Ever since the early application of adjuvant chemotherapy for breast cancer decades ago, it has been recognized that there is always a price to pay for its success in reducing breast cancer mortality. Most of that “cost” is commonly considered in terms of the potential morbid short- and long-term consequences: alopecia, nausea, infection, neuropathy, cardiomyopathy, fatigue, early ovarian failure, and cognitive dysfunction, to name just a few. Serial incremental improvements in adjuvant chemotherapy regimens have been associated with increased proportional and absolute gains in breast cancer–specific survival.1
A recent analysis by Wolff and colleagues of the risk of marrow neoplasms in a large contemporary series of adjuvant breast cancer cases—reviewed in this issue of The ASCO Post—asks us to take a close look at the commonly fatal complication of breast cancer chemotherapy, namely, secondary myelodysplasia and leukemia.2
Assessing the Risk of Marrow Neoplasms
Among 20,063 patients treated in 8 National Comprehensive Cancer Network Centers from 1998 to 2007, 50 cases of marrow neoplasms were reported (0.25%, or 1 of 400 patients), with a median of 5.1 years of follow-up. This figure is similar to the 0.27% 8-year risk associated with doxorubicin and cyclophosphamide reported over a decade ago by the National Surgical Adjuvant Breast and Bowel Project.3 The risk of marrow neoplasms over years 6 to 10 was similar to that over the first 5 years, and the use of a taxane was not associated with an increased risk.
Abnormal cytogenetics was noted in 19 of 27 patients (70%) who had marrow neoplasms and received chemotherapy vs 7 of 14 of those (50%) with marrow neoplasms who did not receive chemotherapy. Radiotherapy without chemotherapy was not clearly a risk factor (hazard ratio = 2.6, 95% confidence interval = 0.57–11.9), nor did its use in addition to chemotherapy seem to be a significant risk modifier.
Given the significantly large absolute survival benefit of adjuvant chemotherapy for most patients with axillary lymph node–positive breast cancer, particularly those with hormone–receptor negative and/or HER2-positive tumors, and for many node-negative patients, the 0.25% risk of marrow neoplasms, although unfortunate, still seems acceptable. For patients with lower-risk breast cancers, where both the physician and patient may be “on the fence” regarding the use of cytotoxic chemotherapy (for example, the T1b/c, estrogen receptor–positive, progesterone receptor–positive, HER2-negative, node-negative breast cancer with an intermediate Oncotype DX recurrence score), this risk becomes a more relevant factor in the decision-making process. Such patients may be best served by extended adjuvant endocrine regimens, for example, as opposed to the addition of chemotherapy.4,5
A discussion of this risk is essential to full informed consent for adjuvant chemotherapy administration and should be couched in the context of the larger looming risk: that of recurrent metastatic breast cancer. Marrow neoplasms notwithstanding, the risk of death from recurrent metastatic breast cancer still remains the overwhelming driver of cancer mortality.
It is unlikely that the use of topoisomerase II inhibitors and alkylating agent–containing adjuvant chemotherapy regimens will disappear anytime soon. Despite the use of the anthracycline-free adjuvant regimen of docetaxel plus cyclophosphamide, the impact of omitting the anthracycline as compared with regimens containing an anthracycline, taxane, and cyclophosphamide has not yet been defined.
In the recently reported CALGB 40101 (Alliance) randomized adjuvant trial of paclitaxel vs doxorubicin and cyclophosphamide (n = 3,871), paclitaxel was not noninferior to cyclophosphamide and doxorubicin (5-year relapse-free survival 91% vs 88%, overall survival 95% vs 94%) among patients with zero to three positive axillary nodes. Notably, however, the death rate from leukemia was 0.36% for cyclophosphamide and doxorubicin (seven cases) vs 0% for paclitaxel.6 The thoughtful application of a cyclophosphamide and anthracycline-free adjuvant regimen, such as weekly paclitaxel and trastuzumab (Herceptin),7 in an appropriately selected lower-risk population is one example of a regimen with less potential for marrow neoplasms.
Leukemogenic Mutations
In the study by Wolff et al, the patients who developed marrow neoplasms were on average older than patients who did not (median age, 59.1 vs 53.9 years, P = .03). Several recent studies have suggested that in otherwise healthy volunteers, morphologically normal hematopoietic cells may harbor mutations in genes associated with leukemia.8-10 The rate of mutations increases with age; specifically, Xie et al9 demonstrated that 2% of the overall population and as many as 6% of individuals older than 70 years harbor mutations associated with clonal hematopoietic expansion.
Furthermore, Jaiswal et al10 showed that age-related clonal hematopoiesis is associated with an increased risk of leukemia. In addition to oncogenic mutations in circulating hematopoietic cells, tumor-infiltrating leukocytes may also possess leukemogenic mutations. In a pilot study of 20 primary breast cancers, 8 possessed tumor-infiltrating leukocytes with oncogenic somatic mutations.11 These leukemogenic mutations were not present in breast cancer cells themselves and were found in patients regardless of age.
In most clinical scenarios in which chemotherapy is warranted, a 0.25% risk of marrow neoplasms seems particularly small relative to survival gains. Yet this risk remains a frightening possibility for patients and continues to drive efforts to refine how we select patients for chemotherapy. An important next step will be to identify whether patients with leukemogenic mutations in tumor-infiltrating and/or tumor-circulating leukocytes are at increased risk for future leukemias. Studies are underway to assess whether chemotherapy selects for preexisting mutated clones as well as whether the presence of aberrant leukocytes merits therapeutic intervention. ■
Disclosure: Drs. Comen and Seidman reported no potential conflicts of interest.
References
1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Peto R, Davies C, Godwin J, et al: Comparisons between different polychemotherapy regimens for early breast cancer: Meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 379:432-444, 2012.
2. 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.
3. Smith RE, Bryant J, DeCillis A, 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 21:1195-1204, 2003.
4. Davies C, Pan H, Godwin J, et al: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 381:805-816, 2013.
5. Goss PE, Ingle JN, Martino S, et al: Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: Updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97:1262-1271, 2005.
6. Shulman LN, Berry DA, Cirrincione CT, et al: Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol 32:2311-2317, 2014.
7. Tolaney SM, Barry WT, Dang CT, et al: Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 372:134-141, 2015.
8. Busque L, Patel JP, Figueroa ME, et al: Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet 11:1179-1181, 2012.
9. Xie M, Lu C, Wang J, et al: Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 20:1472-1478, 2014.
10. Jaiswal S, Fontanillas P, Flannick J, et al: Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371:2488-2498, 2014.
11. Comen EA, Kleppe M, Wen H, et al: Somatic leukemogenic mutations associated with infiltrating white blood cells in breast cancer patients. 2014 San Antonio Breast Cancer Symposium. Abstract PD1-4.
Drs. Comen and Seidman are medical oncologists at Memorial Sloan Kettering Cancer Center in New York.
