In a study reported in the Journal of Clinical Oncology, Antonio C. Wolff, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, and colleagues found a low but higher-than-expected incidence of marrow neoplasms in patients receiving adjuvant radiation therapy or chemotherapy for breast cancer.¹

The study used the National Comprehensive Cancer Network Breast Cancer Outcomes Database to evaluate the frequency of marrow neoplasms among 20,063 patients with stage I to III breast cancer treated at U.S. academic centers between 1998 and 2007.

Neoplasms Identified

Overall, 50 patients developed marrow neoplasms over a median follow-up of 5.1 years, including 42 with myeloid neoplasms and 8 with lymphoid neoplasms, for a 10-year cumulative incidence of 0.48%. Myeloid disorders consisted of acute myelogenous leukemia (AML) in 24 patients, myelodysplastic syndrome (MDS)/AML in 15, and chronic myelogenous leukemia in 3; lymphoid disorders consisted of acute lymphocytic leukemia (ALL) in 3, chronic lymphocytic leukemia in 4, and small lymphocytic lymphoma in 1. Among the 50 patients, 2 received surgery alone, 12 received adjuvant radiation therapy alone, 8 received adjuvant chemotherapy alone, and 28 received adjuvant radiation therapy and chemotherapy.

Patient Characteristics and Survival

Patients developing marrow neoplasms were significantly older than those who did not at the time of breast cancer diagnosis (median = 59.1 vs 53.9 years, P = .03). There were no differences between groups in race, disease stage, tumor characteristics, or adjuvant treatment received.

Among all patients in the cohort, 10-year overall survival was 80% (88% for stage I, 74% for stages II and III). In patients developing marrow neoplasms, overall survival was 62% at 5 years and 9% at 10 years. The median time to diagnosis of marrow neoplasms after breast cancer diagnosis was 4.9 years. Overall survival after diagnosis of marrow neoplasms was 50% at 1 year and 30% at 2 years.

Risk and Rates

Compared with the risk of marrow neoplasms in patients undergoing surgery alone, the risk was nonsignificantly increased in patients receiving adjuvant radiation therapy (hazard ratio [HR] = 2.6, P = .21) and significantly increased in those receiving adjuvant chemotherapy (HR = 6.8, P = .03) and those receiving adjuvant radiation and chemotherapy (HR = 7.6, P = .01). The risk was not significantly increased for patients receiving vs not receiving taxane therapy (HR = 1.46, P = .27).

After 109,560 person-years of follow-up, the overall rate of marrow neoplasms in the entire cohort was 0.46 per 1,000 person-years, with rates per 1,000 person-years of 0.16 in those receiving surgery alone, 0.43 in those receiving adjuvant radiation alone, 0.46 in those receiving adjuvant chemotherapy alone, and 0.54 in those receiving both adjuvant treatments. The cumulative incidence of marrow neoplasms exhibited a continuous increase, with a cumulative incidence of 0.24% after 5 years and 0.48% after 10 years.

Compared with the expected incidence of marrow neoplasms based on Surveillance, Epidemiology, and End Results (SEER) data on breast cancer patients, the observed-to-expected ratio in the study cohort was significantly increased for the whole cohort (3.6, P < .001), patients receiving adjuvant radiation only (3.4, P < .001), those receiving adjuvant chemotherapy only (3.6, P = .005), and those receiving both radiation and chemotherapy (4.2, P < .001); there was no significant increase among those receiving surgery only (1.3, P = .17).

As noted by the authors, a 2003 report from the National Surgical Adjuvant Breast and Bowel Project indicated an 8-year cumulative incidence of MDS or AML of 0.27% among breast cancer patients receiving doxorubicin and cyclophosphamide.

Family History and Marrow Cytogenetics

Family history of cancer and marrow cytogenetics were available for 41 of the patients with marrow neoplasms. Of them, 26 (63%) had abnormal cytogenetics, including 24 (67%) of 36 with myeloid disorders and 2 (40%) of 5 with lymphoid disorders. Abnormal cytogenetics were found in 19 (70%) of 27 patients who had received adjuvant chemotherapy and 7 (50%) of 14 who did not receive adjuvant chemotherapy. Each of these 7 had myeloid neoplasms, with 3 having abnormalities associated with MDS.

A family history of at least one cancer in a first- or second-degree relative was present for 32 patients (78%); 19 (59%) of the 32 patients with a family history of cancer had at least one first- or second-degree relative with breast or ovarian cancer. Among the 36 patients with myeloid neoplasms, a family history of cancer was present for 28 (78%), with 10 having MDS-related abnormalities; of these 10, 8 had a family history of breast or ovarian cancer and 6 had complex cytogenetics.

Of 11 patients with MDS-related cytogenetics, 10 had a family history of cancer. The 21 patients who received adjuvant chemotherapy and had a family history of cancer included 6 of 7 total patients with MLL translocations (4 with AML, 2 with ALL).

The investigators concluded: “In this large early-stage breast cancer cohort, [marrow neoplasm] risk after radiation and/or adjuvant chemotherapy was low but higher than previously described. Risk continued to increase beyond 5 years. Individual risk of [marrow neoplasm] must be balanced against the absolute survival benefit of adjuvant chemotherapy.” ■

Disclosure: The study was supported by grants from the National Cancer Institute and Susan G. Komen for the Cure. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference

1. Wolff AC, Blackford AL, Visvanathan K, et al: Risk of marrow neoplasms after adjuvant breast cancer therapy: The National Comprehensive Cancer Network experience. J Clin Oncol 33:340-348, 2015.

Elizabeth A. Comen, MD, and Andrew D. Seidman, MD, of Memorial Sloan Kettering Cancer Center in New York, present a risk/benefit analysis and offer biologic insights into the increased risk of marrow neoplasms after adjuvant therapy for breast cancer.