Gonadotropin-releasing hormone analogues added to adjuvant chemotherapy protect ovarian function and improve clinical outcomes in young women with early breast carcinoma

Authors


Abstract

BACKGROUND

The objective of the current study was a retrospective evaluation of 100 consecutive premenopausal women with high-risk, early breast carcinoma who received a gonadotropin-releasing hormone (Gn-RH) analogue as ovarian protection during adjuvant chemotherapy.

METHODS

After surgery, patients received a Gn-RH analogue and adjuvant chemotherapy, which was tailored to their peculiar biologic features. The median patient age was 43 years (range, 27–50 yrs). Fifty-two women had positive estrogen receptor (ER) status, and 48 women had negative ER status. There were 64 women with Stage II breast carcinoma and 36 women with UICC Stage III breast carcinoma. All patients had their serum estradiol suppressed to values < 40 pg/mL. The chemotherapy regimens administered included cyclophosphamide, methotrexate, and 5-fluorouracil (n = 26 patients) and anthracycline-based regimens (n = 74 patients, including 9 patients who had > 10 positive axillary lymph nodes, who also received high-dose chemotherapy with autologous peripheral blood progenitor cell transplantation). Patients with positive c-erb-2 status also received a taxane. Eighty patients received radiation therapy. During therapy with the Gn-RH analogue, patients who had a positive ER status after chemotherapy received an aromatase inhibitor.

RESULTS

After a median follow-up of 75 months, normal menses were resumed by all patients younger than age 40 years and by 56% of patients older than age 40 years. Three pregnancies were observed that resulted in two normal deliveries and one voluntary abortion. The projected recurrence-free survival rates at 5 years and 10 years were 84% and 76%, respectively; and the projected overall survival rates at 5 years and 10 years were 96% and 91%, respectively.

CONCLUSIONS

The current data showed that, in premenopausal women with early breast carcinoma, the addition of a Gn-RH analogue to adjuvant therapy and temporary total estrogen suppression in patients with ER-positive disease was tolerated well, protected long-term ovarian function, and appeared to improve the expected clinical outcome. Cancer 2006. © 2005 American Cancer Society.

With the progress and the refinements in oncology, more attention is paid to the side effects induced by chemotherapy, and new ways are sought to decrease toxicity and improve the quality of life. Indeed, adjuvant chemotherapy reduces recurrence rates and prolongs the survival of patients with breast carcinoma at the cost of both acute and chronic toxicities.1 Premenopausal patients, which comprise 25% of all women who are diagnosed with breast carcinoma,2 reportedly have more aggressive tumors and have disease that is associated with a more unfavorable prognosis compared with the disease in older patients.3 For this reason, chemotherapy, rather than hormone therapy, more commonly is included as part of the treatment plan of premenopausal patients. In addition, the absolute benefit from chemotherapy is greater in younger women, and treatment for breast carcinoma increasingly has come to include chemotherapy, even for women early-stage tumors.4 Hence, chemotherapy has become an essential component of the treatment of many premenopausal breast carcinomas.

Breast carcinoma survivors who have received adjuvant chemotherapy may suffer from late effects of chemotherapy, including congestive heart failure, neuropathy, osteoporosis, and premature menopause. Ovarian failure is most likely one of the most significant long-term sequelae of adjuvant chemotherapy in premenopausal breast carcinoma survivors.5 Early menopause has serious vasomotor effects (hot flashes), psychologic effects (depressive illness), cardiac effects (increased risk of cardiovascular disease and mortality),6 skeletal effects (osteoporosis),7 and genitourinary atrophy. The effects of early menopause may be more important at younger biologic ages, with rapid and substantial effects not only on withdrawal of sex hormones but also on androsterone, on adrenal and pituitary functions, and on lipid and carbohydrate metabolism.8 Estrogen-replacement therapy, which may abrogate, at least in part, the negative effects of early menopause, increases the risk of breast carcinoma by 5% per year of use.9 Conversely, there is the finding that chemotherapy, tamoxifen, and ovarian ablation (by surgery or radiation) individually are effective adjuvant treatment modalities in women age 50 years and younger.1

The incidence of chemotherapy-related amenorrhea reportedly was 68% in patients who are treated with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF)-like regimens,5 and it was higher for patients who were treated with anthracycline-based regimens.10 In addition, chemotherapy-induced amenorrhea has been considered beneficial in patients with estrogen receptor (ER)-positive tumors, but its utility in patients with ER-tumors is questionable.

In a previously reported study, we showed that the administration of a gonadotropin-releasing hormone (Gn-RH) analogue for 1 year, during chemotherapy, protected the ovarian function in 86% of patients.11 In that study, after a median follow-up of 55 months, we observed that 86% of patients were disease free. After the observations that the majority of locoregional and systemic recurrences occurred in patients who had ER-positive tumors in the second year, the protocol was emended: The therapy with the analogue was continued for 2 years, and an aromatase inhibitor was given to patients who had ER-positive tumors after the end of chemotherapy, during the second year of treatment with the analogue.

The primary endpoint of the trial was the evaluation of the efficacy in protecting ovarian function of premenopausal women with early breast carcinoma who were treated with adjuvant chemotherapy. Secondary endpoints were the determination of disease-free survival and overall survival. In the current study, we report the clinical outcome of 100 consecutive patients, with a median follow-up of 75 months (minimum, 32 mos), who received treatment with the Gn-RH analogue during adjuvant chemotherapy for early breast carcinoma.

MATERIALS AND METHODS

Study Design and Patient Selection

Patients who were diagnosed with unilateral adenocarcinoma of the breast (pathologic tumor [pT] Stage pT2–pT3a), with positive or negative lymph node status, and with no metastasis who had undergone modified radical mastectomy or breast-conserving surgery plus full axillary lymph node dissection were recruited into the study. Patients had to be menstruating actively and had to be between ages 18 years and 50 years (premenopausal status with follicle-stimulating hormone [FSH] levels < 10 mU/mL, luteinizing hormone [LH] levels < 0.8 mU/mL, 17-β estradiol levels between 20 pg/mL and 693 pg/mL, and progesterone levels between 0.15 ng/mL and 28 ng/mL), and they were required to have an Eastern Cooperative Oncology Group performance status of 0–1. Macroscopic metastatic spread of the disease was excluded by the usual criteria. The following laboratory parameters were required: granulocyte count ≥ 2000 × 109/L, platelet count ≥ 100,000 × 109/L, hematocrit ≥ 30%, total bilirubin and aspartate aminotransferase levels ≤ 1.5 times the upper limit of normal, serum creatinine concentration ≤ 1.8 mg/dL, and left ventricular ejection fraction ≥ 50%. Bilateral bone marrow aspirates and biopsies with cytokeratin immunostaining were performed routinely in patients who had greater than five positive axillary lymph nodes and in the presence of radiographic or scintigraphic pelvic bone abnormalities. Patients who had histologically documented metastases were excluded, as were patients who had malignancies other than curatively treated skin and cervical carcinomas. No prior chemotherapy or hormone therapy was permitted. All patients provided written informed consent. Patients underwent clinical follow-up examinations every 6 months. The study was performed according to the Declaration of Helsinki after local Ethics Committee approval was obtained.

Treatment Plan

During the first part of the study,11 3 weeks after surgery, and 1 week before the initiation of chemotherapy, patients received goserelin at a dose of 3.6 mg subcutaneously and then received it every 28 days for 1 year. In the second part of the study, patients received the same analogue at a dose of 11.25 mg every 84 days for 2 years; in addition, patients received adjuvant chemotherapy, with the appropriate regimen determined according to the characteristic of the tumor and the prognosis of the patient.

Twenty-six patients with a median age of 42 years who had T2–T3 tumors, no axillary lymph node involvement, positive ER and progesterone receptor (PGR) tumors, and a low proliferation rate (evaluated by Ki-67)12 received 4 courses of cyclophosphamide at a dose of 600 mg/m2, 5-fluorouracil at a dose of 600 mg/m2, and methotrexate at a dose of 40 mg/m2 on Days 1 and 8, repeated every 4 weeks; then, patients received 4 courses of the same chemotherapy administered on Day 1 every 3 weeks concomitantly with radiation therapy. These patients received a cumulative cyclophosphamide dose of 7200 mg/m2.

Eleven patients with a median age of 39 years who had T1–T3 tumors, < 3 positive axillary lymph nodes, negative or positive ER status, and negative or positive PGR status received cyclophosphamide at a dose of 600 mg/m2 and epirubicin at a dose of 75 mg/m2 on Days 1 and 5-fluorouracil at a dose of 600 mg/m2 on Days 1 and 8 every 3 weeks for 6 courses. In these patients, radiation therapy was administered after the end of the anthracycline-based chemotherapy, and their total cyclophosphamide dose was 3600 mg/m2.

Fifty-four patients with a median age of 42 years who had the same characteristics as the group of 11 patients described above and who also had < 5 positive axillary lymph nodes, along with 2 patients who had > 10 positive axillary lymph nodes who refused high-dose chemotherapy with peripheral blood progenitor cell (PBPC) transplantation, were treated with 4 courses of epirubicin 120 mg/m2 and 8 courses of CMF every 3 weeks.13 These patients received a total cyclophosphamide dose of 4800 mg/m2. The treatment plan is illustrated in Figure 1.

Figure 1.

This chart illustrates the current study design. AI: aromatase inhibitor; ER+: estrogen receptor positive; TAM: tamoxifen; UID: once daily.

Nine patients who had > 10 axillary positive lymph nodes and a median age of 37 years received the first course of chemotherapy with epirubicin at a dose of 120 mg/m2. Granulocyte colony-stimulating factor (5 μg/kg) was administered after chemotherapy for 9–10 days. Patients underwent leukapheresis, and a median of 8.45 × 106 CD34-positive cells were collected from each patient. These patients received 3 further courses of epirubicin at a dose of 120 mg/m2. High-dose chemotherapy consisted of carboplatin at a dose of 600 mg/m2 on Days − 3 and − 2, etoposide at a dose of 450 mg/m2 on Days − 3 and − 2, and melphalan at a dose of 100 mg/m2 on Day − 1. PBPCs were reinfused on Day 0. After PBPC transplantation, patients received 8 courses of CMF chemotherapy, which were delivered every 21 days, along with radiation therapy. These patients received 100 mg/m2 of melphalan and 4800 mg/m2 of cyclophosphamide. Sixty-nine patients who had undergone segmental mastectomy and 11 patients who had undergone modified radical mastectomy for high-risk axillary lymph nodes or T3 tumors received radiation therapy after the end of the anthracycline-based chemotherapy or concomitantly with CMF.

Patients with c-erb-2-positive tumors received 4 courses of a taxane after the end of anthracycline chemotherapy or CMF and radiation therapy. Twenty-eight ER-positive patients received anastrazole during administration of the Gn-RH analogue, after the end of chemotherapy, to achieve complete estrogen ablation. During the study, all patients received supplemental vitamin D, calcium, and diphosphonates. After the completion of chemotherapy, all patients with ER-positive tumors received either tamoxifen at a dose of 20 mg daily for 5 years or an aromatase inhibitor when there was a contraindication for tamoxifen, if they had become menopausal after the end of chemotherapy.

Statistical Analysis

The date of recurrence was defined as the time when recurrent disease was diagnosed. Disease-free survival was defined as the time from the date of the first Gn-RH dose to any recurrence, the appearance of a second primary tumor, or death, whichever occurred first. Disease-free survival and overall survival were estimated by using the Kaplan–Meier product-limit method.14 Survival curves for subgroups of patients were compared by using the log-rank test. Adverse events were monitored by using Standard World Health Organization criteria.15

Analysis of data was performed in March 2005. All patients were evaluated according to an intention-to-treat principle.

RESULTS

Patient Characteristics

The baseline demographics and tumor characteristics of patients are shown in Table 1. Between September 1993 and October 2004, 125 consecutive patients who had been diagnosed with unilateral adenocarcinoma of the breast, pathologic tumor (pT) Stage pT2–pT3a, with negative or positive lymph node status, and without metastasis who had undergone modified radical mastectomy or breast-conserving surgery plus full axillary lymph node dissection were recruited into the study if there was an indication for adjuvant chemotherapy. In the current analysis, we considered only 100 consecutive patients who were entered on the study until August 2002 and had a minimum follow-up of 32 months. All of these patients could be evaluated fully for ovarian function protection. All patients had a good performance status and a median age of 43 years (range, 27–50 yrs). All women were menstruating at the time of their breast carcinoma diagnosis and had normal gonadotropin, estradiol, and progesterone values. Overall, 40% of patients had 1–3 positive lymph nodes, and 18% of patients had 4–21 positive lymph nodes. ER status was known for all patients, and 52% had ER-positive tumors. Treatment compliance was good, because all patients received the assigned treatment with the Gn-RH analogue, chemotherapy, radiation therapy, and hormone therapy.

Table 1. Patient and Tumor Characteristics
CharacteristicNo. of patientsPercent
  1. ER: estrogen receptor; UICC: International Union Against Cancer; LN: lymph node.

No. of patients100100
Age  
 Median43 yrs 
 Range27–50 yrs 
Hormone receptor status  
 ER positive5252
 ER negative4848
Tumor histology  
 Ductal infiltrating7676
 Lobular infiltrating1313
 Medullary55
 Other66
Histopathologic tumor grade  
 Grade 1–24444
 Grade 35656
Clinical stage (UICC)  
 Stage IIA4848
 Stage IIB1616
 Stage IIIA1111
 Stage IIIB1616
 Stage IIIC99
No. of positive LNs  
 04242
 1–34040
 4–977
 > 101111
Type of primary surgery  
 Mastectomy3232
 Quadrantectomy6868

Time to Disease Progression and Fertility

After a median follow-up of 75 months, all patients had completed chemotherapy and treatment with the Gn-RH analogue. When treatment was discontinued, 67% of women resumed normal menses and recovered appropriate FSH, LH, 17-β estradiol, and progesterone levels. All women younger than age 40 years had normal menses, including 5 women who had received high-dose chemotherapy and PBPC transplantation. One of the patients who received high-dose chemotherapy and PBPC transplantation became pregnant and underwent a voluntary abortion. Five years after chemotherapy and radiation therapy, two patients completed normal pregnancies that resulted in the birth of healthy children at term.

Disease recurred locally in 4 patients between 26 months and 111 months after the start of treatment (Fig. 2). Patients with recurrent disease underwent resection, and they received additional systemic and locoregional therapies as necessary. Contralateral breast carcinoma was observed in two women: Both patients had ER-negative and PGR-negative tumors. Both underwent salvage radical mastectomy, and both remained free of disease at the time of last follow-up. An additional 9 patients developed systemic recurrences, mostly in the second year after mastectomy, after a median of 36 months: two patients had achieved a complete response to chemoimmunotherapy, 2 patients still had disease and were receiving treatment, and 5 patients had died. One patient (age 37 yrs) who had ER-positive breast carcinoma and 1 positive axillary lymph node at the time of study entry developed a recurrence in the pelvic bones 2 years after the completion of the adjuvant treatment. She had a response to taxane-based chemotherapy, and she survived for 29 months. A second patient who had 21 positive lymph nodes and an ER-positive tumor had a bone recurrence 25 months after high-dose chemotherapy and underwent PBPC transplantation. She received radiation therapy, taxanes, and gemcitabine chemotherapy but died 30 months after the recurrence. The third patient, who had 17 positive axillary lymph nodes and ER-positive breast carcinoma, developed bilateral lung metastases 12 months after the end of adjuvant chemotherapy with PBPC transplantation. She was treated with a taxane-based chemotherapy regimen and underwent lung metastasectomy. This patient died 19 months after the recurrence. The fourth patient, who had 11 positive axillary lymph nodes and an ER-positive tumor, developed a recurrence 27 months after high-dose chemotherapy with PBPC transplantation. She died 83 months later, after failing on taxane-based chemotherapy. The fifth patient, who had an ER-negative tumor and 10 positive axillary lymph nodes, had refused high-dose chemotherapy and developed liver metastases within 23 months after surgery; she died 9 months after development of the recurrence.

Figure 2.

This graph illustrates the cumulative incidence of unfavorable events.

The actuarial median time to disease progression and overall survival (Figs. 3, 4) had not been reached at the time of last follow-up, because 77% of patients were disease free, and 92% were alive when the data analyses were performed. The projected disease-free survival rates at 1 year, 5 years, and 10 years were 100%, 84%, and 77%, respectively. The projected overall survival rates at 1 year, 5 years, and 10 years were 100%, 96%, and 92%, respectively. There were no significant differences noted in the subcategories of treated patients with regard to disease-free survival or overall survival (Table 2). Patients who had positive axillary lymph nodes had disease-free survival and overall survival rates that did not differ statistically from the rates in patients who had negative lymph node status (P = 0.3 and P = 0.5, respectively). A borderline, statistically significant difference was observed in disease-free and overall survival of patients who had histopathologic Grade 1 and 2 tumors compared with patients who had Grade 3 tumors (P = 0.06 and P = 0.055, respectively). Patients who had ER-positive tumors at 10 years had a disease-free survival rate of 89%, whereas patients who had ER-negative tumors had a disease-free survival rate of 61% (P = 0.056). With regard to survival, patients who had ER negative tumors had a 10-year survival rate of 93%, whereas patients who had ER-positive tumors had a 10-year survival rate of 91%. Even if this difference in the survival rate did not reach statistical significance, a marginally better survival for premenopausal women with ER-negative tumors has been observed by us16 and by other investigators.17 None of the 38 patients who received the analogue for 2 years developed a disease recurrence after a median follow-up of 36 months (range, 28–58 mos). This was the only statistically significant difference noted in disease-free survival between the 62 patients who received the analogue for 1 year and the 38 patients who received it for 2 years (Fig. 5) and received the aromatase inhibitor after the end of chemotherapy (P = 0.02; log-rank test). In particular, none of the 30 patients who had ER-positive tumors developed recurrent disease.

Figure 3.

The time to disease progression is illustrated (events, 15 [15%]; censored, 85 patients [85%]). The median follow-up was 75 months. The 5-year disease-free survival (DFS) rate was 84%, and the 10-year DFS rate was 76%.

Figure 4.

Overall survival is illustrated (events, 5 [5%]; censored, 95 patients [95%]). The median follow-up was 75 months. The 5-year survival rate was 96%, and the 10-year survival rate was 92%.

Table 2. Tumor Characteristics and Clinical Outcome
CharacteristicPFS rate (%)Survival rate (%)
5 yrs10 yrsP valuea5 yrs10 yrsP valuea
  • PFS: progression-free survival; LN: lymph node; ER: estrogen receptor; LH-RH: luteinizing hormone-releasing hormone.

  • a

    P values were determined using the log-rank test.

LN status      
 Positive81760.309594880.5246
 Negative9168 9168 
Histopathologic tumor grade      
 Grade 1–296750.061001000.055
 Grade 37575 9487 
ER status      
 Positive89890.05696910.116
 Negative7961 9393 
Menses      
 Positive86740.9696880.97
 Negative8080 9789 
Negative LN status      
 ER-negative tumor100670.61001000.2
 ER-positive tumor9090 100100 
LH-RH treatment      
 1 yr79720.0295900.34
 2 yrs100  100  
Figure 5.

At a median follow-up of 2 years, the time to disease progression for the patients who received the analog for 2 years was superior compared with patients who received the analog for 1 year (log-rank test; P = 0.02).

Toxicity

The adverse events that were reported during the chemotherapeutic treatment are shown in Table 3.

Table 3. Grade 3–4 Toxicity
ToxicityType of therapy: No. of patients (%)
Gn-RH analogue (n = 100 patients)CMF (n = 26 patients)Anthracycline-based CT (n = 65 patients)HD-CT and PBPC (n = 9 patients)
  1. Gn-RH: gonadotropin-releasing hormone; CMF: cyclophosphamide, methotrexate, and 5-fluorouracil; CT: chemotherapy; HD-CT: high-dose chemotherapy; PBPC: peripheral blood progenitor cell transplantation.

Hematologic    
 Leukopenia02 (8)18 (28)9 (100)
 Thrombocytopenia0009 (100)
 Anemia   3 (33)
Gastrointestinal    
 Nausea and emesis05 (19)9 (13)3 (33)
 Diarrhea02 (8)3 (5)3 (33)
 Mucositis0 2 (3)4 (44)
Infection002 (3)1 (11)
Neurotoxicity0000
Alopecia0065 (100)9 (100)
Hot flushes26 (26)000

Goserelin

Twenty-six patients (26%) complained of hot flushes.

CMF chemotherapy

No unexpected toxicity occurred during the administration of CMF chemotherapy (toxicity grading performed according to NCI Common Toxicity Criteria), and all 26 patients completed the scheduled treatment. Grade 2 hematologic toxicity occurred in 2 patients (8%), Grade 2 diarrhea occurred in 2 patients (8%), and 5 patients (19%) reported nausea and emesis. There were no treatment-related deaths reported.

Anthracycline-based chemotherapy

Grade 3–4 hematologic toxicity occurred in 18 of 65 patients (28%) who received anthracycline-based chemotherapy. Gastrointestinal toxicity (diarrhea and mucositis) was observed in 5 patients (8%). Severe nausea and emesis occurred in 9 patients (13%). Infection was reported in 2 patients (3%). Grade 3 alopecia was observed in all patients. No significant reduction in left ventricular ejection fraction was observed in any patient, and there were no treatment-related deaths.

High-dose chemotherapy

Nausea and emesis and other episodes of gastrointestinal toxicity occurred in 10 instances but were mild because of the appropriate use of ondansetron and dexamethasone. Neutropenia and thrombocytopenia Grade 4 were observed in all patients. An absolute neutrophil count of < 5 × 103/mL was observed for a median of 4.5 days (range, 3–5 days), and a platelet count of < 20 × 103/mL occurred for a median of 1 day (range, 0–3 days). Three patients required a platelet transfusion (median, 2 units). Anemia, which was infrequent because of the use of erythropoietin, occurred in 3 patients (33%). Three patients had fever > 38 °C for a median of 3 days (range, 0–6) days. Grade 2 mucositis occurred in 4 patients, and Grade 3 diarrhea occurred in 3 patients (33%). One patient had a documented infection with a positive blood culture for Staphylococcus epidermidis. Bone pain was reported by 2 patients and had a median duration of 2 days. There were no treatment-related deaths.

DISCUSSION

In the past, adjuvant chemotherapy was considered the mainstay for the treatment of premenopausal women with early breast carcinoma.1 In recent years, because of the unsatisfactory outcomes of some groups of patients, the improvements in our knowledge, and the search for less toxic therapies, more importance has been attributed to hormone manipulation in premenopausal women with breast carcinoma. Ovarian ablation most likely is the oldest treatment modality for breast carcinoma.18 Moreover, the prognosis for women who develop amenorrhea, even temporarily, from CMF chemotherapy tends to be better compared with the prognosis for women who continue to menstruate,19 and amenorrhea induced by adjuvant chemotherapy has a prognostic value independent of age, number of involved lymph nodes, tumor size, and amount of chemotherapy administered.20 In an analytical overview by the Early Breast Cancer Trialists' Collaborative Group, it was observed that ovarian ablation reduced the annual odds of recurrence and death by 20% for women younger than age 50 years who were affected by breast carcinoma and received ovarian ablation or chemotherapy.21 The value of ovarian ablation in combination with tamoxifen was demonstrated in a study of 709 premenopausal Asian women with operable breast carcinoma. Those patients were randomized to undergo oophorectomy and receive tamoxifen for 5 years or observation only. After a median follow-up of 3.1 years, the disease-free survival rates were 73% and 54%, in the adjuvant and observation groups, respectively (P = 0.001), and the corresponding overall survival rates were 76% and 65%. That trial, which was justified in a society that was deficient of medical resources, demonstrated, without confounding factors, the value of adjuvant ovarian ablation in premenopausal women with breast carcinoma.22 In addition, the results from several large, randomized trials recently have confirmed the role of Gn-RH analogues in the adjuvant treatment of early breast carcinoma either as monotherapy23 or in combination with tamoxifen and/or chemotherapy.24, 25 In particular, the Zoladex Early Breast Cancer Research Association trial, which compared the efficacy and tolerability of goserelin with that of CMF, after a median follow-up of 7.3 years, showed equivalence between goserelin and CMF for disease-free survival and overall survival in patients with ER positive disease and demonstrated the superiority of CMF for both disease-free survival and overall survival compared with goserelin in patients who had ER-negative tumors.25

Because of the presence of several heterogeneous cell populations in the same breast carcinoma, theoretically, neither ovarian ablation nor chemotherapy is capable of eradicating all cell clones that compose a tumor. Moreover, there are great differences between various tumor types. For this reason, we adopted the strategy of tailoring the chemotherapy regimen to the biologic characteristics of each pathologic condition. Patients with low-risk disease received CMF-based chemotherapy. Patients who had higher risk disease received anthracycline-based chemotherapy followed by CMF administered concomitantly with radiation therapy. Patients who had the highest risk received an anthracycline-based regimen followed by high-dose chemotherapy and PBPC transplantation. All patients who had c-erb-2-positive tumors (according to fluorescence in situ hybridization analysis) also received 4 courses of taxane-based chemotherapy. With the objective of protecting the ovaries from the damage of chemotherapy, we administered a Gn-RH analogue to all patients at least 1 week before the initiation of chemotherapy. With this procedure, we may have reduced the likelihood of ovarian damage, because it has been shown that the ovarian epithelium is in G0-phase after the administration of the Gn-RH analogue.26

We also adopted another strategy: total estrogenic blockade in patients with ER-positive tumors. In fact, in the second part of the study, patients who had ER-positive tumors received an aromatase inhibitor, anastrazole, during their therapy with the Gn-RH analogue. In this manner, patients had all of the benefits of chemotherapy and hormone therapy. Fortunately, in fact, the effects of endocrine therapy and chemotherapy tend to be independent of each other, and patients can receive the full benefits of both types of therapy.27 None of the 36 patients who received the analogue and anastrazole for 2 years had developed a recurrence after a median follow-up of 40 months. Patients who received the analogue for 1 year without total estrogen blockade, after the same follow-up, had a 16% probability of developing locoregional and systemic recurrences (P = 0.02).

Even if there are no firmly established data concerning ovarian ablation during adjuvant chemotherapy, our data support the hypothesis that further benefit is added to the adjuvant treatment of women with early breast carcinoma if ovarian ablation and an aromatase inhibitor is added to chemotherapy. In fact, ovarian function was suppressed by using the Gn-RH analogue. With ovarian suppression, the greater source of endogenous estrogen is removed. However, certain amounts of estrogens are derived from the peripheral aromatization of adrenal androgens. With aromatase inhibitors, we have suppressed all sources of estrogens; and, during this treatment, any tumor cells that survive chemotherapy should go into programmed cell death (apoptosis) because of the absence of estrogen-stimulated cell growth.28 In a different disease setting, endometriosis, in which estrogen suppression is fundamental for disease control, a statistically significant advantage has been demonstrated with the Gn-RH analogue plus anastrazole inhibitor compared with the Gn-RH analogue alone.29 In addition, it has been shown recently that the function of the Gn-RH analogues is not restricted to hormone deprivation. In fact, they behave like negative growth factors that are capable of regulating breast carcinoma cell growth, in particular antagonizing the action of minimal quantities of estrogen.30 Both the estrogen deprivation caused by the Gn-RH analogues and their direct effect may induce apoptosis in cells that survive chemotherapy.31 Several studies have described that a subsequent pregnancy after breast carcinoma has no adverse effect on prognosis.32 Indeed, this may contribute to the psychological well being of the young woman who has breast carcinoma. In a series of 227 women who had breast carcinoma at a median age of 31 years and received treatment with a doxorubicin-based chemotherapy regimen, 59% of women continued to menstruate after chemotherapy, and 11% became pregnant.33

In the current study, the incidence of chemotherapy-related amenorrhea was 44% in patients in the group ages 40–50 years. None of the patients younger than age 40 years developed drug-induced amenorrhea. Moreover, we observed three pregnancies, which resulted in two normal deliveries and one voluntary abortion. Five patients who resumed normal menses had received treatment with high-dose chemotherapy and PBPC transplantation.

In a recently published randomized study, the role of ovarian suppression was evaluated in patients with early breast carcinoma who had received previous treatment with surgery and adjuvant chemotherapy.34 In that study, patients who were randomized to the ovarian ablation arm were treated with the Gn-RH analogue or with radiation therapy after the end of locoregional therapy. Ovaries in these patients were not protected during chemotherapy; and, in patients whose ovaries continued to function during chemotherapy, a normal secretion of estrogen occurred until the patients received either radiation therapy or the analogue. In the current trial, there was no difference in recurrences between ER-positive and ER-negative patients. The only subgroup that appeared to benefit from ovarian suppression was the group of patients younger than age 40 years who had ER-positive tumors. It should be considered that, very often, in patients with high body mass, chemotherapy is not capable of inhibiting ovarian function. In this group of young patients, we had to increase the amount of administered Gn-RH analogue up to a quantity of 11.25 mg every 28 days.

Based on data from the current study, it appears that the administration of Gn-RH analogue in combination with chemotherapy is feasible and well tolerated. Furthermore, it may offer a benefit directly to women with ER-positive breast carcinoma through hormone deprivation and indirectly to all patients with breast carcinoma by allowing normal menses to be restored at the cessation of treatment.

Ancillary