Adjuvant Therapy for Very Young Women with Breast Cancer: Response According to Biologic and Endocrine Features

original

contribution

Adjuvant Therapy for Very Young Women with Breast Cancer: Response According to Biologic and Endocrine Features Giuseppe Curigliano, Rodrigo Rigo, Marco Colleoni, Filippo de Braud, Franco Nolè, Vincenzo Formica, Laura Orlando, Saverio Cinieri, Rosalba Torrisi, Anna Cardillo, Giulia Peruzzotti, Marta Medici, Raffaelle Ardito, Ida Minchella, Aron Goldhirsch Abstract Incidence of breast cancer in patients aged < 20 years has been estimated to be 0.1 per 100,000 women. Reported incidences are 1.4 for women aged 20-24 years, 8.1 for women aged 25-29 years, and 24.8 for women aged 30-34 years. Younger patients have been found to have a more aggressive presentation of disease at diagnosis, which is associated with dire prognoses compared with those in premenopausal older patients. Several biologic features might explain the more aggressive behavior of breast cancer in younger patients: higher grade and higher expression of Ki67, higher occurrence of vessel invasion, and less expression of estrogen and progesterone receptors. Choice of adjuvant therapies for women aged < 35 years with breast cancer is based on data derived from trials on cohorts of older patients. On average, the effect of chemotherapy for premenopausal patients is substantial: recent evidence suggested that very young women with endocrine-responsive tumors had a higher risk of relapse than older premenopausal patients with similar tumors. This was not the case for patients with endocrine-nonresponsive tumors, for which effects of chemotherapy were similar across ages. Very young women with this disease are faced with personal, family, professional, and quality-of-life issues that further complicate the phase of treatment decision-making. The development of more effective therapies for very young women with breast cancer requires tailored treatment investigations and research focused on issues specific to these patients. Clinical Breast Cancer, Vol. 5, No. 2, 125-130, 2004 Key words: Amenorrhea, Chemotherapy, Endocrine therapy, Estrogen receptor, Premenopausal patients, Progesterone receptor

Introduction Generally, breast cancer rarely occurs in very young women. The subgroup of women < 35 years of age represents approximately 2% of patients diagnosed with breast cancer.1 Relapse and death occurs earlier and more often in this group of patients than in older patients. Findings from the International Breast Cancer Study Group (IBCSG) showed 10-year European Institute of Oncology, Milan, Italy Submitted: Nov 3, 2003; Revised: Mar 1, 2004; Accepted: Mar 15, 2004 Address for correspondence: Giuseppe Curigliano, MD, Department of Medicine, Division of Medical Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milano, Italy Fax: 39-02-57-489581; e-mail: [email protected]

disease-free survival (DFS) rates of 35% and 47% in younger and older patients, respectively, with corresponding overall survival (OS) rates of 49% and 62%.2 Breast cancer in younger patients has more aggressive biologic behavior. Several biologic features have been found to explain the more aggressive behavior of breast cancer in younger patients: higher grade and higher expression of Ki67, higher percentage of vessel invasion, and less expression of estrogen receptors (ERs) and progesterone receptors (PgRs).3 Information from older series indicated more nodal involvement in younger patients compared with older patients.4 Recent observation at the European Institute of Oncology (EIO) showed that the incidence of nodal metastases in women < 35 years of age is similar to the incidence in older women.5 A review of the National Cancer

Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1526-8209, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.

Clinical Breast Cancer June 2004 • 125

Adjuvant Therapy in Very Young Women Table 1 Chemotherapy-Induced Amenorrhea in Premenopausal Patients with Breast Cancer7 Age

Amenorrhea No Permanent with Subsequent Amenorrhea Resumption of Menses Amenorrhea*

< 35

88%

4%

8%

> 35

34%

7%

59%

*≥ 3 Months.

Database reveals more advanced disease at diagnosis and poorer 5-year survival rates in patients aged < 35 years.6 This review will focus on choice of adjuvant therapy for breast cancer in women aged < 35 years. Although the effect of chemotherapy for premenopausal patients is substantial, recent evidence suggested that very young women with endocrine-responsive tumors had a statistically significantly higher risk of relapse than older premenopausal patients with such tumors.7-9 In contrast, results for younger and older premenopausal patients were similar if their tumors were classified as endocrine-nonresponsive. Information from studies on patients who were treated with chemotherapy alone in trials of 3 major US cooperative groups showed a similar interaction between the effect of age and steroid hormone receptor status of the primary tumors.10 Tailored treatments for very young patients are required; they should involve ovarian function suppression in patients with endocrine-responsive tumors and a more precise investigation of chemotherapy and its timing, duration, and intensity in patients with endocrine-nonresponsive tumors. Therapeutic decision-making in very young women should take into consideration personal, family, pregnancy desire, professional, and quality-of-life issues.

Age and Endocrine Effect of Chemotherapy The use of chemotherapy in an adjuvant setting for premenopausal women is a major issue, especially for those aged < 35 years, because of its effects on outcome. It is important to focus on endocrine effects (suppression of endocrine ovarian function) of chemotherapy in premenopausal women. This is a major issue in the selection of patients for adjuvant therapy. Chemotherapy-induced amenorrhea in patients with

Table 2 Relative Risk of Relapse for Premenopausal Patients with or Without Chemotherapy-Induced Amenorrhea10 Age/Receptor Status

Relative Risk (No Amenorrhea vs. Amenorrhea)

< 35 Years/ER positive

1.53

> 35 Years/ER positive

1.34

< 35 Years/ER negative

1.14

> 35 Years/ER negative

1.11

Patients had lymph node–positive disease treated with ≥ 3 months of classical cyclophosphamide/methotrexate/5-fluorouracil chemotherapy. Abbreviation: ER = estrogen receptor

126 • Clinical Breast Cancer June 2004

endocrine-responsive tumors should be considered during the decision-making process for adjuvant chemotherapy in younger women. In a cohort of 1054 patients who had received chemotherapy with CMF (cyclophosphamide/ methotrexate/5-fluorouracil) for a minimum of 3 courses, 8% of younger patients had permanent amenorrhea compared with 59% of the older patients (Table 1).7 It is known that the incidence of amenorrhea is proportional to the duration of chemotherapy.11 However, chemotherapy, particularly with alkylating agents, has a major endocrine effect, which results in the disruption of hormone production and decreased circulating levels of estrogen. This causes troublesome side effects such as vasomotor symptoms and vaginal dryness. The acceptance of ovarian function suppression is a significant problem for these younger patients. Luteinizing hormone–releasing hormone analogues have been tested in the adjuvant setting. They suppress ovarian function like surgery or irradiation but with the assumed reversibility of menopausal symptoms. Nystedt et al recently showed that the negative side effects of endocrine treatment were limited to the active treatment period and, in contrast, these same side effects were continuously observed in patients treated with chemotherapy.12 A pertinent question is whether failure to achieve chemotherapy-induced amenorrhea is associated with increasing risk of relapse in premenopausal patients with ER-positive tumors. Data from IBCSG trials showed that, for young and older premenopausal patients with ER-positive tumors, absence of amenorrhea is associated with higher risk of relapse, even though the results in younger women are statistically uncertain because of the small sample size2 (Table 2).10 Amenorrhea was achieved only in a small proportion of patients in the young age group and this condition might contribute to the poor outcome of this subgroup of patients with endocrine-responsive disease. Conversely, association between failure to achieve chemotherapy-induced amenorrhea and risk of relapse is not statistically significant for patients with ER-negative tumors. We need randomized clinical trials to know whether treatments that provide ovarian function suppression should be offered to women who continue to menstruate following adjuvant treatment.

Biologic Features More Aggressive Biologic Behavior in Very Young Women Breast cancer diagnosed in young patients has been reported to have a more aggressive biologic behavior and to be associated with a more unfavorable prognosis compared with the disease in older patients. Specifically, in previously published reports, tumors in younger women were less differentiated (higher grade), had a higher proliferating fraction, and had more vascular invasion than those occurring in older patients.4 Two population-based studies yielded a relationship between age at diagnosis and risk of death, with the youngest and the oldest having a higher risk than patients of intermediate age.13,14 Moreover, a review of the National Cancer Database revealed that patients aged < 35 years had more ad-

Giuseppe Curigliano et al vanced disease at diagnosis and a poorer 5-year survival than older premenopausal patients.15 Similar findings have been reported in the past from the US National Cancer Institute Surveillance, Epidemiology, and End Results database, the Finnish Cancer Registry, and other sources.15,16 More positive axillary lymph nodes and higher incidence of local recurrence were detected in younger compared with older patients. However, data on treatment effects are largely dependent on older series collected over several years and extrapolation of data from older age cohorts. Staging procedures, attention given to small metastases in axillary lymph nodes, assessment of overexpression of HER2/neu, and immunohistochemical determination of ERs and PgRs (ie, not with ligand-binding assay) are features that underwent a substantial change in recent years. Thus, it is important to investigate the most recently available details of biologic characteristics and stage at disease presentation in very young patients (< 35 years of age) with operable breast cancer.

European Institute of Oncology Experience In a recent analysis of the EIO, we evaluated biologic features and stage at presentation for 1427 consecutive premenopausal patients aged ≤ 50 years with first diagnosis of invasive breast cancer referred to surgery at the EIO from April 1997 to August 2000.5 A total of 185 patients (13%) were aged < 35 years (very young) and 1242 (87%) were aged 35-50 (less young). The expression of ERs and PgRs, presence of vascular invasion, grading, expression of Ki67, HER2/neu overexpression, pathologic size and stage according to TNM staging system, and axillary lymph node involvement were evaluated. Compared with less young patients, the very young patient group had a higher percentage of tumors classified as ER negative (P < 0.001), PgR negative (P = 0.001), higher expression of Ki67 (in ≥ 20% of cells stained; 62.2% vs. 53%; P < 0.001), vascular or lymphatic invasion (48.6% vs. 37.3%; P = 0.006), and pathologic grade 3 (P < 0.0001). There was no difference between groups for pathologic tumor stage and size and number of positive lymph nodes. We conclude that, compared with less young premenopausal patients, very young women have a greater chance of having an endocrine-unresponsive tumor and are more likely to present with higher grade, more extensively proliferating, and vessel invading disease. Pathologic tumor size, nodal status, and number of positive axillary lymph nodes have a similar distribution among the younger and older cohorts, thereby not supporting previous data indicating more advanced disease in younger patients at diagnosis of operable disease.

Efficacy of Adjuvant Chemotherapy and Immunoreactivity for Estrogen and Progesterone Receptors Two important findings are related to responsiveness to endocrine therapy in very young patients with breast cancer. The first relates to the observation in the current series that very young patients had tumors with less immunoreactivity

for ER and PgR than older premenopausal patients. Reliable information on large cohorts of patients with data on ER and PgR is rare and receptor determination is usually based on ligand-binding assay.17 This method of determination, directed toward the steroid hormone–binding domain, is influenced by endogenous estrogens and progesterone much more so than immunohistochemical staining.18 The relevance of immunohistochemical evaluation for prediction of response to endocrine treatment was recently reported, with the conclusion that immunohistochemical evaluation is superior to the ligand-binding assay for predicting prognosis of patients who were treated with adjuvant endocrine therapy. Response to endocrine therapy was postulated even when tumors expressed as few as 1% of immunohistochemically stained cells. The second finding relates to the reduced efficacy of adjuvant chemotherapy for very young patients with endocrineresponsive tumors compared with less-young premenopausal women. It is well known that chemotherapy exerts some of its effect via an endocrine mechanism in premenopausal women with ER-positive tumors, as recently published.19 The IBCSG assessed the course of the disease in 3700 pre- and perimenopausal patients treated in various trials of timing and duration with adjuvant systemic therapy containing CMF.2 Three hundred fourteen women were < 35 years of age at trial entry. Younger patients with ERpositive tumors had a significantly worse prognosis than younger patients with ER-negative tumors (10-year DFS, 25% vs. 47%; hazard ratio [HR], 1.49; P = 0.014). The largest difference in 10-year DFS between younger and older women was observed for those with ER-positive tumors who did not experience amenorrhea compared with those who had some cessation of menses (23% ± 6 vs. 38% ± 3; HR, 1.67; 95% CI, 1.19-2.34; P = 0.003). This retrospective analysis of treatment outcome leads to the hypothesis that the endocrine effects of chemotherapy alone were insufficient for patients in the younger age group with endocrineresponsive tumors, for whom suppression of estradiol production might be essential.

Efficacy of Available Systemic Treatments Typically, young patients receive chemotherapy, and in many countries, clinicians have been reluctant to employ ovarian ablation or other endocrine treatment. One study from a Danish group led to the conclusion that an age < 35 years is a dire prognostic variable and that young women with breast cancer, on the basis of age alone, should be regarded as being at high risk and should be recommended for adjuvant cytotoxic treatment. Specifically in this study, patients with a lower risk of relapse (based on lymph node status, tumor size, and histologic grade, but not hormone receptor status) were untreated with adjuvant systemic therapy, whereas patients at high risk were offered cytotoxic and endocrine treatment in clinical trials.20 Among patients

Clinical Breast Cancer June 2004 • 127

Adjuvant Therapy in Very Young Women Table 3 Relative Risk of Relapse and 5-Year Disease-Free Survival in ER-Positive and ER-Negative Disease10 Group

ER-Positive Disease

ER-Negative Disease

Age < 35 Years Age > 35 Years Age < 35 Years Age > 35 Years Relative Risk of Relapse

contrast, among older patients, the prognosis was similar for patients with ER-positive tumors compared with patients with ER-negative tumors (10-year DFS rates were 45% vs. 46%; P = 0.27). The interaction between age and ER status on outcome was statistically significant (P = 0.002). Of the 3098 patients with known ER status, 2233 (72%) received ≤ 3 courses of adjuvant chemotherapy alone. This retrospective analysis suggests that the endocrine effects of chemotherapy alone were insufficient for the younger patients with endocrine-responsive breast cancer.10

IBCSG

1.84

1.00 (Reference)

1.13

1.02

NSABP

1.72

1.00

1.27

1.12

ECOG

1.54

1.00

1.40

1.26

SWOG

2.67

1.00

0.81

1.13

Adjuvant Chemotherapy and Outcome According to Age A recent analysis of data from the National Surgical Adjuvant Breast and Bowel Project (NSABP), Eastern Cooperative Oncology Group (ECOG), and Southwest Oncology Group (SWOG) provided information on outcomes of patients assigned to receive chemotherapy alone within premenopausal age cohorts—premenopausal patients for ECOG and SWOG and patients ≤ 49 years of age for NSABP.10 The IBCSG restricted the analysis to patients assigned to receive ≥ 3 courses of classical CMF, a duration similar to 4 courses of AC (doxorubicin/cyclophosphamide), an adjuvant chemotherapy program frequently used in US trials. All patients had known ER status. From the IBCSG trials, 2233 patients met these criteria. This analysis included 5849 patients aged ≤ 49 years whose ER status was ascertained and who were randomly assigned to receive chemotherapy alone in NSABP trials B-06,23,24 B-09,25 B-11,26 B-15,27 B-18,28 B-22,29 and B-25.30 From ECOG trials (EST5177,31 EST5188, and EST3189), data from 1112 premenopausal patients assigned to receive chemotherapy alone were analyzed. Six hundred seventy premenopausal patients were assigned to receive chemotherapy alone for lymph node–negative disease in SWOG trial S8897 (Table 3).10 The results from all 4 cooperative groups demonstrated a relative risk of relapse, estimated from a Cox proportional hazards regression model stratified by study and treatment group, substantially higher for young patients with ER-positive tumors compared with the reference population of older patients with ER-positive tumors. In contrast, the difference in outcome with respect to age group is much smaller for patients with ER-negative tumors. The interaction between age and ER status was statistically significant for the cohorts in the IBCSG, NSABP, and SWOG trials.

5-Year Disease-Free Survival IBCSG

39%

60%

56%

59%

NSABP

49%

66%

59%

63%

ECOG

53%

66%

55%

58%

SWOG

73%

89%

91%

88%

The patients were premenopausal and treated with chemotherapy only. Abbreviations: ECOG = Eastern Cooperative Oncology Group; ER = estrogen receptor; IBCSG = International Breast Cancer Study Group; NSABP = National Surgical Adjuvant Breast and Bowel Project; SWOG = Southwest Oncology Group

who were given no systemic treatment, the youngest cohort had a significantly increased risk of death compared with older women. The increased risks with decreasing age at diagnosis were 1.12 (95% CI, 0.89-1.40) for the group aged 4044 years, 1.40 (95% CI, 1.10-1.78) for the group aged 35-39 years, and 2.18 (95% CI, 1.64-2.89) for the group aged < 35 years. No such trend according to age was seen in patients who were considered to have high-risk disease and who were therefore eligible to receive adjuvant cytotoxic treatment. The negative prognostic effect of young age (< 35 years) compared with age of 45-49 years was confined to those who were not offered a trial including adjuvant cytotoxic treatment. This observation led to the conclusion that young women with breast cancer should be regarded as being at high risk on the basis of age alone and should be given adjuvant cytotoxic treatment. This latter conclusion relies on the assumption that the worse prognosis predicts responsiveness to chemotherapy. Information on differences in treatment effects according to steroid hormone receptor status of the primary tumor was not reported in this analysis. The IBCSG previously reported on 3700 premenopausal and perimenopausal patients who were included in IBCSG Trials I,8 II,21 V,13,22 and VI7 conducted by the group between 1978 and 1993. Of these women, 314 were aged < 35 years at study entry (8.5%). Relapse and death occurred earlier and more often in younger patients (< 35 years) than in older patients (> 35 years). The 10-year DFS for younger patients was 35%, versus 47% for older patients (P < 0.001), and the 10-year OS rates were 49% and 62%, respectively (P < 0.001). Younger patients with ER-positive tumors had a significantly worse prognosis than did younger patients with ER-negative tumors (10-year DFS was 25% for ER-positive tumors vs. 47% for ER-negative tumors; P = 0.014). In

128 • Clinical Breast Cancer June 2004

Tailoring Adjuvant Treatment Endocrine Nonresponsive Patients Regardless of the age of premenopausal patients with ERnegative tumors, adjuvant chemotherapy appears to be a very important component of a successful treatment regimen. Direct cytotoxic effects of chemotherapy should be investigated specifically in patients with endocrine-nonresponsive tumors without the confounding effects of hormonal therapies or endocrine effects of chemotherapy. Several trials are currently ongoing to better define timing of the start of chemotherapy

Giuseppe Curigliano et al after surgery and the type, schedule, and duration of the cytotoxic regimen. In particular, dose escalation and dose density of chemotherapy should be investigated in this patient population. Estrogen receptor–negative status is the typical criterion for defining endocrine-nonresponsive tumors in clinical trials and in the Early Breast Cancer Trialists’ Collaborative Group overview. A large number of markers (eg, HER2/neu, p53) might prove to be useful in the future to refine the selection of chemotherapy for patients whose tumors are exclusively affected by cytotoxic agents.31

Patients with Endocrine-Responsive Disease

Figure 1 Therapeutic Algorithm for Choice of Treatment of Breast Cancer in Patients ≤ 35 Years of Age Based on Biologic and Endocrine Features Breast cancer diagnosis at ≤ 35 years of age ER and/or PgR present

ER and PgR absent Chemotherapy*

Node-negative

No Other Risk Factors† Endocrine therapy GnRH analogue (or ovarian ablation)

Node-positive

Other Risk Factors† Endocrine therapy GnRH analogue (or ovarian ablation) Consider chemotherapy‡

Chemotherapy* GnRH analogue (or ovarian ablation)

Several trials conducted during the past 2 decades demonstrated that younger premenopausal women treated with chemotherapy alone have a higher risk of relapse and death than older premenopausal women treated in the same way. For young patients whose tumors exTamoxifen press hormone receptors, endocrine effects of chemotherapy alone are modest, and endocrine *Chemotherapy regimens: 4 courses of AC or 6 courses of classical CMF or Canadian CEF, CAF, therapies appear be an essential component of FAC (considered for patients at high risk). Other options include individual setting. an effective adjuvant therapy program. Whether †Risk factors include pathologic tumor > 2 cm, grade 2/3 disease, medial tumors, and vascular invasion. use of “optimal” endocrine therapy (eg, ovarian ‡The threshold for considering addition of chemotherapy to endocrine therapies may depend on function suppression plus tamoxifen) may be the degree of confidence in endocrine responsiveness. Considerations about a low relative risk, age, toxic effects, socioeconomic implications, and information on patient preference might sufficient for these patients is a hypothesis that justify the use of endocrine therapy alone. has not been tested adequately. It must be recAbbreviations: AC = doxorubicin/cyclophosphamide; CAF = cyclophosphamide/doxorubicin/ 5-fluorouracil; CEF = cyclophosphamide/epirubicin/5-fluorouracil; ER = estrogen receptor; ognized that factors influencing acceptance of FAC = 5-fluorouracil/doxorubicin/cyclophosphamide; GnRH = gonadotropin-releasing endocrine therapies by very young women are hormone; PgR = progesterone receptor complex, involving issues such as treatment duwomen differ from those of tumors in nonpregnant women, ration (typically several years), induced menopausal sympmainly a more frequent ER- and PgR-negative status34 and toms, and issues of sexual function and family planning. more probable lymph node involvement at diagnosis, theoretically because of delay in tumor appearance.35 Social, Sexual, and Psychologic Issues Chemotherapy is relatively safe after the first trimester, as According to recent consensus, patient preferences are shown by most reports,36 even though its long-term effect is crucial for therapeutic decision-making. The side effects of still unknown. Hormonal therapy should be avoided in the adjuvant endocrine and chemotherapeutic treatments must first trimester because it generates fetal anomalies and, in be carefully explained, and potential gains of its addition to the later phases, the effects remain ambiguous. surgery and, in some circumstances, radiation therapy must be viewed in light of the morbidity of such treatments. Conclusion Younger women might be particularly vulnerable to the Treatment decision-making for very young women with emotional distress of the disease because they need to face newly diagnosed breast cancer may be affected by the strong disease and treatments before attaining many personal acemotional involvement of care providers. There is a lack of complishments. Questions about fertility and pregnancy, information about adjuvant treatment in very young sexual function, early menopausal symptoms, family, work, women. There is an urgent need for tailored treatment inand other personal accomplishments must be discussed with vestigations, especially in this younger population, for whom the intent to significantly reduce anxiety and facilitate treatchemotherapy is prescribed universally. In Figure 1, we proment per the patient’s choice. pose a therapeutic algorithm for the choice of adjuvant therapy in very young women based on biologic and endocrine Breast Cancer and Pregnancy features. Endocrine therapies can be affected by several adApproximately 10% of breast cancer cases in very young verse events on sexual and reproductive functions and are 32 patients occur during pregnancy. Interpretation of issues therefore difficult to offer to very young patients. These apin clinical examination and mammography related to breast proaches need to be investigated in hormone-responsive disfirmness and density represent a limit for breast cancer diease because substantial evidence exists that current apagnosis.33 Some biologic features of tumors in pregnant

Clinical Breast Cancer June 2004 • 129

Adjuvant Therapy in Very Young Women proaches are suboptimal. It is important to improve the understanding of how best to use endocrine approaches, including ovarian function suppression, use of selective ER modulators and other endocrine agents, and possible timing of surgery with respect to the phase in the menstrual cycle. Other questions that should be considered in the group of patients with endocrine-nonresponsive tumors relate to timing, duration, and intensity of chemotherapy. A patient’s desire to become pregnant should be considered in the process of decision-making. Accrual of younger women in current clinical trials is not sufficient to obtain significant information on treatment of these patients. Prospective global cooperative trials to investigate the optimal therapeutic approach in these young patients is needed.

References 1. 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. 2. Aebi S, Gelber S, Castiglione-Gertsch M, et al. Is chemotherapy alone adequate for young women with oestrogen-receptor-positive breast cancer? Lancet 2000; 355:1869-1874. 3. Walker RA, Lees E, Webb MB, et al. Breast carcinomas occurring in young women (<35 years) are different. Br J Cancer 1996; 74:1796-1800. 4. Chung M, Chang HR, Bland KI, et al. Younger women with breast carcinoma have a poorer prognosis than older women. Cancer 1996; 77:97-103. 5. Colleoni M, Rotmensz N, Robertson C, et al. Very young women (<35 years) with operable breast cancer: features of disease at presentation. Ann Oncol 2002; 13:273-279. 6. Winchester DP, Osteen RT, Menck HR. The National Cancer Data Base report on breast carcinoma characteristics and outcome in relation to age. Cancer 1996; 78:1838-1843. 7. The International Breast Cancer Study Group. Duration and reintroduction of adjuvant chemotherapy for node-positive premenopausal breast cancer patients. J Clin Oncol 1996;14:1885-1894. 8. Ludwig Breast Cancer Study Group. A randomized trial of adjuvant combination chemotherapy with or without prednisone in premenopausal breast cancer patients with metastases in one to three axillary lymph nodes. Cancer Res 1985; 45:4454-4459. 9. Ludwig Breast Cancer Study Group. Combination adjuvant chemotherapy for node-positive breast cancer. Inadequacy of a single perioperative cycle. N Engl J Med 1988; 319:677-683. 10. Goldhirsch A, Gelber RD, Yothers G, et al. Adjuvant therapy for very young women with breast cancer: need for tailored treatments. J Natl Cancer Inst Monogr 2001; 30:44-51. 11. Goldhirsch A, Gelber RD, Castiglione M. The magnitude of endocrine effects of adjuvant chemotherapy for premenopausal breast cancer patients. The International Breast Cancer Study Group. Ann Oncol 1990; 1:183-188. 12. Nystedt M, Berglund G, Bolund C et al. Side effects of adjuvant endocrine treatment in premenopausal breast cancer patients: a prospective randomized study. J Clin Oncol 2003; 21:1836-1844. 13. Adami HO, Malker B, Holmberg L, et al. The relation between survival and age at diagnosis in breast cancer. N Engl J Med 1986; 315:559-563. 14. Kollias J, Elston CW, Ellis IO, et al. Early-onset breast cancer— histopathological and prognostic considerations. Br J Cancer 1997; 75:1318-1323. 15. 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. 16. Holli K, Isola J. Effect of age on the survival of breast cancer pa-

130 • Clinical Breast Cancer June 2004

tients. Eur J Cancer 1997; 33:425-428. 17. Jeng MH, Shupnik MA, Bender TP et al. Estrogen receptor expression and function in long-term estrogen-deprived human breast cancer cells. Endocrinol 1998; 139:4164-4174. 18. Harvey JM, Clark GM, Osborne CK, et al. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 1999; 17:1474-1481. 19. Pagani O, O’Neill A, Castiglione M, et al. Prognostic impact of amenorrhoea after adjuvant chemotherapy in premenopausal breast cancer patients with axillary node involvement: results of the International Breast Cancer Study Group (IBCSG) Trial VI. Eur J Cancer 1998; 34:632-640. 20. Kroman N, Jensen MB, Wohlfahrt J, et al. Factors influencing the effect of age on prognosis in breast cancer: population based study. Br Med J 2000; 320:474-478. 21. Ludwig Breast Cancer Study Group. Chemotherapy with or without oophorectomy in high-risk premenopausal patients with operable breast cancer. J Clin Oncol 1985; 3:1059-1067. 22. Fisher B, Bauer M, Margolese R, et al. Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N Engl J Med 1985; 312:665-673. 23. Fisher B, Anderson S, Redmond CK, et al. Reanalysis and results after 12 years of follow-up in a randomised clinical trial comparing total mastectomy with lumpectomy with and without irradiation in the treatment of breast cancer. N Engl J Med 1995; 333:1456-1461. 24. Fisher B, Redmond C, Brown A, et al. Treatment of primary breast cancer with chemotherapy and tamoxifen. N Engl J Med 1981; 305:1-6. 25. Wickerham D, Fisher B, Cronin W. The efficacy of bone scanning in the follow-up of patients with operable breast cancer. Breast Cancer Res Treat 1984; 4:303-307. 26. Fisher B, Wickerham D, Redmond C, et al. Increased benefit from addition of adriamycin to adjuvant therapy for stage II breast cancer: results from NSABP protocols B-11 and –12. Proc Am Soc Clin Oncol 1987; 6:62 (Abstract #62) 27. Fisher B, Brown AM, Dimitrov NV, et al. Two months of doxorubicin–cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 1990; 8:1483-1496. 28. Fisher B, Redmond C, Legault-Poisson S, et al. Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Surgical Adjuvant Breast and Bowel Project B-16. J Clin Oncol 1990; 8:1005-1018. 29. Fisher B, Anderson S, Wickerham DL, et al. Increased intensification and total dose of cyclophosphamide in a doxorubicin–cyclophosphamide regimen for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-22. J Clin Oncol 1997; 15:1858-1869. 30. Fisher B, Anderson S, DeCillis A, et al. Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-25. J Clin Oncol 1999; 17:33743388. 31. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature 2000; 406:747-752. 32. Merkel D. Pregnancy and breast cancer. Semin Surg Oncol 1996; 12:370-375 33. Liberman L, Giess C, Dershaw D, et al. Imaging of pregnancy-associated breast cancer. Radiology 1994; 191:245-248. 34. Elledge R, Ciocca D, Langone G, et al. Estrogen receptor, progesterone receptor and HER-2/neu protein in breast cancers from pregnant patients. Cancer 1993; 71:2499-2506. 35. Guinee VF, Olsson H, Moller T, et al. Effect of pregnancy on prognosis for young women with breast cancer. Lancet 1994; 343:1587-1589. 36. Williams S, Schilsky R. Antineoplastic drugs administred during pregnancy. Semin Oncol 2000; 27:618-622.