唑来膦酸辅助治疗早期乳腺癌？建议不妨先查骨转移生物标志
对于早期乳腺癌，双膦酸盐辅助治疗可以减少骨转移发生率。似乎仅绝经后患者的复发率和生存率得到改善，但是潜在机制尚不明确。
2017年10月13日，英国《柳叶刀肿瘤学分册》在线发表英国谢菲尔德威斯顿公园医院、利兹大学、爱丁堡大学、圣詹姆斯医院、西班牙癌症网络生物医学研究中心、西班牙医学科学院附属医院、巴塞罗那海滨医院、庞佩乌法布拉大学、希门尼斯迪亚兹基金会、巴塞罗那生物医学研究所、加泰罗尼亚高级研究中心、澳大利亚迪肯大学的研究报告，对国际非盲随机对照三期研究（AZURE）进行二次分析，调查了原发肿瘤骨转移生物标志MAF扩增能否预测唑来膦酸辅助治疗的结局。
该研究将参加国际乳腺癌协作组（BIG）非盲随机对照三期研究（AZURE）并且同意使用原发肿瘤标本的II～或III期乳腺癌患者再次入组，按1∶1随机分配接受标准全身辅助治疗（对照治疗组）或每3～4周唑来膦酸给药6次，随后每3～6个月给药直至用满5年结束。将累及腋窝淋巴结数量、临床肿瘤分期、雌激素受体状态、全身治疗类型和时间、绝经状态、他汀类用药、不同治疗中心等影响因素进行最小化校正。主要终点为无病生存（DFS）；次要终点为无浸润病变生存（IDFS）为本报告分析的主要疾病终点。通过两个空心针穿刺活检乳腺肿瘤组织微阵列荧光原位杂交评定MAF扩增，由不了解治疗分配的技术人员在中心实验室进行。使用多变量分析评定意向治疗的疾病结局。还评估了MAF阳性状态和绝经状态对唑来膦酸有效性的相互作用。该研究的世界卫生组织国际标准随机对照研究注册编号：ISRCTN79831382。该研究得到诺华赞助。
结果1739例AZURE患者提供原发肿瘤标本：
865例（50%）有两个可评估空心针穿刺活检标本（对照组445例、唑来膦酸组420例）。
184例（21%）肿瘤为MAF阳性（对照组85例、唑来膦酸组99例），其余肿瘤为MAF阴性。
经过中位随访84.6个月（四分位距：72.0～95.8），MAF阳性与MAF阴性相比：
对照治疗组无浸润病变生存较好（风险比：0.92，95%置信区间：0.59～1.41）
其中绝经前无浸润病变生存较好（风险比：1.58，95%置信区间：0.82～3.03）
其中绝经后无浸润病变生存较差（风险比：0.47，95%置信区间：0.25～0.88）
唑来膦酸组无浸润病变生存较差（风险比：0.52，95%置信区间：0.36～0.75）
其中绝经前无浸润病变生存较差（风险比：0.54，95%置信区间：0.34～0.84）
其中绝经后无浸润病变生存较差（风险比：0.47，95%置信区间：0.23～0.94）
对于MAF阴性患者，唑来膦酸与对照治疗相比，无浸润病变生存较好（风险比：0.74，95%置信区间：0.56～0.98），但是MAF阳性肿瘤患者反之，除了未绝经、年龄<50岁患者。
对于121例随机化时尚未绝经的MAF阳性肿瘤患者，唑来膦酸与对照治疗相比：
无浸润病变生存较差（风险比：2.47，95%置信区间：1.23～4.97）
总生存较差（风险比：2.27，95%置信区间：1.04～4.93）
因此，MAF状态可以预测唑来膦酸辅助治疗获益的可能性，值得进一步研究作为潜在的伴随诊断。MAF阴性乳腺癌女性占可能从唑来膦酸辅助治疗获益乳腺癌患者近80%。女性使用唑来膦酸治疗后，MAF阳性似与不良疾病结局相关，尤其对于尚未明确绝经女性，建议辅助治疗应该避免接触双膦酸盐。
对此，葡萄牙里斯本大学医学院分子医学研究所和圣玛丽亚医院发表同期评论：唑来膦酸辅助治疗乳腺癌并不适用所有患者。
Lancet Oncol. 2017 Oct 13. [Epub ahead of print]
Effect of MAF amplification on treatment outcomes with adjuvant zoledronic acid in early breast cancer: a secondary analysis of the international, open-label, randomised, controlled, phase 3 AZURE (BIG 01/04) trial.
Robert Coleman, Andrew Hall, Joan Albanell, Andrew Hanby, Richard Bell, David Cameron, David Dodwell, Helen Marshall, Joel Jean-Mairet, Juan-Carlos Tercero, Federico Rojo, Walter Gregory, Roger R Gomis.
Weston Park Hospital, Sheffield, UK; University of Leeds, Leeds, UK; IMIM-CIBERONC, Barcelona; Hospital del Mar, Barcelona, Spain; Pompeu Fabra University, Barcelona, Spain; Deakin University, Geelong, VIC, Australia; University of Edinburgh, Edinburgh, UK; St James Hospital, Leeds, UK; Inbiomotion, Barcelona, Spain; Fundación Jiménez Díaz, Madrid, Spain; CIBERONC, Madrid, Spain; Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain; Institució Catalana de Recerca i Estudis Avancats (ICREA), Barcelona, Spain.
BACKGROUND: Adjuvant use of bisphosphonates can reduce the incidence of bone metastases in early breast cancer. Recurrence and survival seem to be improved only in postmenopausal patients, but the underlying mechanisms remain unclear. We investigated whether MAF amplification (a biomarker for bone metastasis) in primary tumours could predict the treatment outcomes of adjuvant zoledronic acid.
METHODS: The study population included patients enrolled in the international, open label, randomised, controlled, phase 3 AZURE trial at eligible UK sites who had stage II or III breast cancer and who gave consent for use of their primary tumour samples. Patients were randomly assigned (1:1) to receive standard adjuvant systemic therapy alone (control group) or with zoledronic acid every 3-4 weeks for six doses, then every 3-6 months until the end of 5 years. Minimisation took into account the number of involved axillary lymph nodes, clinical tumour stage, oestrogen receptor status, type and timing of systemic therapy, menopausal status, statin use, and treating centre. The primary endpoint was disease free survival; the secondary endpoint, invasive disease free survival, was the primary disease endpoint for the analysis in this report. MAF amplification was assessed by fluorescence in situ hybridisation of two cores of breast tumour tissue in a microarray, done in a central laboratory by technicians unaware of treatment assignment. We used multivariate analyses to assess disease outcomes by intention to treat. We also assessed interactions between MAF positive status and menopausal status on efficacy of zoledronic acid. The AZURE trial is registered with the International Standard Randomised Controlled Trial Registry, number ISRCTN79831382.
FINDINGS: 1739 AZURE patients contributed primary tumour samples, of whom 865 (50%) had two assessable cores (445 in the control groups and 420 in the zoledronic acid group). 184 (21%) tumours were MAF positive (85 in the control groups and 99 in the zoledronic acid group) and the remaining tumours were MAF negative. At a median follow up of 84.6 months (IQR 72.0-95.8), MAF status was not prognostic for invasive disease free survival in the control group (MAF positive vs MAF negative: hazard ratio [HR] 0.92, 95% CI 0.59-1.41), but was in the zoledronic acid group (0.52, 0.36-0.75). In patients with MAF negative tumours, zoledronic acid was associated with higher invasive disease free survival than was control treatment (HR 0.74, 95% CI 0.56-0.98), but not in patients who had MAF positive tumours. Additionally, among 121 patients not postmenopausal at randomisation with MAF positive tumours, zoledronic acid was associated with lower invasive disease free survival (HR 2.47, 95% CI 1.23-4.97) and overall survival (2.27, 95% CI 1.04-4.93) than control treatment.
INTERPRETATION: MAF status can predict likelihood of benefit from adjuvant zoledronic acid and merits further investigation as a potential companion diagnostic.
FUNDING: Novartis Global and Inbiomotion.
DOI: 10.1016/S1470-2045(17)30603-4
Lancet Oncol. 2017 Oct 13. [Epub ahead of print]
Adjuvant zoledronic acid to treat breast cancer: not for all.
Luís Costa, Arlindo R Ferreira.
Oncology Division, Hospital de Santa Maria, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
Bisphosphonates have been extensively studied in the adjuvant setting as a host-directed therapy to reduce the risk of breast-cancer relapse. The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) patient-level meta-analysis of adjuvant bisphosphonates, which included 18776 women with breast cancer, showed a reduction in breast-cancer-associated death among postmenopausal women (hazard ratio [HR] 0.82, 95% CI 0.73-0.93). This outcome was mainly due to the reduction in bone recurrence. Thus, several guidelines have included zoledronic acid and clodronic acid as adjuvant treatments for breast cancer in postmenopausal women.[1-3]
Women's age and menopausal status are powerful surrogates for oestrogen concentrations and, thereby, for regulation of bone remodelling. Thus, oestrogen-driven changes in the bone microenvironment might affect the likelihood of women in different age groups developing bone metastases[4]. An important and as yet unresolved subject of scientific debate is how ovarian function regulates host-driven responses to cancer cells and mainly host-directed (and bone-selective) treatments, such as zoledronic acid.
Whether premenopausal women with breast cancer should be considered as candidates for adjuvant treatment with bisphosphonates is a relevant question. Adjuvant bisphosphonates have been reserved for use in postmenopausal women, irrespective of the cause of menopause (physiological, surgical, or due to ovarian function suppression [OFS]). Extending these agents to younger women is an attractive strategy because of the inverse association between age at diagnosis and risk of developing bone or visceral distant metastases[5]. In this regard, and given concerns about bone health, the growing use of endocrine treatment intensification (eg, OFS plus aromatase inhibitors[6]) in premenopausal women with high-risk breast cancer, particularly in those younger than 35 years, is expanding the use of bisphosphonates to younger age groups.
MAF, a transcription factor implicated in control of expression of several genes associated with bone metastasis from breast cancer, has been studied as a predictor of bone relapse[7]. In The Lancet Oncology, Robert Coleman and colleagues[8] report a secondary analysis of the phase 3 AZURE study to investigate whether MAF amplification status, indicated by copy number on fluorescence in-situ hybridisation (FISH), could predict treatment effects with adjuvant zoledronic acid compared with standard care alone. AZURE is the largest trial included in the EBCTCG meta-analysis.
Of 1739 patients who contributed primary tumour samples, 865 (50%) had enough tissue to create two cores assessable by FISH. 184 (21%) had MAF-positive tumours (copy number ≥2.5). At median follow-up of 84.6 months (IQR 72.0-95.8), 282 (33%) patients had distant relapse (147 in the control group and 135 in the zoledronic acid group), 60 of which were in bone (39 and 21, respectively). Although the small number of bone relapses limited the analysis of potential associations between MAF status and bone relapse, in patients receiving zoledronic acid, invasive-disease-free survival (the primary endpoint) was longer in patients with MAF-negative tumours than in patients with MAF-positive tumours (HR 0.52, 95% CI 0.36-0.75). Strikingly, MAF positivity seemed to also predict harm with adjuvant zoledronic acid in non-postmenopausal women, particularly for extraskeletal recurrence (zoledronic acid vs control HR 6.92, 95% CI 2.44-19.60). Thus, among premenopausal women with early breast cancer at high risk of bone loss and osteoporotic fractures, selecting patients with MAF-negative tumours for treatment with adjuvant bisphosphonates might be very important. How functional menopause by OFS affects these findings is unclear.
Validation in an independent cohort and translational research into the effects of adjuvant bisphosphonates in patients with early breast cancer are needed. Creation of a standard test for MAF amplification status could be clinically helpful to exclude premenopausal patients with early breast cancer from receiving zoledronic acid and potentially other bisphosphonates.
How MAF status might inform the use of denosumab in this setting remains uncertain. Data on the use of adjuvant denosumab have so far been derived only from postmenopausal patients and those with hormone-receptor-positive breast cancers who are receiving aromatase inhibitors.[9] The role of adjuvant denosumab in premenopausal and postmenopausal women is being investigated in the D-CARE prospective trial (NCT01077154).
The AZURE trial has prompted other studies looking for correlations between biomarkers and bone relapse. High expression of macrophage-capping protein (CAPG) and PDZ domain-containing protein (GIPC1) in primary breast cancers is associated with an increase in first recurrence in bone[10], which suggests that patients with tumours expressing these biomarkers would benefit from adjuvant treatment with zoledronic acid.
The complex interplay between ovarian function and bisphosphonates for prevention of bone metastases also remains unclear. The findings of Coleman and colleagues8 do not provide a definite explanation for this interaction, but, undoubtedly, leave open the question of whether adjuvant zoledronic acid is suitable for all.
REFERENCES
Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet. 2015;386:1353-1361.
Dhesy-Thind S, Fletcher GG, Blanchette PS, et al. Use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer: a Cancer Care Ontario and American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2017;35:2062-2081.
Hadji P, Coleman RE, Wilson C, et al. Adjuvant bisphosphonates in early breast cancer: consensus guidance for clinical practice from a European Panel. Ann Oncol. 2016;27:379-390.
Hofbauer LC, Rachner TD, Coleman RE, et al. Endocrine aspects of bone metastases. Lancet Diabetes Endocrinol. 2014;2:500-512.
Purushotham A, Shamil E, Cariati M, et al. Age at diagnosis and distant metastasis in breast cancer—a surprising inverse relationship. Eur J Cancer. 2014;50:1697-1705.
Pagani O, Regan MM, Walley BA, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014;371:107-118.
Pavlovic M, Arnal-Estapé A, Rojo F, et al. Enhanced MAF oncogene expression and breast cancer bone metastasis. J Natl Cancer Inst. 2015;107:djv256.
Coleman R, Hall A, Albanell J, et al. Effect of MAF amplification on treatment outcomes with adjuvant zoledronic acid in early breast cancer: a secondary analysis of the international, open-label, randomised, controlled, phase 3 AZURE (BIG 01/04) trial. Lancet Oncol. 2017 Oct 13. DOI: 10.1016/S1470-2045(17)30603-4. [Epub ahead of print]
Gnant M, Pfeiler G, Dubsky PC, et al. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015;386:433-443.
Westbrook JA, Cairns DA, Peng J, et al. CAPG and GIPC1: breast cancer biomarkers for bone metastasis development and treatment. J Natl Cancer Inst. 2016;108:djv360.
DOI: 10.1016/S1470-2045(17)30695-2