The management of breast cancer in women under the age of 40 continues to challenge oncologists despite many recent therapeutic advances. The higher rates of breast cancer recurrence and death in this cohort strongly correlate with unfavorable clinicopathologic features. The author is to be complimented on a comprehensive overview of breast cancer management in young women. In this review, we discuss pregnancy following a diagnosis of breast cancer, fertility concerns related to treatment, and the potentially life-threatening complications cardiotoxicity and leukemogenesis.
Pregnancy-Associated Breast Cancer
Pregnancy-associated breast cancer, which is defined as breast cancer developing during or within 1 year after pregnancy, complicates approximately 0.2% to 3.8% of pregnancies. More specifically, 10% of women under 40 with breast cancer develop the disease while pregnant. Those women with pregnancy-associated breast cancer appear to have more advanced disease at diagnosis when compared to a control population, which may be partly explained by delays in diagnosis. Pathologic evaluation is more likely to reveal a poorly differentiated tumor with a higher proportion of hormone receptor negativity. Contrary to prior opinion, the prognosis for patients with pregnancy-associated breast cancer appears similar when compared to age- and stage-matched nonpregnant controls.
Therapy During Pregnancy
Curative surgery in the third trimester is recommended as there is no known increased fetal risk related to anesthesia. Breast conservation is an option if appropriate and axillary dissection is preferred over sentinel node mapping due to a lack of safety data to support the latter in this setting.
The indications for systemic chemotherapy for the pregnant patient are similar to those for the nonpregnant patient. In a large prospective trial, 57 pregnant breast cancer patients were treated with FAC (fluorouracil [5-FU], doxorubicin [Adriamycin], and cyclophosphamide) in the second and third trimesters. At a median follow-up of 38.5 months, 40 women remained alive and free from disease; no significant short-term complications detected in those children exposed to chemotherapy in utero. Long-term effects, if any, are yet to be determined.
Only case reports exist for the use of other agents during pregnancy, including the taxanes, vinorelbine, trastuzumab (Herceptin), and lapatinib (Tykerb); their routine use is not recommended until after delivery. However, the choice and timing of chemotherapy largely depends on the clinical situation. Consideration should be given to whether delaying effective therapies will result in a worse outcome for an individual patient. Radiation and hormonal therapy should be deferred until after pregnancy. Finally, reports to date do not indicate that termination of pregnancy results in improved outcome for pregnant breast cancer patients.[2,8]
Pregnancy After Breast Cancer Diagnosis
There is no evidence thus far that pregnancy after a diagnosis of breast cancer is associated with worse long-term maternal survival. On the contrary, certain studies suggest a reduced risk of death in such women vs matched controls.[9,10] Whether there is a biologic explanation for this such as a protective effect of high levels of estrogen or whether it indicates a “healthy mother effect” is unclear. In general women are advised to avoid pregnancy in the first 2 years following a diagnosis of breast cancer, as this period is associated with the highest risk of recurrence. For those with hormone-sensitive disease, this also allows at least 2 years of adjuvant hormonal therapy. However, there is no evidence that this strategy reduces recurrence risk in this population.
Fertility Preservation: Ovarian Suppression vs Chemotherapy
As age is an important feature that helps define risk of recurrence, an aggressive adjuvant chemotherapeutic approach is employed in many young women. The author describes how the aim of therapy in the premenopausal population is to maximize breast cancer outcomes, while minimizing both short- and long-term toxicities.
For those who wish to become pregnant or avoid the effects of premature menopause, chemotherapy-induced amenorrhea is a significant and yet often underdiscussed side effect. In a prospective trial, the rate of menstruation after adjuvant chemotherapy was found to be dependent on age, the chemotherapy administered, and the period of time since treatment. Recovery of menses, a surrogate marker for fertility, occurred in approximately 60% of women receiving AC alone at 1 year of follow-up. Far lower rates of recovery were observed with the addition of a taxane or adjuvant treatment with CMF (cyclophosphamide, methotrexate, and 5-FU). Even temporary cessation of menses after chemotherapy appears to predict earlier onset of menopause.
In light of these findings, the role of ovarian suppression as an adjuvant treatment for premenopausal women with hormone-receptor–positive breast cancer has been investigated as an alternative to chemotherapy. Adjuvant goserelin (Zoladex) alone in this patient population results in recovery of menses in the majority of patients after completion of 2 years of therapy. This and other studies have indicated no survival advantage for CMF over ovarian suppression in both node-positive and node-negative cohorts. The PERCHE (Premenopausal Endocrine Responsive CHEmotherapy) trial planned to investigate the efficacy of modern chemotherapy regimens in addition to ovarian suppression in this population, but unfortunately it was closed due to poor accrual.
Based on the available evidence, ovarian suppression may be offered as an alternative to chemotherapy in young women, in particular where fertility is a concern.
Cardiotoxicity and Leukemogenesis
Two other serious and potentially life-threatening complications briefly mentioned in the article by Peppercorn include cardiotoxicity and leukemogenesis. The incidence of cardiotoxicity after AC (doxorubicin [Adriamycin] and cyclophosphamide), for example, can be as high as 5% to 7%. The addition of trastuzumab to adjuvant regimens can further potentiate anthracycline-induced cardiotoxicity, at times precluding subsequent trastuzumab administration in relevant populations. Future assessment of molecular predictors of response to anthracyclines, such as topoisomerase II expression and administration of equally effective non–anthracycline-containing regimens in the management of early breast cancer, may limit this serious adverse effect.[17,18]
The absolute risk of developing treatment-related acute myeloid leukemia at 10 years after any adjuvant chemotherapy for breast cancer has been shown to be 1.8% vs 1.2% for women who have not received chemotherapy. In a recent population-based study of 420,076 women with a diagnosis of breast cancer, both age < 50 (relative risk [RR] 4.14; P < .001) and stage 3 disease at diagnosis (RR 2.19; P < .001) were associated with an increased risk of AML. It was suggested that these patients may have received more intensive adjuvant regimens or may be more likely to have germline mutations in BRCA1, BRCA2, and other genes involved in DNA repair.
Recent evidence has also suggested that the use of colony-stimulating factors may double the risk of hematologic malignancies among women with early breast cancer. This association needs confirmation, but is thought-provoking when we consider the widespread use of adjuvant “third-generation” anthracycline-based chemotherapy regimens incorporating growth factors.
Complex and multidisciplinary treatment planning is often required in young women with early breast cancer because of concerns relating to pregnancy, fertility, long-term toxicities, quality of life, and psychosocial issues. It is imperative that the available evidence is portrayed clearly at initial assessment in order to formulate a treatment plan that will be both safe and acceptable to each individual. Future research should aim to improve on breast cancer outcomes while minimizing toxicity associated with adjuvant therapy.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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