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Home:
Educational Supplement: Appendix
Patient-Specific
FactorsYoung 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 126 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
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Issue
for Discussion
|
Status
of Evidence
|
Current
Options (Sometimes Despite Evidence)
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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
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Abstract.
Aebi S, Gelber
S, Castiglione-Gertsch M, Gelber RD, Collins J, Thürlimann
B, et al., for the International Breast Cancer Study Group (IBCSG).
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Albain KS, Allred
DC, Clark GM. Breast cancer outcome and predictors of outcome: are
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Rubagotti A, Amoroso D, Mesiti M, Romeo D, Sismondi P, et al. Cyclophosphamide,
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HR, Bland KI, Wanebo HJ. Younger women with breast carcinoma have
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K, Teuscher C. The development of male reproductive organ abnormalities
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Swindell R. The prognosis of breast carcinoma in women aged less
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KM, Garber JE, Weeks JC. Decision analysiseffects of prophylactic
mastectomy and oophorectomy on life expectancy among women with
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