The risk for developing a secondary malignancy after chemotherapy for breast cancer is very small, but it is statistically significantly higher than for the general population, a review of the National Comprehensive Cancer Network (NCCN) database revealed in a study presented at the 2012 San Antonio Breast Cancer Symposium.1
Increase over Earlier Data
Ten years after treatment for early breast cancer, approximately 0.5% of women developed leukemia. While this risk is small, it represents a twofold increase over earlier data from studies evaluating the risk of chemotherapy-induced malignancies, according to Antonio C. Wolff, MD, FACP, Professor of Oncology at the Johns Hopkins Kimmel Cancer Center, Baltimore.
“Adjuvant chemotherapy was associated with a cumulative 10-year incidence of leukemia of about 0.5%, which appears to be higher than previously reported,” Dr. Wolff said.
For years, there has been concern that chemotherapy may induce second cancers. A report from the National Surgical Adjuvant Breast and Bowel Project (NSABP) some 10 years ago found a 0.27% risk of myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML) occurring 8 years after treatment with doxorubicin/cyclophosphamide.2 Patients who received radiotherapy or growth factors were at highest risk. In NSABP B-38, reported at the 2012 ASCO Annual Meeting, a 0.49% risk for MDS and AML was found 5 years after treatment for breast cancer that included growth factors.3
To further ascertain the true risk of secondary malignancies, Dr. Wolff and colleagues analyzed prospectively collected data from 20,533 patients with breast cancer (without a prior cancer history) followed for a median of 5.1 years. Patients with stage I to III breast cancers were treated between 1997 and 2008 at eight cancer centers.
Information included patient demographics, tumor stage and phenotype, type of treatment, and patient outcomes. Data were not collected, however, on family history of cancer, use of growth factors, dose of chemotherapy, dose of radiation, or clinical characteristics and treatment related to subsequent cancer diagnoses. Women who developed a recurrence were excluded from the analysis.
51 Hematologic Cancers Diagnosed
The inestigators discovered 51 cases of leukemia among the 20,533 patients, including 44 cases of myeloid leukemia and 7 cases of lymphoid leukemia. “Leukemia risk was not limited to MDS and AML, and cases of high-risk lymphoid leukemia were observed,” he said.
Since the hazard ratios for the two types were similar, data from myeloid and lymphoid leukemia were combined in the analysis. Patients who developed leukemia differed from the noncancer group only in terms of age, with the average leukemia patients aged 60 years vs 54 years for those without leukemia (P = .02).
The systemic chemotherapy they received was largely four or six cycles of anthracycline and/or alkylating agent, with or without a taxane. “This was, for the most part, just four cycles of anthracycline and cyclophosphamide,” he emphasized. “The docetaxel/cyclophosphamide regimen was not well represented, and therefore its leukemia risk remains unknown.”
In the adjusted model, the hazard ratios for the risk of leukemia were 1.29 for radiation vs no radiation, which was not significant (P = .461); 2.51 for any chemotherapy vs not (P = .007); and 1.59 for chemotherapy plus radiation vs a single modality (P = .127).
Stratified Analysis
In a stratified analysis that included women receiving only surgery, there was a trend toward increased risk with radiotherapy only (hazard ratio [HR] = 2.73; P = .194), chemotherapy only (HR = 5.68; P = .037), and chemotherapy plus radiation (HR = 5.64; P = .028). The risk with the combined modality was not significantly higher than was seen with chemotherapy alone, Dr. Wolff reported.
“Radiation alone appears to be a risk factor but may not add much [risk] to patients already treated with chemotherapy,” he concluded.
The analysis yielded rates of leukemia per 1,000 patient-years of 0.46 for the whole cohort, 0.16 for surgery alone, 0.43 for radiation alone, 0.52 for chemotherapy alone, and 0.54 for chemotherapy plus radiation. The cumulative incidence for all patients was 0.25% at 5 years and 0.46% at 10 years, and for the chemotherapy/radiotherapy cohort was 0.32% and 0.51%, respectively.
While he did not report the baseline risk observed in women of similar age without breast cancer, Dr. Wolff noted that the surgery cohort was the best control group to assess the therapy risk in this data set. “Chemotherapy increased the risk,” he said, “but there are challenges in comparing this with risk in patients without cancer because other factors could be in play, like family history and possible associations with mutations in the ATM and BRCA2 genes.” He further noted that since MDS was underreported until fairly recently, the overall leukemia frequency after breast cancer treatment likely is frequently underrepresented in the findings.
Time to Event and 10-year Incidence
Interestingly, while the general belief is that leukemia develops within 5 years of chemotherapy, almost half of the events occurred beyond this time, Dr. Wolff noted. Median time to an event was 3.3 years overall. Within the myeloid group, median time was 4.9 years for patients with adverse MDS-like leukemia often seen after alkylating agents, extending to 8 years in some, and was 1.9 years for those with translocations associated with anthracycline exposure. For the lymphoid group, median time to the event was 2.3 years for chronic lymphocytic leukemia and 1.9 years for acute lymphoblastic leukemia.
Dr. Wolff pointed out that the latency time after exposure to anthracyclines is 1 to 3 years but is much longer for cyclophosphamide. “Patients exposed to cyclophosphamide could be at risk at 10 years or more,” he said.
Regarding the issue of overtreatment, he added, “many times we have been in the unfortunate situation where we make decisions about giving chemotherapy ‘just in case,’” he said. “We need to be very careful, because some of those patients will derive none of the benefit of chemotherapy but all of the harm.” ■
Disclosure: Dr. Wolff reported no potential conflicts of interest.
References
1. Karp JE, Blackford A, Visvanathan K, et al: Myelodysplastic syndrome and/or acute myelogenous leukemia after a breast cancer diagnosis: The National Comprehensive Cancer Network experience. 2012 San Antonio Breast Cancer Symposium. Abstract S3-5. Presented December 6, 2012.
2. André Baruchel, MD et al: Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: The National Surgical Adjuvant Breast and Bowel Project Experience. J Clin Oncol 11:1195-1204, 2003.
3. Swain SM, Tang G, Geyer CE, et al: NSABP B-38: Definitive analysis of a randomized adjuvant trial comparing dose-dense AC→ paclitaxel plus gemcitabine with DD AC→P and with docetaxel, doxorubicin, and cyclophosphamide (TAC) in women with operable, node-positive breast cancer. 2012 ASCO Annual Meeting. Abstract LBA1000. Presented June 5, 2012.
