OR WAIT null SECS
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 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, 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.
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]
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.
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.
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.
1. Wallack MK, Wolf JA Jr, Bedwinek J, et al: Gestational carcinoma of the female breast. Curr Probl Cancer 7:1-58, 1983.
2. Nugent P, O’Connell TX: Breast cancer and pregnancy. Arch Surg 120:1221-1224, 1985.
3. Gwyn K, Theriault R: Breast cancer during pregnancy. Oncology (Williston Park) 15:39-46; discussion 49-51, 2001.
4. Beadle BM, Woodward WA, Middleton LP, et al: The impact of pregnancy on breast cancer outcomes in women < or = 35 years. Cancer 115:1174-1184, 2009.
5. Ezzat A, Raja MA, Berry J, et al: Impact of pregnancy on non-metastatic breast cancer: A case control study. Clin Oncol (R Coll Radiol) 8:367-370, 1996.
6. Hahn KM, Johnson PH, Gordon N, et al: Treatment of pregnant breast cancer patients and outcomes of children exposed to chemotherapy in utero. Cancer 107:1219-1226, 2006.
7. Mir O, Berveiller P, Ropert S, et al: Emerging therapeutic options for breast cancer chemotherapy during pregnancy. Ann Oncol 19:607-613, 2008.
8. Gemignani ML, Petrek JA, Borgen PI: Breast cancer and pregnancy. Surg Clin North Am 79:1157-1169, 1999.
9. Kroman N, Jensen MB, Wohlfahrt J, et al: Pregnancy after treatment of breast cancer-A population-based study on behalf of Danish Breast Cancer Cooperative Group. Acta Oncol 47:545-549, 2008.
10. Mueller BA, Simon MS, Deapen D, et al: Childbearing and survival after breast carcinoma in young women. Cancer 98:1131-1140, 2003.
11. Goldhirsch A, Glick JH, Gelber RD, et al: Meeting highlights: International expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol 16:1569-1583, 2005.
12. Petrek JA, Naughton MJ, Case LD, et al: Incidence, time course, and determinants of menstrual bleeding after breast cancer treatment: A prospective study. J Clin Oncol 24:1045-1051, 2006.
13. Partridge A, Gelber S, Gelber RD, et al: Age of menopause among women who remain premenopausal following treatment for early breast cancer: Long-term results from International Breast Cancer Study Group Trials V and VI. Eur J Cancer 43:1646-1653, 2007.
14. Castiglione-Gertsch M, O’Neill A, Price KN, et al: Adjuvant chemotherapy followed by goserelin versus either modality alone for premenopausal lymph node-negative breast cancer: A randomized trial. J Natl Cancer Inst 95:1833-1846, 2003.
15. Kaufmann M, Jonat W, Blamey R, et al: Survival analyses from the ZEBRA study. Goserelin (Zoladex) versus CMF in premenopausal women with node-positive breast cancer. Eur J Cancer 39:1711-1717, 2003.
16. Tan-Chiu E, Yothers G, Romond E, et al: Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 23:7811-7819, 2005.
17. Jones S, Holmes FA, O’Shaughnessy J, et al: Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology Research Trial 9735. J Clin Oncol 27:1177-1183, 2009.
18. Di Leo A, Biganzoli L, Claudino W, et al: Topoisomerase II alpha as a marker predicting anthracyclines’ activity in early breast cancer patients. Eur J Cancer 44:2791-2798, 2008.
19. Patt DA, Duan Z, Fang S, et al: Acute myeloid leukemia after adjuvant breast cancer therapy in older women: Understanding risk. J Clin Oncol 25:3871-3876, 2007.
20. Hershman D, Neugut AI, Jacobson JS, et al: Acute myeloid leukemia or myelodysplastic syndrome following use of granulocyte colony-stimulating factors during breast cancer adjuvant chemotherapy. J Natl Cancer Inst 99:196-205, 2007.