SOFT＋TEXT研究13年随访结果

　　19年前，除了SARS，还发生了两件大事：针对激素受体阳性早期乳腺癌术后绝经前患者内分泌辅助治疗，国际乳腺癌研究协作组（IBCSG）和国际乳腺协作组（BIG）发起两项大规模随机对照三期临床研究：卵巢功能抑制＋他莫昔芬或依西美坦对比他莫昔芬单药的SOFT研究、曲普瑞林＋他莫昔芬或依西美坦的TEXT研究。从2014年开始，这两项研究的长期随访结果3次登上美国麻省医学会《新英格兰医学杂志》、1次登上欧洲肿瘤内科学会《肿瘤学报》、1次登上英国《柳叶刀肿瘤学》、4次登上美国临床肿瘤学会《临床肿瘤学杂志》。中位随访9年结果表明，依西美坦＋卵巢功能抑制与他莫昔芬＋卵巢功能抑制相比，无病变生存率和无远处复发率显著提高，但是并未提高总生存率。

• SOFT / IBCSG 24-02 / BIG 2-02 (NCT00066690): Suppression of Ovarian Function With Either Tamoxifen or Exemestane Compared With Tamoxifen Alone in Treating Premenopausal Women With Hormone-Responsive Breast Cancer (A Phase III Trial Evaluating the Role of Ovarian Function Suppression and the Role of Exemestane as Adjuvant Therapies for Premenopausal Women With Endocrine Responsive Breast Cancer)

• TEXT / IBCSG 25-02 / BIG 3-02 (NCT00066703): Triptorelin With Either EXemestane or Tamoxifen in Treating Premenopausal Women With Hormone-Responsive Breast Cancer (A Phase III Trial Evaluating The Role Of Exemestane Plus GnRH Analogue As Adjuvant Therapy For Premenopausal Women With Endocrine Responsive Breast Cancer)

　　2022年12月15日，美国临床肿瘤学会《临床肿瘤学杂志》第5次发表IBCSG和BIG的SOFT＋TEXT研究长期随访结果，对卵巢功能抑制＋依西美坦或他莫昔芬辅助治疗激素受体阳性早期乳腺癌术后绝经前患者的无病变生存率、无远处复发率、总生存率进行再次比较。

　　SOFT＋TEXT研究于2003年11月～2011年4月入组激素受体阳性早期乳腺癌术后绝经前女性合计4690例（其中HER2阴性乳腺癌4035例，占86.0%）被随机分配接受5年依西美坦或他莫昔芬，并且通过手术切除或曲普瑞林进行卵巢功能抑制。

　　结果，截至2021年5月，中位随访13年，对于4690例意向治疗患者，依西美坦与他莫昔芬相比：

• 12年无病变生存率：提高4.6%（80.5%比75.9%）

• 12年病变死亡风险：降低21%（风险比：0.79，95%置信区间：0.70～0.90，P<0.001）

• 12年无远处复发率：提高1.8%（88.4%比86.6%）

• 12年远处复发风险：降低17%（风险比：0.83，95%置信区间：0.70～0.98，P=0.03）

• 12年总生存率：提高1.0%（90.1%比89.1%）

• 12年总死亡风险：降低7%（风险比：0.93，95%置信区间：0.78～1.11，P=0.43）

　　对于4035例HER2阴性乳腺癌患者，依西美坦与他莫昔芬相比：

• 12年总生存率：提高2.0%（90.8%比88.8%）

• 12年总死亡风险：降低15%（风险比：0.85，95%置信区间：0.70～1.04）

　　对于2152例（45.9%）HER2阴性乳腺癌化疗患者，依西美坦与他莫昔芬相比：

• SOFT总生存率：提高3.3%（84.4%比81.1%）

• TEXT总生存率：提高3.3%（86.8%比83.5%）

　　对于高风险患者，依西美坦与他莫昔芬相比，总生存获益有临床意义，例如：

• 年龄<35岁：81.6%比77.6%（提高4.0%）

• 肿瘤>2厘米：83.8%比79.3%（提高4.5%）

• 肿瘤3级：83.6%比78.1%（提高5.5%）

　　因此，SOFT＋TEXT研究中位随访13年结果表明，对于激素受体阳性早期乳腺癌术后绝经前卵巢功能抑制女性，依西美坦与他莫昔芬相比，复发风险持续降低，总死亡风险相似，但是对于HER2阴性乳腺癌、化疗、年龄<35岁、肿瘤>2厘米、肿瘤3级等高风险患者，总生存获益有临床意义，再次为卵巢功能抑制患者选择依西美坦优于他莫昔芬提供了证据。

　　对此，爱尔兰科克大学医学院、美国印第安纳大学梅尔文和布伦西蒙综合癌症中心发表同期评论：卵巢抑制对绝经前女性激素敏感乳腺癌治疗的作用回到起点。

相关链接

• 优化绝经前乳腺癌内分泌辅助治疗

• 绝经前乳腺癌手术后个体化内分泌治疗
  

J Clin Oncol. 2022 Dec 15. IF: 50.717

Adjuvant Exemestane With Ovarian Suppression in Premenopausal Breast Cancer: Long-Term Follow-Up of the Combined TEXT and SOFT Trials.

Pagani O, Walley BA, Fleming GF, Colleoni M, Láng I, Gomez HL, Tondini C, Burstein HJ, Goetz MP, Ciruelos EM, Stearns V, Bonnefoi HR, Martino S, Geyer CE Jr, Chini C, Puglisi F, Spazzapan S, Ruhstaller T, Winer EP, Ruepp B, Loi S, Coates AS, Gelber RD, Goldhirsch A, Regan MM, Francis PA; SOFT and TEXT Investigators and the International Breast Cancer Study Group.

Interdisciplinary Cancer Service Hospital Riviera-Chablais Rennaz, Vaud, Switzerland; Geneva University Hospitals, Lugano University and Swiss Group for Clinical Cancer Research, Vaud, Switzerland; University of Basel, Swiss Group for Clinical Cancer Research, Basel, Switzerland; International Breast Cancer Study Group Coordinating Center, Bern, Switzerland; University of Calgary and Canadian Cancer Trials Group, Calgary, AB, Canada; The University of Chicago Medical Center, Chicago, IL; Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute, Harvard Medical School, Harvard TH Chan School of Public Health, Frontier Science Foundation, Boston, MA; Mayo Clinic, Rochester, MN; Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD; The Angeles Clinic and Research Institute and SWOG, Santa Monica, CA; University of Pittsburgh Medical Center Hillman Cancer Center and NRG Oncology, Pittsburgh, PA; Yale Cancer Center, Yale School of Medicine, Smilow Cancer Hospital, New Haven, CT; European Institute of Oncology, Milan, Italy; Osp. Papa Giovanni XXIII, Bergamo, Italy; Ospedale di Circolo e Fondazione, Lombardy, Italy; University of Udine, Centro di Riferimento Oncologico CRO di Aviano, Aviano, Italy; Centro di Riferimento Oncologico CRO di Aviano, Aviano, Italy; Clinexpert-research, Budapest, Hungary; National Institute of Oncology, Budapest, Hungary; Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru; International Breast Cancer Study Group, Lima, Peru; University Hospital 12 de Octubre and SOLTI Breast Cancer Research Cooperative Group, Madrid, Spain; Institut Bergonié Comprehensive Cancer Centre, Université de Bordeaux, European Organisation for Research and Treatment of Cancer, Bordeaux, France; Peter MacCallum Cancer Center, St Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia; University of Sydney, Sydney, Australia; Breast Cancer Trials Australia & New Zealand, University of Newcastle, Australia.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.

The combined analysis of SOFT-TEXT compared outcomes in 4,690 premenopausal women with estrogen/progesterone receptor-positive (ER/PgR ) early breast cancer randomly assigned to 5 years of exemestane ovarian function suppression (OFS) versus tamoxifen OFS. After a median follow-up of 9 years, exemestane OFS significantly improved disease-free survival (DFS) and distant recurrence-free interval (DRFI), but not overall survival, compared with tamoxifen OFS. We now report DFS, DRFI, and overall survival after a median follow-up of 13 years. In the intention-to-treat (ITT) population, the 12-year DFS (4.6% absolute improvement, hazard ratio [HR], 0.79; 95% CI, 0.70 to 0.90; P < .001) and DRFI (1.8% absolute improvement, HR, 0.83; 95% CI, 0.70 to 0.98; P = .03), but not overall survival (90.1% v 89.1%, HR, 0.93; 95% CI, 0.78 to 1.11), continued to be significantly improved for patients assigned exemestane OFS over tamoxifen OFS. Among patients with human epidermal growth factor receptor 2-negative tumors (86.0% of the ITT population), the absolute improvement in 12-year overall survival with exemestane OFS was 2.0% (HR, 0.85; 95% CI, 0.70 to 1.04) and 3.3% in those who received chemotherapy (45.9% of the ITT population). Overall survival benefit was clinically significant in high-risk patients, eg, women age < 35 years (4.0%) and those with > 2 cm (4.5%) or grade 3 tumors (5.5%). These sustained reductions of the risk of recurrence with adjuvant exemestane OFS, compared with tamoxifen OFS, provide guidance for selecting patients for whom exemestane should be preferred over tamoxifen in the setting of OFS.

Trial registration: ClinicalTrials.gov NCT00066703 NCT00066690.

PMID: 36521078

DOI: 10.1200/JCO.22.01064

J Clin Oncol. 2022 Dec 15. IF: 50.717

Back to the Beginning: The Role of Ovarian Suppression in Management of Hormone Sensitive Breast Cancer in Premenopausal Women.

Connolly RM, Miller KD.

University College Cork, Cork, Ireland; Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Bloomington, IN.

Although many consider targeted therapy a modern concept, targeted therapy in breast cancer dates back to 1889, when Schinzinger first proposed oophorectomy as adjunctive therapy for breast cancer to alter the hormonal milieu of the malignancy. Beatson2 put the proposal into practice, reporting decreases in cutaneous metastases in a premenopausal woman after oophorectomy in 1896. The mechanism underlying the response to oophorectomy remained mysterious until Jenson identified the estrogen receptor (ER) 75 years later.3 Since that time, the ER has become the most well-studied, and arguably the most important, target for breast cancer therapy.

In the articles that accompany this editorial, SOFT and TEXT investigators report a sustained improvement in long-term outcomes (disease-free survival) and for the first time an improvement in overall survival for premenopausal women with estrogen receptor-positive breast cancer through incorporation of ovarian suppression as a component of endocrine therapy. Based on these data, ovarian suppression with an aromatase inhibitor should become the preferred initial hormone therapy recommendation for all premenopausal women with high-risk (ie, grade 3, T2, and age < 35 years) estrogen receptor-positive breast cancer.

PMID: 36521079

DOI: 10.1200/JCO.22.02319

2021版CBCS指南与规范完整版