编者按：15年前，国际乳腺癌研究协作组（IBCSG）启动了两项大型随机对照临床研究：卵巢功能抑制研究（SOFT）、他莫昔芬＋依西美坦研究（TEXT），入组激素受体阳性早期乳腺癌绝经前女性共计5738例。根据2014年和2015年公布的中位随访5.6年和5.7年结果发现：依西美坦＋卵巢抑制与他莫昔芬＋卵巢抑制相比，复发率显著降低；他莫昔芬＋卵巢抑制与他莫昔芬相比，复发率并未显著降低。那么，中位随访8年后结果如何？
2018年6月4日，美国麻省医学会《新英格兰医学杂志》在线发表澳大利亚和新西兰乳腺癌研究协作组、墨尔本大学、圣文森特医院、彼得·麦卡勒姆癌症中心、纽卡斯尔大学、悉尼大学、瑞士南部肿瘤研究所、圣若望医院、圣加仑乳腺癌中心、伯尔尼大学小岛医院、美国芝加哥大学、苏珊·史密斯女性癌症中心、哈佛大学医学院、哈佛大学陈曾熙公共卫生学院、达纳法伯癌症研究所、波士顿前沿科学技术研究基金会、洛杉矶医院研究所、弗吉尼亚联邦大学梅西癌症中心、梅奥医学中心、霍普金斯大学西德尼·基梅尔综合癌症中心、华盛顿大学、弗雷德·哈钦森癌症研究中心、加拿大卡尔加里大学、意大利米兰大学、欧洲肿瘤研究所、教皇若望二十三世医院、马基基金会医院、阿维亚诺国家癌症研究所、乌迪内大学、沙瓦托·毛格里基金会医院、托斯卡纳大区普拉托省医院、匈牙利国家肿瘤研究所、秘鲁国家肿瘤疾病研究所、西班牙马德里大学附属国庆日医院、巴塞罗那大学瓦尔德希布伦医院肿瘤研究所、巴伦西亚肿瘤研究所、法国波尔多大学、贝格尼研究所综合癌症中心、英国谢菲尔德大学威斯顿公园医院、德国雷根斯堡大学医学中心的国际乳腺癌研究协作组报告，更新了SOFT和TEXT两项研究患者中位随访8年的结果。
SOFT: Suppression of Ovarian Function With Either Tamoxifen or Exemestane Compared With Tamoxifen Alone in Treating Premenopausal Women With Hormone-Responsive Breast Cancer.
TEXT: Triptorelin With Either Exemestane or Tamoxifen in Treating Premenopausal Women With Hormone-Responsive Breast Cancer.
SOFT研究于2003年12月～2011年1月入组激素受体阳性早期乳腺癌绝经前女性3066例，按1∶1∶1随机分配接受5年他莫昔芬、他莫昔芬＋卵巢抑制、依西美坦＋卵巢抑制。
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绝经前女性2672例，按1∶1随机分配接受他莫昔芬＋卵巢抑制、依西美坦＋卵巢抑制。
两项研究根据接受化疗与否进行随机化分层，并且根据HER2状态进行亚组分析。
结果发现，SOFT研究的8年无病生存率：
他莫昔芬：78.9%
他莫昔芬＋卵巢抑制：83.2%（与他莫昔芬相比，P=0.009）
依西美坦＋卵巢抑制：85.9%
SOFT研究所有女性的8年总生存率：
他莫昔芬：91.5%
他莫昔芬＋卵巢抑制：93.3%（与他莫昔芬相比，P=0.01）
依西美坦＋卵巢抑制：92.1%
SOFT研究接受化疗女性的8年总生存率：
他莫昔芬：85.1%
他莫昔芬＋卵巢抑制：89.4%
依西美坦＋卵巢抑制：87.2%
SOFT研究HER2阴性接受化疗女性的8年无远处复发生存率：
他莫昔芬：80.8%
他莫昔芬＋卵巢抑制：79.8%
依西美坦＋卵巢抑制：86.8%
TEXT研究HER2阴性接受化疗女性的8年无远处复发生存率：
他莫昔芬＋卵巢抑制：84.6%
依西美坦＋卵巢抑制：89.6%
两项研究报告≥3级不良事件发生率：
他莫昔芬：24.6%
他莫昔芬＋卵巢抑制：31.0%
依西美坦＋卵巢抑制：32.3%
因此，对于绝经前乳腺癌女性，他莫昔芬＋卵巢抑制与他莫昔芬相比，无病生存率和总生存率显著较高；依西美坦＋卵巢抑制与他莫昔芬＋卵巢抑制相比，无病生存率较高、总生存率较低，但是对于HER2阴性接受化疗女性，无远处复发生存率较高。加用卵巢抑制与单用他莫昔芬相比，不良事件发生率较高。
对此，迈阿密大学医学院综合癌症中心副主任马克·利普曼教授发表同期述评：早期乳腺癌的内分泌辅助疗法。
相关阅读
N Engl J Med. 2018 Jun 4. [Epub ahead of print]
Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer.
Prudence A. Francis, Olivia Pagani, Gini F. Fleming, Barbara A. Walley, Marco Colleoni, István Láng, Henry L. Gómez, Carlo Tondini, Eva Ciruelos, Harold J. Burstein, Hervé R. Bonnefoi, Meritxell Bellet, Silvana Martino, Charles E. Geyer, Jr., Matthew P. Goetz, Vered Stearns, Graziella Pinotti, Fabio Puglisi, Simon Spazzapan, Miguel A. Climent, Lorenzo Pavesi, Thomas Ruhstaller, Nancy E. Davidson, Robert Coleman, Marc Debled, Stefan Buchholz, James N. Ingle, Eric P. Winer, Rudolf Maibach, Manuela Rabaglio-Poretti, Barbara Ruepp, Angelo Di Leo, Alan S. Coates, Richard D. Gelber, Aron Goldhirsch, Meredith M. Regan; SOFT and TEXT Investigators; International Breast Cancer Study Group.
Peter MacCallum Cancer Centre, St. Vincent's Hospital, University of Melbourne, Melbourne, VIC; Breast Cancer Trials Australia and New Zealand, University of Newcastle, Newcastle, NSW; University of Sydney, Sydney, Australia; Institute of Oncology of Southern Switzerland, Ospedale San Giovanni, Bellinzona; Breast Cancer St. Gallen, St. Gallen; International Breast Cancer Study Group Coordinating Center, University Hospital Inselspital, Bern, Switzerland; University of Chicago Medical Center, Chicago; University of Calgary, Calgary, AB, Canada; European Institute of Oncology, International Breast Cancer Study Group, Milan, Ospedale Papa Giovanni XXIII, Bergamo; Azienda Socio Sanitaria Territoriale Sette Laghi-Ospedale di Circolo and Fondazione Macchi, Varese; Medical Oncology and Cancer Prevention, IRCCS, National Cancer Institute, Aviano; University of Udine, Udine; Salvatore Maugeri Foundation, Pavia; Hospital of Prato-Azienda Unità Sanitaria Locale Toscana Centro, Prato, Italy; National Institute of Oncology, Budapest, Hungary; Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru; University Hospital 12 de Octubre, Madrid ; Vall d'Hebron Institute of Oncology and Vall d'Hebron University Hospital, Barcelona; Instituto Valenciano de Oncologia, Valencia, Spain; Susan F. Smith Center for Women's Cancers, International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, Harvard T.H. Chan School of Public Health, Frontier Science and Technology Research Foundation, Boston; Institut Bergonié Comprehensive Cancer Center, Université de Bordeaux, Bordeaux, France; Angeles Clinic and Research Institute, Santa Monica, CA; Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond; Mayo Clinic, Rochester, MN; Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore; Fred Hutchinson Cancer Research Center, University of Washington, Seattle; Weston Park Hospital, Sheffield, United Kingdom; University Medical Center, Regensburg, Germany.
BACKGROUND: In the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT), the 5-year rates of recurrence of breast cancer were significantly lower among premenopausal women who received the aromatase inhibitor exemestane plus ovarian suppression than among those who received tamoxifen plus ovarian suppression. The addition of ovarian suppression to tamoxifen did not result in significantly lower recurrence rates than those with tamoxifen alone. Here, we report the updated results from the two trials.
METHODS: Premenopausal women were randomly assigned to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression in SOFT and to receive tamoxifen plus ovarian suppression or exemestane plus ovarian suppression in TEXT. Randomization was stratified according to the receipt of chemotherapy.
RESULTS: In SOFT, the 8-year disease-free survival rate was 78.9% with tamoxifen alone, 83.2% with tamoxifen plus ovarian suppression, and 85.9% with exemestane plus ovarian suppression (P=0.009 for tamoxifen alone vs. tamoxifen plus ovarian suppression). The 8-year rate of overall survival was 91.5% with tamoxifen alone, 93.3% with tamoxifen plus ovarian suppression, and 92.1% with exemestane plus ovarian suppression (P=0.01 for tamoxifen alone vs. tamoxifen plus ovarian suppression); among the women who remained premenopausal after chemotherapy, the rates were 85.1%, 89.4%, and 87.2%, respectively. Among the women with cancers that were negative for HER2 who received chemotherapy, the 8-year rate of distant recurrence with exemestane plus ovarian suppression was lower than the rate with tamoxifen plus ovarian suppression (by 7.0 percentage points in SOFT and by 5.0 percentage points in TEXT). Grade 3 or higher adverse events were reported in 24.6% of the tamoxifen-alone group, 31.0% of the tamoxifen-ovarian suppression group, and 32.3% of the exemestane-ovarian suppression group.
CONCLUSIONS: Among premenopausal women with breast cancer, the addition of ovarian suppression to tamoxifen resulted in significantly higher 8-year rates of both disease-free and overall survival than tamoxifen alone. The use of exemestane plus ovarian suppression resulted in even higher rates of freedom from recurrence. The frequency of adverse events was higher in the two groups that received ovarian suppression than in the tamoxifen-alone group.
Supported by Pfizer, International Breast Cancer Study Group, National Cancer Institute for the conduct of SOFT and TEXT. Pfizer and Ipsen provided the trial drugs. Support for the International Breast Cancer Study Group was provided by the Frontier Science and Technology Research Foundation, Swiss Group for Clinical Cancer Research, Cancer Research Switzerland, Oncosuisse, Cancer League Switzerland, Foundation for Clinical Cancer Research of Eastern Switzerland, a grant (CA075362) from the National Institutes of Health, and a grant (16-185) from the Breast Cancer Research Foundation.
SOFT and TEXT ClinicalTrials.gov numbers, NCT00066690 and NCT00066703, respectively.
DOI: 10.1056/NEJMoa1803164
N Engl J Med. 2018 Jun 4. [Epub ahead of print]
Endocrine Adjuvant Therapy for Localized Breast Cancer.
Marc E. Lippman.
University of Miami Miller School of Medicine, Miami.
Investigators now report in the Journal the updated results of two critical trials of endocrine therapy in early-stage breast cancer — SOFT (Suppression of Ovarian Function Trial) and TEXT (Tamoxifen and Exemestane Trial) — with overlapping groups that permitted a combined analysis. As in many other endocrine-therapy trials, the effects were not apparent in earlier analyses, but after 8 to 9 years of follow-up, the results are clear. In premenopausal women, the addition of ovarian suppression to tamoxifen was more effective in increasing disease-free survival than tamoxifen alone, and the addition of the aromatase inhibitor exemestane to ovarian suppression was even better than tamoxifen plus ovarian suppression, although at a cost of a longer list of adverse events. This finding held true across essentially all subgroups of patients, regardless of lymph-node status, chemotherapy status before the initiation of endocrine therapy, and age among premenopausal patients.
These data make sense. Since these trials were restricted to patients with tumors that were estrogen-receptor-positive, we would anticipate that the patients with the greatest reduction in estrogen levels would have the greatest benefit. The use of tamoxifen in premenopausal patients is clearly effective as a treatment for metastatic tumors and as adjuvant therapy, since it acts as an antiestrogen in breast cells. However, the drug increases ambient estrogen levels in other tissues (e.g., the uterus and bones). Because of the pharmacokinetic properties of tamoxifen, levels of the drug may build up in the blood, reaching several micromolars. Nonetheless, in a variety of experimental systems, a dose of estradiol at 1% of the dose of tamoxifen can reverse the inhibitory effects of tamoxifen and its metabolites. Thus, it is not surprising that blocking ovarian sources of estrogens could add to the effectiveness of tamoxifen.
In postmenopausal women, aromatase inhibition is more effective than tamoxifen as a treatment for metastatic tumors and as adjuvant therapy. Although the adrenal glands do not produce estradiol or estrone, adrenal androgens, which are made in large quantities by the adrenal cortex, can be aromatized to estrone and estradiol in many tissues, including fat, skin, liver, breast, and breast cancer. Since ovarian ablation in premenopausal women essentially renders them postmenopausal, it is not surprising that the addition of exemestane to ovarian suppression was superior to either tamoxifen alone or tamoxifen plus ovarian suppression, since exemestane can also prevent the production of estrogens by peripheral aromatization and provide even lower ambient estrogen levels. (In the SOFT and TEXT trials, ovarian suppression was achieved by the intramuscular injection of triptorelin every 28 days, by bilateral oophorectomy, or by ovarian irradiation.)
Even though the data from essentially all clinical trials are analyzed on an intention-to-treat basis, it seems worth pointing out that at least one quarter of the patients in the combined analyses in SOFT and TEXT discontinued treatment, mainly because of therapy-related side effects. The degree of such subjective side effects was clearly higher with ovarian suppression, a factor that has led many clinicians to reserve this treatment for patients whom they consider to be at highest risk. However, the benefits of ovarian suppression combined with either exemestane or tamoxifen were substantially the same in all categories of risk. It is unfortunate that the use of bone-strengthening agents (e.g., bisphosphonates) or inhibitors of receptor activator of nuclear factor-κB ligand (RANKL) was not permitted in this trial unless such use was medically indicated, since it is now clear that such agents reduce skeletal events associated with aromatase inhibitors, reduce fracture recurrences, and increase overall survival.
It is very difficult to predict which women who receive endocrine treatment will have few side effects and which will be seriously harmed in terms of sexual functioning, depression, and osteoporosis. It is also challenging to determine which side effects are associated with which drugs. This problem was highlighted in the International Breast Cancer Intervention Study II (IBIS-II) of aromatase inhibition versus placebo for breast cancer prevention, in which the frequencies of such adverse events as musculoskeletal symptoms and vaginal dryness were nearly identical in the placebo group and the treatment group. These results suggest an important role for physicians in addressing patients' concerns about adverse events during treatment.
One appropriate approach for premenopausal women may be to initiate medical ovarian suppression (because of its reversibility) combined with any of the three available aromatase inhibitors. We believe that the gains in outcomes will encourage physicians to attempt the more effective therapy and manage side effects if they occur. In our view, the data strongly favor adding either a bisphosphonate or RANKL inhibitor administered at 6-month intervals for 3 years to help prevent problems with loss of bone density and increase survival in such patients.
DOI: 10.1056/NEJMe1806130
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