Purpose To describe benefits and toxicities of adjuvant endocrine therapies in women younger than 35 years with breast cancer (n = 582) enrolled in the Suppression of Ovarian Function Trial (SOFT) ...and Tamoxifen and Exemestane Trial (TEXT). Methods In SOFT, women still premenopausal after surgery with or without chemotherapy were randomly assigned to tamoxifen alone, tamoxifen plus ovarian function suppression (OFS), or exemestane plus OFS. In TEXT, all received OFS with or without concomitant chemotherapy and were randomly assigned to exemestane plus OFS or tamoxifen plus OFS. We summarize treatment efficacy, quality of life, and adherence of the cohort of women younger than 35 years in SOFT and TEXT, alongside data from the cohort of older premenopausal women. Results For 240 human epidermal growth factor receptor 2-negative patients younger than 35 years enrolled in SOFT after receiving chemotherapy, the 5-year breast cancer-free interval (BCFI) was 67.1% (95% CI, 54.6% to 76.9%) with tamoxifen alone, 75.9% with tamoxifen plus OFS (95% CI, 64.0% to 84.4%), and 83.2% with exemestane plus OFS (95% CI, 72.7% to 90.0%). For 145 human epidermal growth factor receptor 2-negative patients younger than 35 years in TEXT, 5-year BCFI was 79.2% (95% CI, 66.2% to 87.7%) with tamoxifen plus OFS and 81.6% (95% CI, 69.8% to 89.2%) with exemestane plus OFS. The most prominent quality of life symptom for patients younger than 35 years receiving OFS was vasomotor symptoms, with the greatest worsening from baseline at 6 months (on the order of 30 to 40 points), but loss of sexual interest and difficulties in becoming aroused were also clinically meaningful (≥ 8-point change). The level of symptom burden was similar in older premenopausal women. A total of 19.8% of women younger than 35 years stopped all protocol-assigned endocrine therapy early. Conclusion In women younger than 35 years with hormone receptor-positive breast cancer, adjuvant OFS combined with tamoxifen or exemestane produces large improvements in BCFI compared with tamoxifen alone. Menopausal symptoms are significant but are not worse than those seen in older premenopausal women.
The Tamoxifen and Exemestane Trial (TEXT)/Suppression of Ovarian Function Trial (SOFT) showed superior outcomes for premenopausal women with hormone receptor (HR)-positive breast cancer treated with ...adjuvant exemestane plus ovarian function suppression (OFS) or tamoxifen plus OFS versus tamoxifen alone. We previously reported the magnitude of absolute improvements in freedom from any recurrence across a continuous, composite measure of recurrence risk to tailor decision making. With longer follow-up, we now focus on distant recurrence.
The TEXT/SOFT HR-positive/human epidermal growth factor receptor 2 (HER2)-negative analysis population included 4,891 women stratified by predetermined chemotherapy use. Kaplan-Meier estimates of 8-year freedom from distant recurrence were analyzed using subpopulation treatment effect pattern plot (STEPP) methodology across subpopulations defined by the continuous composite measure of recurrence risk. For each patient, the composite risk value was obtained from a Cox model that incorporated age; nodal status; tumor size; grade; and estrogen receptor, progesterone receptor, and Ki-67 labeling index expression levels.
The overall rate of 8-year freedom from distant recurrence was 91.1% and ranged from approximately 100% to 63% across lowest to highest composite risks. TEXT patients who received chemotherapy had an average absolute improvement with exemestane plus OFS versus tamoxifen plus OFS of 5.1%, and STEPP analysis showed improvements from less than 1% to more than 15% from lowest to highest composite risks. SOFT patients who remained premenopausal after chemotherapy had an average 5.2% absolute improvement with exemestane plus OFS versus tamoxifen and reached 10% across composite risks; for tamoxifen plus OFS versus tamoxifen, the maximum improvement was approximately 3.5%. Women who did not receive chemotherapy had a more than 97% rate of 8-year freedom from distant recurrence, and improvements with exemestane plus OFS ranged from 1% to 4%.
Premenopausal women with HR-positive/HER2-negative breast cancer and high recurrence risk, as defined by clinicopathologic characteristics, may experience a 10% to 15% absolute improvement in 8-year freedom from distant recurrence with exemestane plus OFS versus tamoxifen plus OFS or tamoxifen alone. The potential benefit of escalating endocrine therapy versus tamoxifen alone is minimal for those at low recurrence risk.
This trial did not support routine use of ovarian suppression in premenopausal breast cancer. Nevertheless, there may be some benefit from ovarian suppression in the subgroup of younger patients ...whose menses return after adjuvant chemotherapy, but also more symptoms.
Adjuvant endocrine therapy with tamoxifen has been recommended for premenopausal women with hormone-receptor–positive breast cancer (positive for estrogen receptor, progesterone receptor, or both) during the past 15 years.
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The value of therapeutic suppression of ovarian estrogen production in premenopausal women who receive tamoxifen is uncertain.
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The American Society of Clinical Oncology endorsed guidelines recommending that ovarian ablation or suppression (hereafter, ovarian suppression) not be added routinely to adjuvant therapy in premenopausal women.
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Chemotherapy-induced ovarian suppression (amenorrhea) is correlated with a reduced risk of relapse
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but is less likely to be achieved in very young women. International consensus guidelines . . .
Summary Background The combined efficacy analysis of the TEXT and SOFT trials showed a significant disease-free survival benefit with exemestane plus ovarian function suppression (OFS) compared with ...tamoxifen plus OFS. We present patient-reported outcomes from these trials. Methods Between Nov 7, 2003, and April 7, 2011, 4717 premenopausal women with hormone-receptor positive breast cancer were enrolled in TEXT or SOFT to receive unmasked adjuvant treatment with 5 years of exemestane plus OFS or tamoxifen plus OFS. Gonadotropin-releasing hormone analogue triptorelin, bilateral oophorectomy, or bilateral ovarian irradiation were used to achieve OFS. Chemotherapy use was optional. Randomisation with permuted blocks was done with the International Breast Cancer Study Group's internet-based system and was stratified by chemotherapy use and status of lymph nodes. Patients completed a quality of life (QoL) form comprising several global and symptom indicators at baseline, every 6 months for 24 months, and then every year during years 3 to 6. Differences in the change of QoL from baseline between the two treatments were tested at 6 months, 24 months, and 60 months with mixed-models for repeated measures for each trial with and without chemotherapy and overall. The analysis was by intention to treat. At the time of analysis, the median follow-up was 5·7 years (IQR 3·7–6·9); treatment and follow-up of patients continue. The trials are registered with ClinicalTrials.gov , as NCT00066703 (TEXT) and NCT00066690 (SOFT). Findings Patients on tamoxifen plus OFS were more affected by hot flushes and sweats over 5 years than were those on exemestane plus OFS, although these symptoms improved. Patients on exemestane plus OFS reported more vaginal dryness, greater loss of sexual interest, and difficulties becoming aroused than did patients on tamoxifen plus OFS; these differences persisted over time. An increase in bone or joint pain was more pronounced, particularly in the short term, in patients on exemestane plus OFS than patients on tamoxifen plus OFS. Changes in global QoL indicators from baseline were small and similar between treatments over the 5 years. Interpretation Overall, from a QoL perspective, there is no strong indication to favour either exemestane plus OFS or tamoxifen plus OFS. The distinct effects of the two treatments on the burden of endocrine symptoms need to be addressed with patients individually. Funding Pfizer, International Breast Cancer Study Group, and US National Cancer Institute.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Risk of recurrence is the primary consideration in breast cancer adjuvant therapy recommendations. The TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) trials ...investigated adjuvant endocrine therapies for premenopausal women with hormone receptor-positive breast cancer, testing exemestane plus ovarian function suppression (OFS), tamoxifen plus OFS, and tamoxifen alone. We examined absolute treatment effect across a continuum of recurrence risk to individualize endocrine therapy decision making for premenopausal women with human epidermal growth factor receptor 2 (HER2) -negative disease.
The TEXT and SOFT hormone receptor-positive, HER2-negative analysis population included 4,891 women. The end point was breast cancer-free interval (BCFI), defined as time from random assignment to first occurrence of invasive locoregional, distant, or contralateral breast cancer. A continuous, composite measure of recurrence risk for each patient was determined from a Cox model incorporating age, nodal status, tumor size and grade, and estrogen receptor, progesterone receptor, and Ki-67 expression levels. Subpopulation treatment effect pattern plot methodology revealed differential treatment effects on 5-year BCFI according to composite risk.
SOFT patients who remained premenopausal after chemotherapy experienced absolute improvement of 5% or more in 5-year BCFI with exemestane plus OFS versus tamoxifen plus OFS or tamoxifen alone, reaching 10% to 15% at intermediate to high composite risk; the benefit of tamoxifen plus OFS versus tamoxifen alone was apparent at the highest composite risk. The SOFT no-chemotherapy cohort-for whom composite risk was lowest on average-did well with all endocrine therapies. For TEXT patients, the benefit of exemestane plus OFS versus tamoxifen plus OFS in 5-year BCFI ranged from 5% to 15%; patients not receiving chemotherapy and with lowest composite risk did well with both treatments.
Premenopausal women with hormone receptor-positive, HER2-negative disease and high recurrence risk, as defined by clinicopathologic characteristics, may experience improvement of 10% to 15% in 5-year BCFI with exemestane plus OFS versus tamoxifen alone. An improvement of at least 5% may be achieved for women at intermediate risk, and improvement is minimal for those at lowest risk.
JCO
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;
< .001) and DRFI (1.8% absolute improvement, HR, 0.83; 95% CI, 0.70 to 0.98;
= .03), but not overall survival (90.1%
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.Media: see text.
Aromatase inhibitors are somewhat more effective than tamoxifen as adjuvant therapy in postmenopausal women with early breast cancer. This benefit was extended to premenopausal women when they also ...received ovarian suppression to prevent ovarian compensation for aromatase inhibition.
The most effective adjuvant endocrine therapy for premenopausal women with hormone-receptor (estrogen, progesterone, or both)–positive breast cancer is uncertain. Tamoxifen for at least 5 years is a standard of care.
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Adjuvant suppression of ovarian function (hereafter, ovarian suppression) may be recommended in addition. For postmenopausal women, adjuvant therapy with an aromatase inhibitor, as compared with tamoxifen, improves outcomes.
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In 2003, the International Breast Cancer Study Group (IBCSG) initiated two randomized, phase 3 trials, the Tamoxifen and Exemestane Trial (TEXT) and the Suppression of Ovarian Function Trial (SOFT), involving premenopausal women with hormone-receptor–positive early breast cancer, through collaboration with . . .
JCO
The Suppression of Ovarian Function Trial (SOFT; ClinicalTrials.gov identifier: NCT00066690) randomly assigned premenopausal women with hormone receptor-positive breast cancer to 5 years of ...adjuvant tamoxifen, tamoxifen plus ovarian function suppression (OFS), or exemestane plus OFS. The primary analysis compared disease-free survival (DFS) between tamoxifen plus OFS versus tamoxifen alone; exemestane plus OFS versus tamoxifen was a secondary objective. After 8 years, SOFT reported a significant reduction in recurrence and improved overall survival (OS) with adjuvant tamoxifen plus OFS versus tamoxifen alone. Here, we report outcomes after median follow-up of 12 years. DFS remained significantly improved with tamoxifen plus OFS versus tamoxifen (hazard ratio, 0.82; 95% CI, 0.69 to 0.98) with a 12-year DFS of 71.9% with tamoxifen, 76.1% with tamoxifen plus OFS, and 79.0% with exemestane plus OFS. OS was improved with tamoxifen plus OFS versus tamoxifen (hazard ratio, 0.78; 95% CI, 0.60 to 1.01) and was 86.8% with tamoxifen, 89.0% with tamoxifen plus OFS, and 89.4% with exemestane plus OFS at 12 years. Among those who received prior chemotherapy for human epidermal growth factor receptor-2-negative tumors, OS was 78.8% with tamoxifen, 81.1% with tamoxifen plus OFS, and 84.4% with exemestane plus OFS. In conclusion, after 12 years, there remains a benefit from including OFS in adjuvant endocrine therapy, with an absolute improvement in OS more apparent with higher baseline risk of recurrence.Media: see text.
Advanced prostate cancer commonly metastasizes to bone, but transit of malignant cells across the bone marrow endothelium (BMEC) remains a poorly understood step in metastasis. Prostate cancer cells ...roll on E-selectin(+) BMEC through E-selectin ligand-binding interactions under shear flow, and prostate cancer cells exhibit firm adhesion to BMEC via β1, β4, and αVβ3 integrins in static assays. However, whether these discrete prostate cancer cell-BMEC adhesive contacts culminate in cooperative, step-wise transendothelial migration into bone is not known. Here, we describe how metastatic prostate cancer cells breach BMEC monolayers in a step-wise fashion under physiologic hemodynamic flow. Prostate cancer cells tethered and rolled on BMEC and then firmly adhered to and traversed BMEC via sequential dependence on E-selectin ligands and β1 and αVβ3 integrins. Expression analysis in human metastatic prostate cancer tissue revealed that β1 was markedly upregulated compared with expression of other β subunits. Prostate cancer cell breaching was regulated by Rac1 and Rap1 GTPases and, notably, did not require exogenous chemokines as β1, αVβ3, Rac1, and Rap1 were constitutively active. In homing studies, prostate cancer cell trafficking to murine femurs was dependent on E-selectin ligand, β1 integrin, and Rac1. Moreover, eliminating E-selectin ligand-synthesizing α1,3 fucosyltransferases in transgenic adenoma of mouse prostate mice dramatically reduced prostate cancer incidence. These results unify the requirement for E-selectin ligands, α1,3 fucosyltransferases, β1 and αVβ3 integrins, and Rac/Rap1 GTPases in mediating prostate cancer cell homing and entry into bone and offer new insight into the role of α1,3 fucosylation in prostate cancer development.
Purpose
Sexual dysfunction is an important concern of premenopausal women with early breast cancer. We investigated predictors of sexual problems in two randomized controlled trials.
Methods
A subset ...of patients enrolled in TEXT and SOFT completed global and symptom-specific quality-of-life indicators, CES-Depression and MOS-Sexual Problems measures at baseline, six, 12 and 24 months. Mixed models tested the association of changes in treatment-induced symptoms (baseline to 6 months), depression at 6 months, and age at randomization with changes in sexual problems over 2 years.
Results
Sexual problems increased by 6 months and persisted at this level. Overall, patients with more severe worsening of vaginal dryness, sleep disturbances and bone or joint pain at 6 months reported a greater increase in sexual problems at all time-points. Depression scores were significantly associated with sexual problems in the short-term. All other symptoms had a smaller impact on sexual problems. Age was not associated with sexual problems at any time-point.
Conclusion
Among several key symptoms, vaginal dryness, sleep disturbance, and bone and joint pain significantly predicted sexual problems during the first 2 years. Early identification of these symptoms may contribute to timely and tailored interventions.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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