored PKD1 expression in cancer cells and significantly decreased the cells' invasive abilities in vitro. In an animal model, decitabine blocked tumor spread and metastasis to the lung through the effects of PKD1.

The results suggest that epigenetic regulation of the PRKD1 promoter can reveal information about the invasiveness of breast tumors, and increasing PKD1 expression may be used as a therapeutic approach to reverse the invasiveness of breast cancer cells.

When patients with estrogen-, progesterone-, and HER2 receptor–negative (triple-negative) breast cancer are treated with chemotherapy before undergoing surgery, tumor cells that survive treatment show a variety of gene mutations, reported researchers who profiled residual tumor tissue from 102 patients with this particularly aggressive tumor type.

“Patients who have residual disease . . . after neoadjuvant chemotherapy have much worse outcomes, and it's unknown how to effectively treat these patients,” said Justin Balko, PharmD, PhD, of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn. “We hypothesized that molecular analysis of the residual disease would identify genetic alterations that are ultimately responsible for disease recurrence. We could potentially target these alterations using clinically available medications.”

In 81 evaluable tumors, the investigators used sequencing technology to examine 182 oncogenes and tumor suppressor genes known to be mutated in human cancers. They found that a diverse number of genes were altered.

Although this information reveals added complexity of triple-negative breast cancer, 90% of patients had alterations in at least 1 of the following: the phosphatidylinositol 3 kinase pathway, the DNA repair pathway, the Ras/MAP kinase pathway, the cell cycle pathway, and growth factor receptor amplification.

“These data provide a targetable catalog of alterations present in residual disease of triple-negative breast cancer after neoadjuvant chemotherapy, and we believe that they support genomically driven adjuvant trials in this patient population,” said Balko.

Other researchers, after discovering that triple-negative tumors frequently express high levels of the MYC proto-oncogene, sought to identify new so-called synthetic-lethal strategies to selectively kill triple-negative breast tumors with MYC protein overexpression. Synthetic lethality occurs when a combination of mutations in 2 or more genes leads to cell death, whereas a mutation in only 1 of the genes has little effect. Alternatively, it may occur when a specific oncogene signaling pathway is activated in combination with inactivation of a different pathway.

“Using this strategy, we can take advantage of the elevated MYC signaling in triple-negative tumors to selectively kill them, while sparing normal tissues in which MYC is expressed at much lower levels,” said Andrei Goga, MD, PhD, of the University of California, San Francisco.

Goga's team screened human mammary epithelial cells that have inducible MYC overexpression, finding 13 kinases whose inhibition blocked cell growth by more than 50%. Two of these, ARK5 and GSK3A, have been shown by others to have a synthetic-lethal interaction with MYC (Liu L et al. Nature. 2012;483[7391]:608-612; Rottman S et al. Proc Natl Acad Sci U S A. 2005;102[42]:15195-15200).

The investigators are currently characterizing and validating the 11 novel targets identified in their screen and are using human cancer cell lines and mouse cancer models to determine the effect of inhibiting these targets on triple-negative breast cancer development and proliferation. An earlier study by the group revealed that cyclin-dependent kinase 1 inhibitors can selectively kill triple-negative breast cancers with elevated MYC expression (Horiuchi D et al. J Exp Med. 2012;209[4]:679-696.)

Another study found that a treatment that inhibits DNA repair in cancer cells may be effective against triple-negative breast cancer. Investigators at the University of Kansas Cancer Center in Kansas City discovered that exposure of triple-negative breast cancer cells to a histone deacetylase (HDAC) inhibitor—which helps modulate the coiling and uncoiling of DNA around histone proteins—indirectly impaired the cells' ability to repair damaged DNA. It also sensitized the cancer cells to treatment with a poly (ADP-ribose) polymerase (PARP) inhibitor and cisplatin.

The HDAC inhibitor did so by blocking expression of a heat shock protein that chaperones other proteins (such as BRCA1) involved in DNA repair. By impeding this DNA repair response, HDAC inhibition created an environment within cells that was similar to that seen in breast cancer cells with BRCA1 mutations.

“In simple terms, we are trying to cause a ‘BRCAness’—so that you confer on triple-negative breast cancer cells the sensitivity to PARP inhibitors or platinum therapy seen when BRCA1 mutations are present,” said Kapil Bhalla, MD, who is chief of personalized cancer medicine at the University of Kansas Cancer Center.

In addition to inhibiting the DNA damage response through depletion of DNA repair proteins, the HDAC inhibitor also induced DNA damage. Combined treatment with an HDAC inhibitor (either vorinostat or panobinostat) and the PARP inhibitor ABT888 killed triple-negative breast cancer cells with or without BRCA1 mutations. Vorinostat treatment made the cancer cells more susceptible to treatment with cisplatin as well.

“These studies support the rationale to test the efficacy of an in vivo treatment regimen that includes a PARP inhibitor combined with an HDAC inhibitor and cisplatin against triple-negative breast cancer,” said Bhalla.

Another group provided new information on the role of the HER2/ERBB2 gene in some breast cancers. Typically, patients with breast cancers that have HER2 gene amplifications (which cause overexpression of the HER2 protein) are considered candidates for HER2-targeted drugs. This latest work indicates that patients whose cancers harbor various other HER2 gene alterations may also benefit from such therapies.

After reviewing data from 8 genome sequencing studies that included approximately 1500 patients, the investigators found that 25 of the patients had tumors with HER2 mutations, nearly all of which did not have HER2 gene amplifications. The majority of these mutations drove breast cancer cell growth in tissue culture (by causing excessive HER2 activity) and were sensitive to lapatinib and trastuzumab; all were sensitive to neratinib, which is currently under development. The findings were published to coincide with the symposium (Bose R et al. Cancer Discov. doi: 10.1158/2159-8290.CD-12-0349 [published online December 7, 2012]).

“Patients with these mutations will be missed by current HER2 testing. Gene sequencing is required to identify these mutations,” said Ron Bose, MD, PhD, of the Washington University School of Medicine and the Siteman Cancer Center in St Louis. Therefore, patients with HER2 mutations currently would not qualify to receive drugs that target HER2.

If a multicenter, phase 2 clinical trial testing neratinib in patients with HER2 mutations in their breast cancer cells is successful, an estimated 4000 US women per year could benefit, Bose said. “Worldwide, that number could be 5 times as large,” he said.

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