Inherited mutations common in therapy-related leukemia

By Will Boggs MD

Survivors of breast cancer who develop therapy-related leukemia (TRL) commonly have inherited mutations in cancer susceptibility genes, researchers have found.

While TRL is thought to result from mutational events caused by prior cytotoxic exposures, the exact mechanisms and risk factors remain unclear. Some TRLs may, in fact, be second primary cancers unrelated to prior cytotoxic exposures.

Dr. Jane E. Churpek from the University of Chicago and colleagues used the university's TRL registry to examine the clinical and TRL characteristics of 88 survivors of breast cancer with TRL, 47 of whom had DNA available.

Nineteen patients (22%) had an additional primary cancer diagnosis, and 40 patients (57%) reported at least one first-degree or second-degree relative with breast, ovarian, or pancreatic cancer. About three-quarters of the women (78%) had received chemotherapy as part of their treatment.

Ten survivors with DNA available who developed TRL (21%) carried a deleterious inherited mutation, including three (6%) with BRCA1, three (6%) with TP53, two (4%) with BRCA2, and one each (2%) with CHEK2 and PALB2 mutations.

All three patients with TP53 mutations developed TRL, including two patients who developed therapy-related acute lymphoblastic leukemia (t-ALL), the researchers report in Cancer, online December 7.

Patients with BRCA1 or BRCA2 mutations had much longer latency to development of TRL (median, 133 months) than those without an inherited mutation (median, 53 months).

Eight of nine patients with leukemia samples available had somatic mutations distributed among 17 genes, most commonly in FLT3, TET2, ASXL1, NRAS, and WT1.

"The data from the current study support a role for inherited cancer susceptibility in TRL after breast cancer," the researchers conclude. "The data from the current study suggest that a long-term prospective trial following similarly treated women with BC for whom germline mutation status is known for the development of TRL as well as functional testing of the role of these genes in bone marrow dysfunction after cytotoxic exposures are warranted."

"Currently, and as exemplified in the most recent National Comprehensive Cancer Network guideline (v1.2015), germline testing is viewed as informative for patient management with regard to decisions concerning preventive options such as prophylactic surgeries and for immediate relatives as part of genetic counseling," write Dr. Judith E. Karp and Dr. Antonio C. Wolff from Johns Hopkins University School of Medicine in Baltimore, Maryland, in an accompanying editorial. "However, we can envision a time when genetic testing might also be used to guide systemic therapy decisions."

"In the interim, we expect that the ongoing discovery of germline mutations in additional genes affecting DNA repair pathways and TRL susceptibility may further refine our understanding of TRL pathogenesis and risk," they note.

Dr. Giuseppe Leone from Universita Cattolica S. Cuore in Rome, who was not involved in the new work, recently summarized the outcomes of 277 patients with therapy-related myeloid neoplasms. He told Reuters Health by email that previous studies have "focused on the type of drug inducing the leukemia and not the primary tumor. It is a merit of this research to have applied this approach to so large a number of patients with therapy-related leukemia following breast cancer."

"Physicians should be aware of the possibility of therapy-related leukemia after chemoradiotherapy, in particular in breast cancer," Dr. Leone said. "Family history positive for cancer is very important."

"The authors do not suggest a preemptive screening of all patients with breast cancer submitted to chemo-radiotherapy," he added. "That should be expensive and at present data are scarce to impose such an approach. However, a search for mutations for BCRA1 and BCRA2 should be performed in all patients with a positive family history of gynecological cancers."


Cancer 2015.

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