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Mar 23, 2012

Telomeric Allelic Instability Predicts Triple Negative Breast Cancer Response to Chemotherapy

  • Scientists say that evaluating breast and ovarian tumors for allelic imbalance that extends to the telomeres (NtAI) can help predict sensitivity to platinum anticancer agents such as cisplatin. A Dana-Farber Cancer Institute-led team has found that high levels of NtAI effectively represents a marker of a DNA repair dysfunction, irrespective of BRCA mutations. In other words, the tumor is less capable of repairing double-stranded DNA breaks resulting from chemotherapy, making the cancer more likely to respond to treatment.

    Reporting in Cancer Discovery, Andrea L. Richardson, M.D., and colleagues suggest their findings could lead to the development of a test for identifying patients whose tumors may respond to just one platinum-based treatment, avoiding the need to employ more toxic combinations of chemotherapy. Their paper is titled “Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA damaging agents.”

    Cancer cells with intact DNA repair mechanisms can avoid the accumulation of genome damage as the tumor grows, and can also repair DNA damage induced by certain chemotherapy agents. Ovarian and breast cancers carrying BRCA1 or BRCA2 mutations, for example, are more likely to be sensitive to platinum-based chemotherapy than wild-type BRCA gene tumors because the mutations disrupt DNA repair mechanisms. Sporadic triple-negative breast cancers (TNBC) characterized by lack of both estrogen and progesterone receptor expression and lack of Her2 amplification share characteristics with germline BRCA1-mutated breast cancers, including a common pattern of genomic abnormalities, and high levels of chromosomal abnormalities including allelic imbalance (AI). This is effectively the loss of one parental copy of the DNA in various regions of the chromosome.

    The Dana-Farber team postulated that the high level of allelic imbalance demonstrated by BRCA1-related cancers and sporadic TNBCs could mean that the latter type of tumor may also be sensitive to platinum-based chemotherapy. To test this, two clinical trials have previously been carried out by Dana-Farber researchers to evaluate cisplatin monotherapy or cisplatin combined with the angiogenesis inhibitor bevacizumab in patients with operable sporadic TNBC, prior to their surgery. The combined data from both these studies showed that cisplatin therapy led to nearly 40% of patients achieving greater than 90% tumor reductions, and in some cases patients demonstrated a pathologic complete response (pCR). In both studies pCR was achieved in patients both with and without germline BRCA1 or BRCA2 mutations.

    Dr. Richardson et al have now analyzed pretreatment tumor biopsies from patients in the two cisplatin studies to determine whether treatment response was associated with the presence of subchromosomal abnormalities, and in particular AI. Their decision to focus on AI specifically was made following studies in cancer cell lines, which indicated that the most accurate predictor of sensitivity to cisplatin was in fact NtAI.

    What they found from their tumor biopsy analyses was that in both the cisplatin-1 and cisplatin-2 studies, sensitivity to chemotherapy correlated significantly with high levels of NtAI, irrespective of BRCA1 and BRCA2 mutations. Encouragingly, the same association between NtAI and chemotherapy sensitivity was subsequently also found in The Cancer Genome Atlas (TCGA) cohort of serous ovarian cancer patients that had received adjuvant platinum and taxane chemotherapy.  In this cohort, the sensitivity of wild-type BRCA1 and BRCA2 ovarian cancers was again linked with a significantly higher NtAI than found in the platinum-resistant tumors.

    Interestingly, the distribution of DNA breaks causing telomeric allelic imbalance didn’t appear to be random, as many were located in close proximity to each other, the team notes. In the Cisplatin-1 and Cisplatin-2 biopsies, 49-57% of NtAI breakpoints were associated with copy number variants. This finding indicated that stalled replication forks, replication stress, or other CNV-associated mechanisms may be involved in NtAI.

    The researchers say their results suggest that evaluating NtAI may be a useful predictor of tumor response to platinum therapy. “We currently don’t have any targeted therapies for patients with TNBC, so if these laboratory findings are confirmed and an assay is created to predict sensitivity to drugs that target defective DNA repair, it would be a major step forward," Dr. Richardson states.

    The researchers say such an assay is feasible using formalin fixed paraffin embedded tumor samples, and algorithms such as ASCAT, which enable the accurate determination of copy number and allelic imbalance even in samples with low tumor cell count.  


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