5. Adjuvant bisphosphonates

cardiovascular events, whereas sequenced therapy compared with AI had lower risk of car-

Breast cancer treatment guidelines recommend that higher risk premenopausal patients should receive ovarian function suppression as part of adjuvant endocrine therapy. However, if chemotherapy is also given, until recently, it was uncertain whether concurrent or sequential sequential ovarian function suppression (OFS) initiation has any detrimental effect on progno-

Recently, in a phase 3, open-label, parallel, randomized controlled trial, 216 premenopausal patients younger than 45 years with invasive ER+ breast cancer were randomized at a 1:1 ratio to receive (neo)adjuvant chemotherapy combined with sequential or simultaneous GnRHa treatment between July 2009 to May 2013 [53]. All patients were advised to receive GnRHa for at least 2 years. The rates of early menopause were 22.8% (21/92) in the sequential group and 23.1% (18/78) in the simultaneous group (simultaneous vs. sequential: OR 1.01; P = 0.969; age-adjusted OR 1.13; P = 0.737). The median menstruation resumption period was 12.0 months and 10.3 months for the sequential and simultaneous groups, respectively (HR 0.83; P = 0.274; age-adjusted HR 0.90; P = 0.567). During a median follow-up time of 56.9 months (IQR 49.5–72.4 months), there were no significant differences in disease-free

In an exploratory analysis of phase III TEXT and SOFT trials, 1872 patients who received adjuvant chemotherapy for HR+, HER2-negative breast cancer and upon randomization to an OFS-containing adjuvant endocrine therapy, initiated GnRHa triptorelin were analyzed [54]. Breast cancer-free interval (BCFI) was compared between patients who received OFS concurrently with chemotherapy in TEXT (n = 1242) versus sequentially post-chemotherapy in SOFT (n = 630). Because timing of trial enrollment relative to adjuvant chemotherapy differed, landmark analysis was implemented to re-define BCFI beginning 1 year after final dose of chemotherapy (median, 15.5 months in TEXT and 8.1 months from enrollment to landmark in SOFT). The median duration of adjuvant chemotherapy was 18 weeks in both groups. Patients who were premenopausal post-chemotherapy in SOFT were younger on average. After postlandmark median follow-up of about 5 years, post-landmark BCFI was found to be statistically similar between concurrent use of triptorelin with chemotherapy and sequential use of triptorelin after chemotherapy, either in the overall population (HR = 1.11; P = 0.72; 4-year BCFI 89% in both groups), or in the subgroup of 692 women < 40 years at diagnosis (HR = 1.13)

Because the sequential use of GnRHa and chemotherapy showed similar ovarian preservation and survival outcomes when compared with simultaneous use ER+ premenopausal patients, addition of GnRHa to oncologic treatment can probably be delayed until menstruation resumption after chemotherapy. However, based on comparative-effectiveness modeling of TEXT and SOFT after about 5 years median follow-up, concurrent administration of OFS with chemotherapy is neither detrimental nor beneficial effect on the efficacy of adjuvant therapy which includes

chemotherapy, with limited statistical power especially for the subgroup < 40 years.

survival (P = 0.290) or in overall survival (P = 0.514) between the two groups.

who are less likely to develop chemotherapy-induced amenorrhea.

diovascular events (moderate level of evidence).

sis or menstruation resumption.

138 Breast Cancer and Surgery

4.3. Concurrent or sequential ovarian function suppression

Cancer Care Ontario and ASCO convened a Working Group and Expert Panel to develop evidence-based recommendations by a systematic review of the literature [55]. The women with natural menopause or the women who were postmenopausal induced by ovarian suppression or ablation were included. Adjuvant bisphosphonates were reported to reduce bone recurrence and improve survival in postmenopausal women with early stage breast cancer. Absolute benefit was found to be greater in patients who are at higher risk of recurrence, and almost all trials were conducted in patients who also received systemic therapy. The data are extremely limited for bisphosphonates other than zoledronic acid or clodronate due to most studies performed with these two bisphosphonates. ASCO clinical guidelines recommends that, if available, zoledronic acid (4 mg intravenously every 6 months) or clodronate (1600 mg/d orally) be considered as an adjuvant therapy for postmenopausal patients with breast cancer who are deemed candidates for adjuvant systemic therapy. However, further research comparing different bone-modifying agents, doses, dosing intervals, and durations is required. Risk factors for osteonecrosis of the jaw and renal impairment should be assessed, and any pending dental or oral health problems should be dealt with prior to starting treatment. While adjuvant denosumab reduces fractures and it looks promising in adjuvant setting, long-term survival data are still insufficient to make any recommendation. The use of these agents to reduce fragility fractures in patients with low bone mineral density is beyond the scope of the guideline.
