Compared with first-generation regimens such as CMF (cyclophosphamide, methotrexate, and 5-fluorouracil), treatment with anthracyclines has been associated with a significant reduction in breast cancer–related mortality and overall mortality (Early Breast Cancer Trialists’ Collaborative Group 2012). However, anthracycline use increases the risk of congestive heart failure in a dose-dependent fashion (Bristow et al. 1981). The risk of anthracycline-related cardiomyopathy increases with age, combination with trastuzumab, and combination with mediastinal radiation therapy (Pinder et al. 2007).

In contrast with anthracycline-related cardiomyopathy, trastuzumab-related cardiotoxicity is often reversible with treatment discontinuation and is not dose-dependent (Keefe 2002). Most often, trastuzumab-related cardiomyopathy is detected by echocardiogram or multigated acquisition scan and is not clinically apparent at the time of diagnosis. Monitoring for cardiac complications from each regimen requires a multidisciplinary approach, with input from each patient’s primary care physician, oncologist, and cardiologist.

Review of cross-sectional cognitive outcome studies reveals that the prevalence of chemotherapy-associated cognitive decline ranges from 17% to 75% (Correa and Ahles 2008). Prospective studies of breast cancer survivors undergoing chemotherapy have generated conflicting results, with some studies noting a significant decline in cognitive function and others finding no difference compared with baseline (Wefel et al. 2004b; Shilling et al. 2005; Bender et al. 2006; Hurria et al. 2006; Jenkins et al. 2006; Stewart et al. 2008; Quesnel et al. 2009). However, the patient’s self-perceived cognitive dysfunction is integrally linked to increased psychological distress (Wefel et al. 2004a). Boykoff et al. (2009) published compelling qualitative evidence of the negative effects of “chemobrain” on the economic, emotional, and interpersonal aspects of breast cancer survivors’ lives. Furthermore, a recent prospective study of 101 patients with breast cancer noted that self-perceived cognitive dysfunction was significantly related to negative affectivity (p = .015) and depression (p < .001; Hermelink et al. 2010). Thus, even in the setting of cancer “cure” following chemotherapy, breast cancer survivors continue to face the critical barrier of worsened cognition and its downstream emotional distress in their daily lives.

The risk of chemotherapy-related ovarian failure is related to the dose and type of chemotherapy and the age at diagnosis (Goodwin et al. 1999). Specifically, risk of ovarian failure is markedly increased when the chemotherapy regimen includes cyclophosphamide or anthracycline and is administered to women older than 35 years. Patients with breast cancer may experience hot flashes, vaginal dryness, and mood changes. Early evaluation and symptomatic treatment is essential to facilitate improved quality of life. Furthermore, early ovarian failure increases the risk of osteopenia or osteoporosis, for which close monitoring should occur. Treatment with calcium, vitamin D, and bisphosphonates may be necessary to maintain adequate bone health in this setting (Hillner et al. 2003; see algorithm for breast cancer survivorship bone health, presented at the end of this chapter).

Research from our institution has demonstrated a small increased risk of acute myeloid leukemia after adjuvant chemotherapy (1.8% vs 1.2%) in women older than 65 years (Patt et al. 2007). Use of more intense regimens that included two or more cycles containing 2,400 mg/m² cyclophosphamide with granulocyte colony-stimulating factor support resulted in a cumulative incidence of acute myeloid leukemia of 1.01% (95% confidence interval, 0.63–1.62%), compared with 0.21% (95% confidence interval, 0.11–0.41%) for patients treated with standard AC (doxorubicin and cyclophosphamide) regimens (Smith et al. 2003). Although the benefit from adjuvant chemotherapy exceeds the risk of developing acute myeloid leukemia, appropriate understanding of this risk is necessary for long-term follow-up.

Historically, postmastectomy radiation was found to increase the risk of cardiovascular toxicity. A large retrospective study of breast cancer survivors demonstrated a significant increase in overall mortality rates in patients who had received postmastectomy radiation; this effect was attributed to deaths from cardiovascular disease (Jones and Ribeiro 1989). However, with advances in radiation therapy and development of adaptive techniques to reduce cardiac exposure to radiation, recent randomized trials evaluating patients who received postmastectomy radiation therapy have shown no increase in cardiovascular morbidity (Hojris et al. 1999). But even with modern radiation therapy techniques, careful monitoring for symptoms of cardiac toxicity remains essential during follow-up visits.

Although they are rare, secondary malignancies are a potential late effect of radiation for the treatment of breast cancer. A retrospective study of the Surveillance, Epidemiology, and End Results (SEER) Cancer Incidence Database demonstrated that, at 15 years after diagnosis of breast cancer, the cumulative incidence of angiosarcoma was 0.9 per 1,000 patients who had received radiation therapy, compared with 0.1 per 1,000 patients who had not received radiation therapy (Yap et al. 2002). In patients who have received radiation therapy, an angiosarcoma presents in the irradiated field as a purple macule or papule; clinical suspicion of malignancy should lead to immediate core biopsy for further assessment. In addition to risk of solid tumor malignancies such as angiosarcoma, risk of hematologic malignancies such as acute myeloid leukemia and myelodysplastic syndrome is also slightly increased following radiation therapy (Kaplan et al. 2011).