On average, aromatase inhibitors are better than tamoxifen when used as initial or sequential therapy for postmenopausal women with endocrine-responsive early breast cancer. Because there may be ...contraindications to their use based on side-effects or cost, we investigated subgroups in which aromatase inhibitors may be more or less important.
Breast International Group 1-98 trial randomized 6182 women among four groups comparing letrozole and tamoxifen with sequences of each agent; 5177 (84%) had centrally confirmed estrogen receptor (ER) positivity. We assessed whether centrally determined ER, progesterone receptor (PgR), human epidermal growth factor receptor 2, and Ki-67 labeling index, alone or in combination with other prognostic features, predicted the magnitude of letrozole effectiveness compared with either sequence or tamoxifen monotherapy.
Individually, none of the markers significantly predicted differential treatment effects. Subpopulation treatment effect pattern plot analysis of a composite measure of prognostic risk revealed three patterns. Estimated 5-year disease-free survival for letrozole monotherapy, letrozole→tamoxifen, tamoxifen→letrozole, and tamoxifen monotherapy were 96%, 94%, 93%, and 94%, respectively, for patients at lowest risk; 90%, 91%, 93%, and 86%, respectively, for patients at intermediate risk; and 80%, 76%, 74%, and 69%, respectively, for patients at highest risk.
A composite measure of risk informs treatment selection better than individual biomarkers and supports the choice of 5 years of letrozole for patients at highest risk for recurrence.
Background: Current information on the prognostic importance of body mass index (BMI) for patients with early breast cancer is based on a variety of equivocal reports. Few have data on BMI in ...relationship to systemic treatment. Patients and methods: Patients (6792) were randomized to International Breast Cancer Study Group trials from 1978 to 1993, studying chemotherapy and endocrine therapy. BMI was evaluated with eight other factors: menopausal status, nodal status, estrogen receptor status, progesterone receptor status, tumor size, vessel invasion, tumor grade and treatment. BMI was categorized as normal (≤24.9), intermediate (25.0–29.9) or obese (≥30.0). Results: Patients with normal BMI had significantly longer overall survival (OS) and disease-free survival (DFS) than patients with intermediate or obese BMI in pairwise comparisons adjusted for other factors. Subset analyses showed the same effect in pre- and perimenopausal patients and in those receiving chemotherapy alone. When assessed globally and adjusted for other factors, BMI significantly influenced OS (P = 0.03) but not DFS (P = 0.12). Conclusions: BMI is an independent prognostic factor for OS in patients with breast cancer, especially among pre-/perimenopausal patients treated with chemotherapy without endocrine therapy.
To explore prognostic factors for locoregional failures (LRF) among women treated for invasive breast cancer within clinical trials of adjuvant therapies.
The study population consisted of 5,352 ...women who were treated with a modified radical mastectomy and enrolled in one of seven International Breast Cancer Study Group randomized trials. A total of 1,275 women with node-negative disease received either no adjuvant therapy or a single cycle of perioperative chemotherapy, and 4,077 women with node-positive disease received adjuvant chemotherapy of at least 3 months' duration and/or tamoxifen. Median follow-up is 12 to 15.5 years.
In women with node-negative disease, factors associated with increased risk of LRF were vascular invasion (VI) and tumor size greater than 2 cm for premenopausal and VI for postmenopausal patients. Of the 1,275 patients, 345 (27%) met criteria for the highest risk groups, and the 10-year cumulative incidences of LRF with or without distant metastases were 16% for premenopausal and 19% for postmenopausal women. For the node-positive cohort, number of nodes and tumor grade were factors for both menopausal groups, with additional prediction provided by VI for premenopausal and tumor size for postmenopausal patients. Of the 4,077 patients, 815 (20%) met criteria for the highest risk groups, and 10-year cumulative incidences were 35% for premenopausal and 34% for postmenopausal women.
LRFs are a significant problem after mastectomy alone even for some patients with node-negative breast cancer, as well as after mastectomy and adjuvant treatment for some subgroups of patients with node-positive disease. In addition to number of positive lymph nodes, predictors of LRF include tumor-related factors, such as vascular invasion, higher grade, and larger size.
St Gallen Expert Consensus meetings update evidence on treatment of early breast cancer every 2 years and interpret its significance for treatment of individual patients. Such interpretation is ...controversial. Clinical decisions cannot, however, be postponed, and the harms of failing to tailor treatment must be balanced against those of overinterpretation. Since the ninth meeting in January 2005, an extraordinary year of progress has significantly changed the landscape in breast cancer therapy. The panel in January recommended a fundamental change in selection of adjuvant systemic therapy, giving prime attention to endocrine responsiveness. Primarily, three categories were acknowledged: endocrine responsive in which the primary treatment should be endocrine, endocrine non-responsive in which endocrine therapy should not be used, and an intermediate group for which both endocrine and other therapies should be offered. Secondarily, three risk groups were defined: low, intermediate, and high, slightly modifying the previous classification. In June 2005, three trials, supported in December by a fourth, demonstrated the additional contribution of targeted therapy with trastuzumab in appropriately selected patients. Reports from several trials strengthened the evidence supporting the inclusion of taxanes, though controversy persists concerning their use in endocrine-responsive disease. This commentary midway between St Gallen meetings, therefore, emphasizes how new information influences algorithms for selecting adjuvant therapy in a rapidly changing environment.
This account of the highlights of the eighth St Gallen (Switzerland) meeting in 2003 emphasizes new information that has emerged during the 2 years since the seventh meeting in 2001. This article ...should be read in conjunction with the report of that earlier meeting. Recommendations for patient care are so critically dependent on assessment of endocrine responsiveness that the importance of high-quality steroid hormone receptor determination and standardized quantitative reporting cannot be overemphasized. The International Consensus Panel modified the risk categories so that only endocrine receptor-absent status was sufficient to reclassify an otherwise low-risk, node-negative disease into the category of average risk. Absence of steroid hormone receptors also was recognized as indicating endocrine nonresponsiveness. Some important areas highlighted at the recent meeting include: (1) recognition of the separate nature of endocrine-nonresponsive breast cancer-both invasive cancers and ductal carcinoma-in-situ; (2) improved understanding of the mechanisms of acquired endocrine resistance, which offer exciting prospects for extending the impact of successful sequential endocrine therapies; (3) presentation of high-quality evidence indicating that chemotherapy and tamoxifen should be used sequentially rather than concurrently; (4) availability of a potential alternative to tamoxifen for treatment of postmenopausal women with endocrine-responsive disease; and (5) the promise of newly defined prognostic and predictive markers.
To compare the incidence and timing of bone fractures in postmenopausal women treated with 5 years of adjuvant tamoxifen or letrozole for endocrine-responsive early breast cancer in the Breast ...International Group (BIG) 1-98 trial.
We evaluated 4895 patients allocated to 5 years of letrozole or tamoxifen in the BIG 1-98 trial who received at least some study medication (median follow-up 60.3 months). Bone fracture information (grade, cause, site) was collected every 6 months during trial treatment.
The incidence of bone fractures was higher among patients treated with letrozole 228 of 2448 women (9.3%) versus tamoxifen 160 of 2447 women (6.5%). The wrist was the most common site of fracture in both treatment groups. Statistically significant risk factors for bone fractures during treatment included age, smoking history, osteoporosis at baseline, previous bone fracture, and previous hormone replacement therapy.
Consistent with other trials comparing aromatase inhibitors to tamoxifen, letrozole was associated with an increase in bone fractures. Benefits of superior disease control associated with letrozole and lower incidence of fracture with tamoxifen should be considered with the risk profile for individual patients.
Recent breast cancer treatment guidelines recommend that higher-risk premenopausal patients should receive ovarian function suppression (OFS) as part of adjuvant endocrine therapy. If chemotherapy is ...also given, it is uncertain whether to select concurrent or sequential OFS initiation.
We analyzed 1872 patients enrolled in the randomized phase III TEXT and SOFT trials who received adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer and upon randomization to an OFS-containing adjuvant endocrine therapy, initiated gonadotropin-releasing-hormone-agonist triptorelin. 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, we implemented landmark analysis re-defining BCFI beginning 1 year after final dose of chemotherapy (median, 15.5 and 8.1 months from enrollment to landmark in TEXT and SOFT, respectively). As a non-randomized treatment comparison, we implemented comparative-effectiveness propensity score methodology with weighted Cox modeling.
Distributions of several clinico-pathologic characteristics differed between groups. Patients who were premenopausal post-chemotherapy in SOFT were younger on average. The median duration of adjuvant chemotherapy was 18 weeks in both groups. There were 231 (12%) BC events after post-landmark median follow-up of about 5 years. Concurrent use of triptorelin with chemotherapy was not associated with a significant difference in post-landmark BCFI compared with sequential triptorelin post-chemotherapy, either in the overall population (HR = 1.11, 95% CI 0.72–1.72; P = 0.72; 4-year BCFI 89% in both groups), or in the subgroup of 692 women <40 years at diagnosis (HR = 1.13, 95% CI 0.69–1.84) who are less likely to develop chemotherapy-induced amenorrhea.
Based on comparative-effectiveness modeling of TEXT and SOFT after about 5 years median follow-up, with limited statistical power especially for the subgroup <40 years, neither detrimental nor beneficial effect of concurrent administration of OFS with chemotherapy on the efficacy of adjuvant therapy that includes chemotherapy was detected.
NCT00066690 and NCT00066703.
Transforming how plastics are made, unmade, and remade through innovative research and diverse partnerships that together foster environmental stewardship is critically important to a sustainable ...future. Designing, preparing, and implementing polymers derived from renewable resources for a wide range of advanced applications that promote future economic development, energy efficiency, and environmental sustainability are all central to these efforts. In this
contribution, we take a comprehensive, integrated approach to summarize important and impactful contributions to this broad research arena. The Review highlights signature accomplishments across a broad research portfolio and is organized into four wide-ranging research themes that address the topic in a comprehensive manner: Feedstocks, Polymerization Processes and Techniques, Intended Use, and End of Use. We emphasize those successes that benefitted from collaborative engagements across disciplinary lines.
To evaluate the benefit of low-dose cyclophosphamide and methotrexate (CM) maintenance, which previously demonstrated antitumor activity and few adverse effects in advanced breast cancer, in early ...breast cancer.
International Breast Cancer Study Group (IBCSG) Trial 22-00, a randomized phase III clinical trial, enrolled 1,086 women (1,081 intent-to-treat) from November 2000 to December 2012. Women with estrogen receptor- and progesterone receptor-negative (< 10% positive cells by immunohistochemistry) early breast cancer any nodal and human epidermal growth factor receptor 2 status, were randomly assigned anytime between primary surgery and 56 days after the first day of last course of adjuvant chemotherapy to CM maintenance (cyclophosphamide 50 mg/day orally continuously and methotrexate 2.5 mg twice/day orally on days 1 and 2 of every week for 1 year) or to no CM. The primary end point was disease-free survival (DFS), which included invasive recurrences, second (breast and nonbreast) malignancies, and deaths.
After a median of 6.9 years of follow-up, DFS was not significantly better for patients assigned to CM maintenance compared with patients assigned to no CM, both overall (hazard ratio HR, 0.84; 95% CI, 0.66 to 1.06;P = .14) and in triple-negative (TN) disease (n = 814; HR, 0.80; 95% CI, 0.60 to 1.06). Patients with TN, node-positive disease had a nonstatistically significant reduced HR (n = 340; HR, 0.72; 95% CI, 0.49 to 1.05). Seventy-one (13%) of 542 patients assigned to CM maintenance did not start CM. Of 473 patients who received at least one CM maintenance dose (including two patients assigned to no CM), 64 (14%) experienced a grade 3 or 4 treatment-related adverse event; elevated serum transaminases was the most frequently reported (7%), followed by leukopenia (2%).
CM maintenance did not produce a significant reduction in DFS events in hormone receptor-negative early breast cancer. The trend toward benefit observed in the TN, node-positive subgroup supports additional exploration of this strategy in the TN, higher-risk population.
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