Home: Educational Supplement: Appendix

Patient-Specific Factors—Young Patients

Aron Goldhirsch, M.D., and Richard D. Gelber, Ph.D.

Breast cancer rarely occurs in young women. About 2 percent of female patients with the disease are less than 35 years old at diagnosis (NCI, 2000). Below the age of 20 the incidence is estimated to be 0.1 per 100,000 women, increasing to 1.4 for those 20 to 24 years old, 8.1 for those 25 to 29 years old, and 24.8 for those 30 to 34 years old (NCI, 2000). Breast cancer at a young age has a more aggressive biological behavior and is associated with a more unfavorable prognosis than when the disease arises in older patients. Specifically, tumors in younger women are less well differentiated (higher grade) and have a higher proliferating fraction and more vascular invasion than those occurring in older patients (Walker, Lees, Webb, et al., 1996; Adami, Malker, Holmberg, et al., 1986; Chung, Chang, Bland, et al., 1996; Kollias, Elston, Ellis, et al., 1997). A larger number of positive axillary lymph nodes are detected in young than in older patients. Results from two population-based studies indicate that the risk of death is highest among the youngest and the oldest cohorts when compared with patients of intermediate age (Adami, Malker, Holmberg, et al., 1986), even when the analysis allows for differences in initial tumor stage (Kollias, Elston, Ellis, et al., 1997).

A review of the National Cancer Data Base reveals that patients younger than 35 years of age have more advanced disease at diagnosis and a poorer 5-year survival rate than older premenopausal patients (Winchester, Osteen, Menck, et al., 1996). Similar findings have been reported from the National Cancer Institute SEER database (Swanson, Lin, 1994), from the Finnish Cancer Registry (Holli, Isola, 1997), and from a recent Danish study on young patients who did not receive adjuvant therapy (Kroman, Jensen, Wohlfahrt, et al., 2000), as well as from several series described from single centers (Albain, Allred, Clark, 1994; Noyes, Spanos, Montague, 1982; Ribeiro, Swindell, 1981).

Typically, young patients receive chemotherapy, and in many countries clinicians have been reluctant to employ ovarian ablation or other endocrine treatment (Kroman, Jensen, Wohlfahrt, et al., 2000). No adjuvant systemic therapy was prescribed to young women with early stage breast cancer thought to have favorable prognostic factors in a large Danish study (Kroman, Jensen, Wohlfahrt, et al., 2000). In that study, which included 10,356 women with primary breast cancer who were less than 50 years old, the youngest (predefined as having a low-risk disease and therefore given no adjuvant systemic treatment) had a significantly increased risk of dying. The increased risk with decreasing age at diagnosis (adjusted relative risk [RR] with a cohort 45 to 49 years of age as a reference group having a RR of 1) was 1.12 (95 percent confidence interval [CI] 0.89 to 1.40) for 40 to 44 years of age, 1.40 (1.10 to 1.78) for 35 to 39 years of age, and 2.18 (1.64 to 2.89) for <35 years of age. No such trend was seen in patients who were considered at the time of the study to be eligible to receive adjuvant cytotoxic treatment. Thus, the negative prognostic effect of young age was confined to those who did not receive adjuvant cytotoxic treatment, leading to the conclusion that young women with breast cancer, on the basis of age alone, should be regarded as high-risk patients and be given adjuvant cytotoxic treatment. This conclusion relies on the assumption that a worse prognosis predicts responsiveness to chemotherapy.

The International Breast Cancer Study Group (IBCSG) treated 3,700 pre- and perimenopausal patients with various timing and duration of adjuvant cyclophosphamide, methotrexate, and fluorouracil (classical CMF with or without low-dose prednisone, with or without oophorectomy) (Aebi, Gelber, Castiglione-Gertsch, et al., 2000). Of these women, 314 were less than 35 years of age at study entry. The trials were conducted between 1978 and 1993. Relapse and death occurred earlier and more often in younger (<35 years) than in older (>35) patients. The 10-year disease-free survival rate (DFS; ± SE) was 35 percent (+3) vs. 47 percent (+1) (hazards ratio [HR], 1.41; 95 percent CI, 1.22 to 1.62; p<0.001) and overall survival was 49 percent (+3) vs. 62 percent (+1) (HR, 1.50; 95 percent CI, 1.28 to 1.77; p<0.001), respectively. Younger patients with estrogen receptor positive (ER+) tumors had a significantly worse prognosis than younger patients with estrogen receptor negative (ER–) tumors. The 10- year DFS was 25 percent (+4) vs. 47 percent (+5); HR, 1.49; 95 percent CI, 1.09 to 2.04; p=0.014.

In contrast, among older patients the prognosis was similar for patients with ER+ compared with patients with ER– tumors (10-year DFS 45 percent [+1] vs. 46 percent [+2]; HR, 0.94; 95 percent CI, 0.85 to 1.04; p=0.27). The largest difference in 10-year DFS between younger and older patients was observed for those with ER+ tumors who did not achieve amenorrhea (23 percent [+6] vs. 38 percent [+3]; HR, 1.67; 95 percent CI, 1.19 to 2.34; p=0.003). This retrospective analysis of treatment outcome suggests that the endocrine effects of chemotherapy alone were insufficient for the younger age group (only about 30 percent of the patients had some cessation of menses from the 12–6 courses of classical CMF). Additional endocrine therapies (tamoxifen or ovarian ablation, or a combination of both) should be considered for these patients if their tumors express steroid hormone receptors. Such endocrine therapies might be the most effective component of their adjuvant treatment program.

Additional issues to be considered when approaching treatment and personal decisions for young patients with breast cancer (excluding issues related to genetic predisposition) are included in table 1.

Treatment decision-making for very young women with newly diagnosed breast cancer may be affected by the strong emotional involvement of care providers. Furthermore, the belief that an increased risk of relapse justifies use of cytotoxics to increase the demise of cancer cells might also contribute to lack of progress in evaluating endocrine therapies for this rare presentation of breast cancer.

Table 1. Treatment and personal issues: evidence and current options
Issue for Discussion	Status of Evidence	Current Options (Sometimes Despite Evidence)
Local disease control, very late effects of radiation therapy	Young patients have a higher risk for locoregional relapse (Kim, Simkovich-Heerdt, Tran, et al., 1998; Elkhuizen, van de Vijver, Hermans, et al., 1998). No data on late effects on the heart of anthracyclines and taxanes plus radiation therapy.	Breast conservation with radiation therapy is considered a standard treatment (Guenther, Kirgan, Giuliano, 1996). Total or bilateral (prophylactic) mastectomy is increasingly discussed (Schrag, Kuntz, Garber, et al., 1997).
Pregnancy after breast Cancer	Pregnancy seems to be safe afterbreast cancer and after adjuvant systemic cytotoxic therapy (Kroman, Jensen, Melbye, et al.,1997; Velentgas, Daling, Malone, et al., 1999; Gelber, Coates, Goldhirsch, et al., in press), (except for BRCA1 and BRCA2 carriers) (Jernstrom, Lerman, Ghadirian, et al., 1999). Uncertainty about pretreatment with tamoxifen and neonatal genital tract malformations (Nakai, Uchida, Teuscher, 1999).	Reluctance to consider pregnancyeven for women with node-negative disease (Surbone, Petrek, 1997). Availablility of GnRH analog as an effective endocrine treatment, especially if given with tamoxifen (Boccardo, Rubagotti, Amoroso, et al., 2000). New endocrine therapiesare being investigated, mainly in postmenopausal patients.
Interpersonal and family relations	Younger women might be particularly vulnerable to the emotional distress of the disease (Northouse, 1994).	Psychological support (trials aretesting this type of intervention).

References

Adami HO, Malker B, Holmberg L, Persson I, Stone B. The relation between survival and age at diagnosis in breast cancer. N Engl J Med 1986;315:559-63. Abstract.

Aebi S, Gelber S, Castiglione-Gertsch M, Gelber RD, Collins J, Thürlimann B, et al., for the International Breast Cancer Study Group (IBCSG). Is chemotherapy alone adequate for young women with oestrogen-receptor-positive breast cancer? Lancet 2000;355:1869-74. Abstract.

Albain KS, Allred DC, Clark GM. Breast cancer outcome and predictors of outcome: are there age differentials? J Natl Cancer Inst Monogr 1994;16:35-42. Abstract.

Boccardo F, Rubagotti A, Amoroso D, Mesiti M, Romeo D, Sismondi P, et al. Cyclophosphamide, methotrexate, and fluorouracil versus tamoxifen plus ovarian suppression as adjuvant treatment of estrogen receptor-positive pre-/perimenopausal breast cancer patients: results of the Italian Breast Cancer Adjuvant Study Group 02 randomized trial. J Clin Oncol 2000;18:2718-27. Abstract.

Chung M, Chang HR, Bland KI, Wanebo HJ. Younger women with breast carcinoma have a poorer prognosis than older women. Cancer 1996;77:97-103. Abstract.

Elkhuizen PH, van de Vijver MJ, Hermans J, Zonderland HM, van der Velde CJ, Leer JW. Local recurrence after breast conserving therapy for invasive breast cancer: high incidence in young patients and association with poor survival. Int J Radiat Oncol Biol Phys 1998;40:859-67. Abstract.

Gelber S, Coates AS, Goldhirsch A, Castiglione-Gertsch M, Marini G, Lindtner J, et al. Effect of pregnancy on overall survival following the diagnosis of early stage breast cancer. J Clin Oncol (in press). Abstract.

Guenther JM, Kirgan DM, Giuliano AE. Feasibility of breast-conserving therapy for younger women with breast cancer. Arch Surg 1996;131:632-6. Abstract.

Holli K, Isola J. Effect of age on the survival of breast cancer patients. Eur J Cancer 1997;33:425-8. Abstract.

Jernstrom H, Lerman C, Ghadirian P, Lynch HT, Weber B, Garber J, et al. Pregnancy and risk of early breast cancer in carriers of BRCA1 and BRCA2. Lancet 1999;354:1846-50. Abstract.

Kim SH, Simkovich-Heerdt A, Tran KN, Maclean B, Borgen PI. Women 35 years of age or younger have higher locoregional relapse rates after undergoing breast conservation therapy. J Am Coll Surg 1998,187:1-8. Abstract.

Kollias J, Elston CW, Ellis IO, Robertson JF, Blamey RW. Early-onset breast cancer— histopathological and prognostic considerations. Br J Cancer 1997;75:1318-23. Abstract.

Kroman N, Jensen MB, Melbye M, Wohlfahrt J, Mouridsen HT. Should women be advised against pregnancy after breast-cancer treatment? Lancet. 1997;350:319-22. Abstract.

Kroman N, Jensen MB, Wohlfahrt J, Mouridsen HT, Andersen PK, Melbye M. Factors influencing the effect of age on prognosis in breast cancer: population based study. BMJ 2000:320:474-8. Abstract.

Nakai M, Uchida K, Teuscher C. The development of male reproductive organ abnormalities after neonatal exposure to tamoxifen is genetically determined. J Androl 1999;20:626-34. Abstract.

Northouse LL. Breast cancer in younger women: effects on interpersonal and family relations. J Natl Cancer Inst Monogr 1994;16:183-90. Abstract.

Noyes RD, Spanos WJ Jr, Montague ED. Breast cancer in women aged 30 and under. Cancer 1982;49:1302-7. Abstract.

Ribeiro GG, Swindell R. The prognosis of breast carcinoma in women aged less than 40 years. Clin Radiol 1981;32:231-6. Abstract.

Schrag D, Kuntz KM, Garber JE, Weeks JC. Decision analysis–effects of prophylactic mastectomy and oophorectomy on life expectancy among women with BRCA1 or BRCA2 mutations. N Engl J Med 1997;336:1465-71. [Erratum appeared in N Engl J Med 1997;337:434.] Abstract.

Surbone A, Petrek JA. Childbearing issues in breast carcinoma survivors. Cancer 1997;79:1271-8. Abstract.

Surveillance, Epidemiology, and End Results (SEER) Program Public-Use CD ROM (1973- 1997), National Cancer Institute, DCCPS, Cancer Surveillance Research Program, Cancer Statistics Branch, released April 2000, based on the August 1999 submission. Abstract.

Swanson GM, Lin CS. Survival patterns among younger women with breast cancer: the effects of age, race, stage, and treatment. J Natl Cancer Inst Monogr 1994;16:69-77. Abstract.

Velentgas P, Daling JR, Malone KE, Weiss NS, Williams MA, Self SG, et al. Pregnancy after breast carcinoma. Cancer 1999;85:2424-32. Abstract.

Walker RA, Lees E, Webb MB, Dearing SJ. Breast carcinomas occurring in young women (<35 years) are different. Br J Cancer 1996;74:1796-800. Abstract.

Winchester DP, Osteen RT, Menck HR. The National Cancer Data Base report on breast carcinoma characteristics and outcome in relation to age. Cancer 1996;78:1838-43. Abstract.