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A 34-year-old mother of a four-year-old son presented to her GP with a left breast lump of three months’ duration. She had no significant past medical or surgical histories and no family history of breast or ovarian cancer. There was a mass in the upper outer quadrant of the left breast with no palpable lymphadenopathy.
Mammography and breast ultrasound revealed a malignant-appearing left breast lesion with no axillary lymphadenopathy. Biopsy of the breast lesion revealed a grade III invasive ductal carcinoma, which was oestrogen- and progesterone receptor-positive and HER2-negative. Lymphovascular invasion was present.
The patient proceeded to breast-conserving surgery, which was uneventful. Histopathology revealed a tumour with axillary node-positive disease. The patient proceeded to have adjuvant systemic chemotherapy. Prior to starting this therapy, she began subcutaneous triptorelin injections monthly in an effort to preserve her ovarian function.
Following completion of chemotherapy, the patient began radiation therapy to the conserved breast and commenced adjuvant hormonal therapy with tamoxifen. Ten months after completion of chemotherapy, her menses returned. Her tamoxifen was switched to a combination of a luteinising hormone-releasing hormone antagonist and an aromatase inhibitor.
Breast cancer is the most common cancer in women worldwide. A report from the National Cancer Registry Ireland showed that from 2007-2009, approximately 2,670 women were diagnosed with breast cancer annually in Ireland. About 70 per cent of newly-diagnosed breast cancer patients have hormone receptor-positive disease. Approximately 6 per cent of women with breast cancer are diagnosed before the age 40 years, and the probability of developing breast cancer before the age 40 years is nearly one in every 200 women.
Young age is an independent predictor of an adverse outcome, and the majority of young patients with breast cancer receive systemic treatment with chemotherapy, hormonal therapy, or both.
These patients are at significant risk of transient or permanent amenorrhoea, and for those women who continue to menstruate or who recover their cycles, there is an additional long-term risk of premature ovarian failure. One estimate showed that each month of chemotherapy translates into 1.5 years of lost reproductive life.
The incidence of premature menopause depends on the type of chemotherapy and the patient’s age. Chemotherapy regimens may be associated with an incidence of long-term amenorrhoea of at least 40 per cent, with a more pronounced effect being associated with the use of regimens containing a high cumulative dose of cyclophosphamide.
In women younger than 35 years, the long-term (three years after diagnosis) incidence of amenorrhoea is similar to that of women who do not receive chemotherapy (nearly 10 per cent), but it increases to 50 per cent in women aged 35-to-40 years and to 85 per cent in women older than 40 years.
Premature menopause has significant consequences, including vasomotor symptoms, sexual dysfunction and infertility. This last effect is a major concern for young women with breast cancer. Young survivors of breast cancer consider premature menopause, sexual dysfunction and infertility the most distressing aspects of their cancer experience.
Fertility preservation after cytotoxic treatment
Recently-reported studies have potential implications for the fertility and childbearing of young women with early-stage breast cancer. Two such studies have provided useful information concerning the potential capacity of luteinising hormone-releasing hormone (LHRH) partial agonists such as triptorelin to preserve ovarian function in women undergoing contemporaneous, systemic adjuvant chemotherapy for breast cancer.
The PROMISE-GIM6 (Prevention of Menopause Induced by Chemotherapy) study was conducted at 16 sites in Italy and enrolled 281 patients between October 2003 and January 2008.
Eligible patients were pre-menopausal women with stages I through III breast cancer who were candidates for adjuvant or neoadjuvant chemotherapy. Patients in the control arm received chemotherapy alone, while those in the study group received chemotherapy plus triptorelin to suppress ovarian function during the administration of chemotherapy.
Twelve months after the last cycle of chemotherapy (last follow-up August 18, 2009), the rate of early menopause was 25.9 per cent in the chemotherapy-alone group but only 8.9 per cent in the chemotherapy plus triptorelin group; an absolute difference of -17 per cent and a result that was statistically significant.
The incidence rate of pregnancy was 0.9 per 100 person-years in the triptorelin arm vs 0.4 per 100 person-years in the chemotherapy-alone arm, and the five-year cumulative incidence of pregnancy was 2.9 per cent in the triptorelin arm and 1.6 per cent in the chemotherapy-alone arm, respectively, yielding a hazard ratio of 2.56 (P = .142).
The POEMS trial (Prevention of Early Menopause Study) has also evaluated LHRH antagonist-mediated ovarian suppression during chemotherapy to reduce ovarian failure in early-stage, hormone receptor-negative breast cancer patients.
A total of 257 premenopausal patients to be treated with adjuvant combination systemic chemotherapy were randomised to receive standard cyclophosphamide-containing chemotherapy with or without monthly goserelin (GN) 3.6mg SQ, starting one week prior to the first chemotherapy dose. The primary endpoint was two-year premature ovarian failure (POF) rate. Other endpoints included pregnancy rate and survival.
Premature menopause has significant consequences, including vasomotor symptoms, sexual dysfunction and infertility. This last effect is a major concern for young women with breast cancer
In a total of 135 patients in whom complete data were available, the results revealed that POF rates were 22 per cent in the standard arm and 8 per cent in the GN arm. In a sensitivity analysis defining two-year POF more liberally as either amenorrhoea or elevated follicle stimulating hormone (FSH), 45 per cent in the standard arm and 20 per cent in the GN arm had POF. There were 13 pregnancies in the standard arm and 22 in the GN arm. Disease-free survival and overall survival were better in the GN arm, for reasons that are not immediately apparent, given that the patients had hormone-insensitive breast cancers.
The results were statistically significant and the authors concluded that LHRH analog administration with chemotherapy was associated with less POF and more pregnancies.
These two studies present randomised data to support the use of ovarian suppression to protect fertility in young women undergoing chemotherapy for breast cancer. There are small numbers in both trials, however, and uncertainty remains about the long-term efficacy and safety of this approach.
This treatment is a reasonable consideration, however, in a young woman who is about to undergo cytotoxic treatment and does not wish to proceed with other more established methods of fertility preservation, such as embryo preservation.
Adjuvant hormonal therapy
Tamoxifen has been the standard adjuvant hormonal therapy for premenopausal women for more than two decades. It has been unclear if more intensive hormonal manipulation, such as the addition of ovarian suppression, would result in better outcomes for younger women who maintained ovarian function during adjuvant hormonal therapy with tamoxifen. This question has been addressed in the recently-reported TEXT and SOFT trials. These studies suggest an improvement in outcomes with ovarian suppression in combination with an aromatase inhibitor compared to tamoxifen alone or to tamoxifen with ovarian suppression in high-risk subgroups.
Recurrences in high-risk patients who were less than 35 years of age, had node-positive disease, large tumours of high grade, and who received chemotherapy and remained premenopausal, were significantly reduced by the use of the aromatase inhibitor exemestane plus ovarian suppression in comparison to tamoxifen plus ovarian suppression and to tamoxifen alone (with absolute improvements of 7.7, 4.5 and 2.0 percentage points at five years, respectively).
Overall survival did not differ significantly between the two groups. Selected adverse events of grade 3 or 4 were reported for 30.6 per cent of the patients in the exemestane-ovarian suppression group and 29.4 per cent of those in the tamoxifen ovarian suppression group, with profiles similar to those for postmenopausal women.
Such combined therapy should be considered in these high-risk premenopausal subgroups that retain ovarian function after chemotherapy. The longer-term effects of more comprehensive hormonal suppression should be carefully considered and monitored in patients undergoing this therapy.
These recently-reported studies have practice-changing results, as they illustrate that the addition of ovarian suppression during chemotherapy in premenopausal early breast cancer patients may be associated with less premature ovarian failure and more pregnancies in patients with both hormone receptor-positive and hormone receptor -negative breast cancer.
Furthermore, adjuvant exemestane plus ovarian suppression treatment should be considered for high-risk younger patients with hormone receptor-positive early breast cancer who maintain ovarian function following completion of adjuvant chemotherapy.
References on request