Trends in use of neoadjuvant systemic therapy in patients with clinically node-positive breast cancer in Europe: prospective TAXIS study (OPBC-03, SAKK 23/16, IBCSG 57-18, ABCSG-53, GBG 101).

PURPOSE: The aim of this study was to evaluate clinical practice heterogeneity in use of neoadjuvant systemic therapy (NST) for patients with clinically node-positive breast cancer in Europe. METHODS: The study was preplanned in the international multicenter phase-III OPBC-03/TAXIS trial (ClinicalTrials.gov Identifier: NCT03513614) to include the first 500 randomized patients with confirmed nodal disease at the time of surgery. The TAXIS study's pragmatic design allowed both the neoadjuvant and adjuvant setting according to the preferences of the local investigators who were encouraged to register eligible patients consecutively. RESULTS: A total of 500 patients were included at 44 breast centers in six European countries from August 2018 to June 2022, 165 (33%) of whom underwent NST. Median age was 57 years (interquartile range [IQR], 48-69). Most patients were postmenopausal (68.4%) with grade 2 and 3 hormonal receptor-positive and human epidermal growth factor receptor 2-negative breast cancer with a median tumor size of 28 mm (IQR 20-40). The use of NST varied significantly across the countries (p < 0.001). Austria (55.2%) and Switzerland (35.8%) had the highest percentage of patients undergoing NST and Hungary (18.2%) the lowest. The administration of NST increased significantly over the years (OR 1.42; p < 0.001) and more than doubled from 20 to 46.7% between 2018 and 2022. CONCLUSION: Substantial heterogeneity in the use of NST with HR+/HER2-breast cancer exists in Europe. While stringent guidelines are available for its use in triple-negative and HER2+ breast cancer, there is a need for the development of and adherence to well-defined recommendations for HR+/HER2-breast cancer.

Surgical Outcomes After Neoadjuvant Chemoradiation Followed by Curative Surgery in Patients With Esophageal Cancer: An Intergroup Phase III Trial of the Swiss Group for Clinical Cancer Research (SAKK 75/08).

OBJECTIVE: To assess the impact of surgical technique in regard to morbidity and mortality after neoadjuvant treatment for esophageal cancer. BACKGROUND: The SAKK trial 75/08 was a multicenter phase III trial (NCT01107639) comparing induction chemotherapy followed by chemoradiation and surgery in patients with locally advanced esophageal cancer. METHODS: Patients in the control arm received induction chemotherapy with cisplatin and docetaxel, followed by concomitant chemoradiation therapy with cisplatin, docetaxel, and 45Gy. In the experimental arm, the same regimen was used with addition of cetuximab. After completion of neoadjuvant treatment, patients underwent esophagectomy. The experimental arm received adjuvant cetuximab. Surgical outcomes and complications were prospectively recorded and analyzed. RESULTS: Total of 259 patients underwent esophagectomy. Overall complication rate was 56% and reoperation rate was 15% with no difference in complication rates for transthoracic versus transhiatal resections (56% vs 54%, P = 0.77), nor for video assisted thoracic surgeries (VATS) versus open transthoracic resections (67% vs 55%, P = 0.32). There was a trend to higher overall complication rates in squamous cell carcinoma versus adenocarcinoma (65% vs 51%, P = 0.035), and a significant difference in ARDS in squamous cell carcinoma with 14% versus 2% in adenocarcinoma (P = 0.0002). For patients with involved lymph nodes, a lymph node ratio of ≥0.1 was an independent predictor of PFS (HR 2.5, P = 0.01) and OS (HR 2.2, P = 0.03). CONCLUSIONS: This trial showed no difference in surgical complication rates between transthoracic and transhiatal resections. For patients with involved lymph nodes, lymph node ratio was an independent predictor of progression free survival and overall survival.

Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer.

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. (Funded by Pfizer and others; SOFT and TEXT ClinicalTrials.gov numbers, NCT00066690 and NCT00066703 , respectively.).

Correction: Quality of life under extended continuous versus intermittent adjuvant letrozole in lymph node-positive, early breast cancer patients: the SOLE randomised phase 3 trial.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Plasma HER2ECD a promising test for patient prognosis and prediction of response in HER2 positive breast cancer: results of a randomized study - SAKK 22/99.

BACKGROUND: The HER2 extracellular domain shed in blood (HER2ECD) is reported to rise and fall in parallel with HER2+ breast cancer behavior. In this study, we evaluated the clinical relevance of plasma HER2ECD values in patients with metastatic breast cancer treated in the SAKK22/99 trial comparing trastuzumab monotherapy followed by trastuzumab-chemotherapy combination at progression versus upfront combination therapy. METHODS: Quantitative assessment of plasma HER2ECD was performed in 133 patients at baseline; after 2-24 h; at 3 weeks; at first response evaluation (8-9 weeks); and at tumor progression. Associations with tumor characteristics, disease course and trial treatment were evaluated. RESULTS: Baseline HER2ECD levels were stable within 24 h after the first trastuzumab injection. These plasma values correlated positively with the HER2 gene ratio (rs = 0.39, P < 0.001) and HER2 protein expression levels (rs = 0.36, P < 0.001) but not with ER/PR status of the primary tumor. HER2ECD baseline levels were positively associated with the presence of visceral disease (P = 0.05) and poor patients' outcome (Cox-regression: P = 0.009). Patients with high baseline levels (> 35 ng/ml) had the worst overall survival (P = 0.03) if treated with upfront combination therapy. Conversely, patients with low HER2ECD baseline values (< 15 ng/ml) had longer time to progression on combined trastuzumab-chemotherapy when first treated with trastuzumab monotherapy (P = 0.02). Monitoring HER2ECD levels during the course of the trial revealed significant time (P = 0.001) and time-treatment arm interactions (P = 0.0007). Under upfront trastuzumab alone, the HER2ECD levels remained stable until just before disease progression. In patients responding to combination treatment HER2ECD levels decreased to > 20%. CONCLUSIONS: Plasma HER2ECD levels in patients with metastatic breast cancer reflect HER2 disease status. This robust biomarker might help identifying patients without visceral disease profiting from a sequential treatment's modality. Monitoring HER2ECD levels during trastuzumab monotherapy could help defining the optimal time to introduce chemotherapy. TRIAL REGISTRATION: Registration Number by ClinicalTrials.gov: NCT00004935, Trial number: SAKK22/99. Registered on 27 January 2003.

High thromboembolic event rate in patients with locally advanced oesophageal cancer during neoadjuvant therapy. An exploratory analysis of the prospective, randomised intergroup phase III trial SAKK 75/08.

BACKGROUND: High rates of venous thromboembolic events (VTEs), mainly in advanced disease, are reported for patients with cancer of the upper gastrointestinal tract (stomach, pancreas) and for treatment with cisplatin. METHODS: Exploratory analysis of VTEs reported as adverse events and serious adverse events in a prospective, randomised, multicentre, multimodal phase III trial according to VTEs reported as adverse events and severe adverse events. Patients with resectable oesophageal cancer (T2N1-3, T3-4aNx) were randomized to 2 cycles of chemotherapy with docetaxel 75 mg/m2, cisplatin 75 mg/m2 followed by chemo-radiotherapy (CRT) and subsequent surgery (control arm) or the same treatment with addition of cetuximab (investigational arm). RESULTS: VTEs occurred in 26 of 300 patients included in the trial, resulting in an incidence rate (IR) of 8.7% [95% CI 5.7-12.4%]. A total of 29 VTEs were reported:13 (45%) VTEs were grade 2, 13 (45%) grade 3 and three (10%) fatal grade 5 events. 72% (21/29) of all VTEs occurred preoperatively (IR 6.7%): 14% (4/29) during chemotherapy and 59% (17/29) during CRT. In multivariable logistic regression only adenocarcinoma (IR 11.1%, 21/189 patients) compared to squamous cell cancer (IR 4.5%, 5/111 patients) was significantly associated with VTE-risk during treatment, OR 2.9 [95%CI 1.0-8.4], p = 0.046. Baseline Khorana risk score was 0 in 73% (19/26), 1-2 in 23% (6/26) and 3 in only 4% (1/26) of patients with VTEs. CONCLUSION: A high incidence of VTEs during preoperative therapy of resectable oesophageal cancer is observed in this analysis, especially in patients with adenocarcinoma. The role of prophylactic anticoagulation during neoadjuvant therapy in resectable esophageal cancer should be further evaluated in prospective clinical trials. According to our data, which are in line with other analysis of VTE-risk in patients with oesophageal cancer patients treated with neoadjuvant cisplatin-based chemotherapy and CRT, prophylactic anticoagluation could be considered balanced against individual bleeding risks, especially in patients with adenocarcinoma. In addition to the established risk factors, oesophageal adenocarcinoma treated with neoadjuvant cisplatin-based therapy may be regarded as a high-risk situation for VTEs. TRIAL REGISTRATION: Registered at clinicaltrials.gov, NCT01107639, on 21 April 2010.

Quality of life under extended continuous versus intermittent adjuvant letrozole in lymph node-positive, early breast cancer patients: the SOLE randomised phase 3 trial.

BACKGROUND: In the phase III SOLE trial, the extended use of intermittent versus continuous letrozole for 5 years did not improve disease-free survival in postmenopausal women with hormone receptor-positive breast cancer. Intermittent therapy with 3-month breaks may be beneficial for patients' quality of life (QoL). METHODS: In the SOLE QoL sub-study, 956 patients completed the Breast Cancer Prevention Trial (BCPT) symptom and further QoL scales up to 24 months after randomisation. Differences in change of QoL from baseline between the two administration schedules were tested at 12 and 24 months using repeated measures mixed-models. The primary outcome was change in hot flushes at 12 months. RESULTS: There was no difference in hot flushes at 12 months between the two schedules, but patients receiving intermittent letrozole reported significantly more improvement at 24 months. They also indicated less worsening in vaginal problems, musculoskeletal pain, sleep disturbance, physical well-being and mood at 12 months. Overall, 25-30% of patients reported a clinically relevant worsening in key symptoms and global QoL. CONCLUSION: Less symptom worsening was observed during the first year of extended treatment with the intermittent administration. For women experiencing an increased symptom burden of extended adjuvant endocrine therapy, an intermittent administration is a safe alternative. CLINICAL TRIAL INFORMATION: Clinical trial information: NCT00651456.

Recurrence Patterns and Long-term Results After Induction Chemotherapy, Chemoradiotherapy, and Curative Surgery in Patients With Locally Advanced Esophageal Cancer.

OBJECTIVE: The long-term follow up data of 2 prospective phase II trials is reported (NCT00072033, NCT00445861), which investigated neoadjuvant chemoradiation followed by surgery in patients with esophageal carcinoma. Postoperative complications as well as prognostic factors and patterns of relapse during long-term observation are shown. SUMMARY OF BACKGROUND DATA: Long-term follow-up is often missing in the complex setting of multimodal treatments of esophageal carcinoma; this leads to rather undifferentiated follow-up guidelines for this tumor entity. METHODS: In the first trial, patients received induction chemotherapy followed by chemoradiation and surgery. In the second trial, cetuximab was added to the same neoadjuvant treatment concomitant with induction chemotherapy and chemoradiation. RESULTS: Eighty-two patients underwent surgery; the median follow-up time was 6.8 and 6.4 years, respectively. Fifty-five percent were diagnosed with adenocarcinoma, 80% clinically node-positive, 68% received transthoracic esophagectomy, and 32% transhiatal or transmediastinal resection. Five patients died postoperatively in-hospital due to complications (6%). The median overall survival was 4.3 years, and the median event-free survival was 2.7 years. Patients with adenocarcinoma rarely relapsed after a 3-year event-free survival. Whereas patients with residual tumor cells after neoadjuvant therapy primarily experienced relapse within the first 2 postoperative years, this in contrast to several patients with complete remission who also experienced late relapses 4 years after surgery. CONCLUSION: After curative surgery in a multimodal setting, the histological type and the response to neoadjuvant therapy predicted the time frame of relapse; this knowledge may influence further follow-up guidelines for esophageal carcinoma.

Long-term responders to trastuzumab monotherapy in first-line HER-2+ advanced breast cancer: characteristics and survival data.

BACKGROUND: The impact of HER2-targeted therapy alone followed by the addition of chemotherapy at disease progression (PD) versus upfront combination was investigated by the SAKK 22/99 trial. The aim of this exploratory analysis of the SAKK 22/99 trial was to characterize the specific subset of patients deriving long-term benefit from trastuzumab monotherapy alone and to identify potential predictive factors of long-term response. METHODS: This is an unplanned post-hoc analysis of patients randomized to Arm A (trastuzumab monotherapy). Patients were divided in two groups: patients with durable clinical benefit from trastuzumab monotherapy and short-term responders without durable clinical benefit from trastuzumab monotherapy Univariate and multivariate analyses of clinical characteristics correlating with response duration was performed. RESULTS: Eighty six patients were randomized in arm A, 24 patients (28%) were long-term responders and 62 (72%) were short-term responders with a 5y-overall survival (OS) of 54% (95% CI 31-72) and of 18% (95%CI 10-30), respectively. Absence of ER expression, absence of PgR expression and presence of visceral disease emerged as possible negative predictive factors for durable clinical benefit. CONCLUSION: Durable clinical benefit can be achieved with trastuzumab monotherapy in a subgroup of HER2-positive patients with advanced disease and it is predictive for longer OS. Further investigations of predictive biomarkers are necessary to better characterize this subgroup of patients and develop further de-escalating strategies. TRIAL REGISTRATION: NCT00004935 ; first posted 27.01.2003, retrospectively registered.

Extended adjuvant intermittent letrozole versus continuous letrozole in postmenopausal women with breast cancer (SOLE): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: In animal models of breast cancer, resistance to continuous use of letrozole can be reversed by withdrawal and reintroduction of letrozole. We therefore hypothesised that extended intermittent use of adjuvant letrozole would improve breast cancer outcome compared with continuous use of letrozole in postmenopausal women. METHODS: We did the multicentre, open-label, randomised, parallel, phase 3 SOLE trial in 240 centres (academic, primary, secondary, and tertiary care centres) in 22 countries. We enrolled postmenopausal women of any age with hormone receptor-positive, lymph node-positive, and operable breast cancer for which they had undergone local treatment (surgery with or without radiotherapy) and had completed 4-6 years of adjuvant endocrine therapy. They had to be clinically free of breast cancer at enrolment and without evidence of recurrent disease at any time before randomisation. We randomly assigned women (1:1) to treatment groups of either continuous use of letrozole (2·5 mg/day orally for 5 years) or intermittent use of letrozole (2·5 mg/day orally for 9 months followed by a 3-month break in years 1-4 and then 2·5 mg/day during all 12 months of year 5). Randomisation was done by principal investigators or designee at respective centres through the internet-based system of the International Breast Cancer Study Group, was stratified by type of previous endocrine therapy (aromatase inhibitors only vs selective oestrogen receptor modulators only vs both therapies), and used permuted block sizes of four and institutional balancing. No one was masked to treatment assignment. The primary endpoint was disease-free survival, analysed by the intention-to-treat principle using a stratified log-rank test. All patients in the intention-to-treat population who initiated protocol treatment during their period of trial participation were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT00553410, and EudraCT, number 2007-001370-88; and long-term follow-up of patients is ongoing. FINDINGS: Between Dec 5, 2007, and Oct 8, 2012, 4884 women were enrolled and randomised after exclusion of patients at a non-adherent centre, found to have inadequate documentation of informed consent, immediately withdrew consent, or randomly assigned to intervention groups in error. 4851 women comprised the intention-to-treat population that compared extended intermittent letrozole use (n=2425) with continuous letrozole use (n=2426). After a median follow-up of 60 months (IQR 53-72), disease-free survival was 85·8% (95% CI 84·2-87·2) in the intermittent letrozole group compared with 87·5% (86·0-88·8) in the continuous letrozole group (hazard ratio 1·08, 95% CI 0·93-1·26; p=0·31). Adverse events were reported as expected and were similar between the two groups. The most common grade 3-5 adverse events were hypertension (584 [24%] of 2417 in the intermittent letrozole group vs 517 [21%] of 2411 in the continuous letrozole group) and arthralgia (136 [6%] vs 151 [6%]). 54 patients (24 [1%] in the intermittent letrozole group and 30 [1%] in the continuous letrozole group) had grade 3-5 CNS cerebrovascular ischaemia, 16 (nine [<1%] vs seven [<1%]) had grade 3-5 CNS haemorrhage, and 40 (19 [1%] vs 21 [1%]) had grade 3-5 cardiac ischaemia. In total, 23 (<1%) of 4851 patients died while on trial treatment (13 [<1%] of 2417 patients in the intermittent letrozole group vs ten [<1%] of 2411 in the continuous letrozole group). INTERPRETATION: In postmenopausal women with hormone receptor-positive breast cancer, extended use of intermittent letrozole did not improve disease-free survival compared with continuous use of letrozole. An alternative schedule of extended adjuvant endocrine therapy with letrozole, including intermittent administration, might be feasible and the results of the SOLE trial support the safety of temporary treatment breaks in selected patients who might require them. FUNDING: Novartis and the International Breast Cancer Study Group.

Mutational analysis of triple-negative breast cancers within the International Breast Cancer Study Group (IBCSG) Trial 22-00.

PURPOSE: We investigated the occurrence and the prognostic and predictive relationship of a selected number of somatic mutations in triple-negative breast cancer (TNBC) patients having known clinical outcomes treated within the IBCSG Trial 22-00. METHODS: A matched case-control sampling selected patients enrolled in the IBCSG Trial 22-00 who had TNBC tumors, based on local assessment. Cases had invasive breast cancer recurrence (at local, regional, or distant site) according to the protocol definition. Matched controls had not recurred. Mutational analysis was performed with OncoCarta panel v1.0 using Mass Array System. The panel includes 19 genes belonging to different functional pathways as PI3K pathway, receptor tyrosine kinase, and cell cycle-metabolic group. Conditional logistic regression assessed the association of mutation status with breast cancer recurrence. RESULTS: Mutation assessment was successful for 135 patients (49 cases, 86 controls). A total of 37 (27.4%) of the 135 patients had at least one mutation in the selected genes. PIK3CA was the most common mutated gene (18/135; 13.3%), followed by BRAF, KIT and PDGFRA (each 4/135, 3.0%) and AKT1 (3/135; 2.2%). TNBC patients with at least one mutation had increased odds of recurrence compared with those with wild-type tumors (odds ratio (OR) 2.28; 95% CI 0.88-5.92), though this difference was not statistically significant (p = 0.09). We found no evidence that these mutations were predictive for the value of maintenance metronomic chemotherapy. CONCLUSIONS: Mutations in the tested oncogenes were not associated with breast cancer recurrence in this TNBC subset of patients. The question of whether any of these mutated genes (e.g., PIK3CA) may represent a useful therapeutic target in TNBC may be answered by ongoing clinical trials and/or larger dataset analysis.

Impact of a Surgical Sealing Patch on Lymphatic Drainage After Axillary Dissection for Breast Cancer: The SAKK 23/13 Multicenter Randomized Phase III Trial.

BACKGROUND: Several studies and a meta-analysis showed that fibrin sealant patches reduced lymphatic drainage after various lymphadenectomy procedures. Our goal was to investigate the impact of these patches on drainage after axillary dissection for breast cancer. METHODS: In a phase III superiority trial, we randomized patients undergoing breast-conserving surgery at 14 Swiss sites to receive versus not receive three large TachoSil® patches in the dissected axilla. Axillary drains were inserted in all patients. Patients and investigators assessing outcomes were blinded to group assignment. The primary endpoint was total volume of drainage. RESULTS: Between March 2015 and December 2016, 142 patients were randomized (72 with TachoSil® and 70 without). Mean total volume of drainage in the control group was 703 ml [95% confidence interval (CI) 512-895 ml]. Application of TachoSil® did not significantly reduce the total volume of axillary drainage [mean difference (MD) -110 ml, 95% CI -316 to 94, p = 0.30]. A total of eight secondary endpoints related to drainage, morbidity, and quality of life were not improved by use of TachoSil®. The mean total cost per patient did not differ significantly between the groups [34,253 Swiss Francs (95% CI 32,625-35,880) with TachoSil® and 33,365 Swiss Francs (95% CI 31,771-34,961) without, p = 0.584]. In the TachoSil® group, length of stay was longer (MD 1 day, 95% CI 0.3-1.7, p = 0.009), and improvement of pain was faster, although the latter difference was not significant [2 days (95% CI 1-4) vs. 5.5 days (95% CI 2-11); p = 0.2]. CONCLUSIONS: TachoSil® reduced drainage after axillary dissection for breast cancer neither significantly nor relevantly.

Adjuvant exemestane with ovarian suppression in premenopausal breast cancer.

BACKGROUND: Adjuvant therapy with an aromatase inhibitor improves outcomes, as compared with tamoxifen, in postmenopausal women with hormone-receptor-positive breast cancer. METHODS: In two phase 3 trials, we randomly assigned premenopausal women with hormone-receptor-positive early breast cancer to the aromatase inhibitor exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The primary analysis combined data from 4690 patients in the two trials. RESULTS: After a median follow-up of 68 months, disease-free survival at 5 years was 91.1% in the exemestane-ovarian suppression group and 87.3% in the tamoxifen-ovarian suppression group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.72; 95% confidence interval [CI], 0.60 to 0.85; P<0.001). The rate of freedom from breast cancer at 5 years was 92.8% in the exemestane-ovarian suppression group, as compared with 88.8% in the tamoxifen-ovarian suppression group (hazard ratio for recurrence, 0.66; 95% CI, 0.55 to 0.80; P<0.001). With 194 deaths (4.1% of the patients), overall survival did not differ significantly between the two groups (hazard ratio for death in the exemestane-ovarian suppression group, 1.14; 95% CI, 0.86 to 1.51; P=0.37). Selected adverse events of grade 3 or 4 were reported for 30.6% of the patients in the exemestane-ovarian suppression group and 29.4% of those in the tamoxifen-ovarian suppression group, with profiles similar to those for postmenopausal women. CONCLUSIONS: In premenopausal women with hormone-receptor-positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. (Funded by Pfizer and others; TEXT and SOFT ClinicalTrials.gov numbers, NCT00066703 and NCT00066690, respectively.).

Adjuvant treatment recommendations for patients with ER-positive/HER2-negative early breast cancer by Swiss tumor boards using the 21-gene recurrence score (SAKK 26/10).

BACKGROUND: To evaluate the effect of Recurrence Score® results (RS; Oncotype DX® multigene assay ODX) on treatment recommendations by Swiss multidisciplinary tumor boards (TB). METHODS: SAKK 26/10 is a multicenter, prospective cohort study of early breast cancer patients: Eligibility: R0-resection, ≥10% ER+ malignant cells, HER2-, pN0/pN1a. Patients were stratified into low-risk (LR) and non-low-risk (NLR) groups based on involved nodes (0 vs 1-3) and five additional predefined risk factors. Recommendations were classified as hormonal therapy (HT) or chemotherapy plus HT (CT + HT). Investigators were blinded to the statistical analysis plan. A 5%/10% rate of recommendation change in LR/NLR groups, respectively, was assumed independently of RS (null hypotheses). RESULTS: Two hundred twenty two evaluable patients from 18 centers had TB recommendations before and after consideration of the RS result. A recommendation change occurred in 45 patients (23/154 (15%, 95% CI 10-22%) in the LR group and 22/68 (32%, 95% CI 22-45%) in the NLR group). In both groups the null hypothesis could be rejected (both p < 0.001). Specifically, in the LR group, only 5/113 (4%, 95% CI 1-10%) with HT had a recommendation change to CT + HT after consideration of the RS, while 18/41 (44%, 95% CI 28-60%) of patients initially recommended CT + HT were subsequently recommended only HT. In the NLR group, 3/19 (16%, 95% CI 3-40%) patients were changed from HT to CT + HT, while 19/48 (40%, 95% CI 26-55%) were changed from CT + HT to HT. CONCLUSION: There was a significant impact of using the RS in the LR and the NLR group but only 4% of LR patients initially considered for HT had a recommendation change (RC); therefore these patients could forgo ODX testing. A RC was more likely for NLR patients considered for HT. Patients considered for HT + CT have the highest likelihood of a RC based on RS.

Tumor-infiltrating lymphocytes (TILs) are a powerful prognostic marker in patients with triple-negative breast cancer enrolled in the IBCSG phase III randomized clinical trial 22-00.

The purpose of this study was to assess the prognostic and predictive value of tumor-infiltrating lymphocytes (TILs) in the triple-negative breast cancer (TNBC) cohort of the phase III IBCSG trial 22-00, comparing low-dose oral 'metronomic' cyclophosphamide-methotrexate maintenance chemotherapy (CM-maintenance) to no-CM-maintenance in early breast cancer. TILs were evaluated in full-face hematoxylin-and-eosin-stained sections of tumor samples confirmed centrally as TNBC (< 1 % of ER and PgR immunoreactivity and absence of HER2 overexpression or amplification). Mononuclear cells were evaluated in the stromal area within the borders of the invasive tumor. The primary endpoint was breast cancer-free interval (BCFI). Cox proportional hazards regression model assessed the association of BCFI and secondary endpoints with TILs score. In the 647 tumor samples, the median percentage of TILs was 18 % (IQR = 8-40 %), with 18 % having TILs ≥ 50 % (lymphocyte-predominant breast cancer, LPBC). At a median follow-up of 6.9 years, TILs were associated with better prognosis. For every 10 % increase of TILs, BCFI risk reduction was 13 % (HR 0.87, 95 % CI 0.79-0.95,P = 0.003). DFS, DRFI, and OS risk reductions were 11 % (P = 0.005), 16 % (P = 0.003), and 17 % (P < 0.001), respectively. Multivariable analysis confirmed the independent prognostic value of TILs. No significant TILs-by-treatment interaction was observed (P = 0.39) for associations of TILs with BCFI, although patients with LPBC receiving CM-maintenance had a greater breast cancer risk reduction (HR 0.64,95 % CI 0.23-1.78) than those with non-LPBC (TILs < 50 %) (HR 0.96, 95 % CI 0.67-1.40). TILs score is a potent prognostic factor in patients with TNBC. Low-dose chemotherapy confers a greater (not statistically significant) clinical benefit in patients with LPBC.

SAKK 24/09: safety and tolerability of bevacizumab plus paclitaxel vs. bevacizumab plus metronomic cyclophosphamide and capecitabine as first-line therapy in patients with HER2-negative advanced stage breast cancer - a multicenter, randomized phase III trial.

BACKGROUND: Adding bevacizumab to chemotherapy improves response rates and progression-free survival (PFS) in metastatic breast cancer (mBC). We aimed to demonstrate decreased toxicity with metronomic chemotherapy/bevacizumab compared with paclitaxel/bevacizumab. METHODS: This multicenter, randomized phase III trial compared bevacizumab with either paclitaxel (arm A) or daily oral capecitabine-cyclophosphamide (arm B) as first-line treatment in patients with HER2-negative advanced breast cancer. The primary endpoint was the incidence of selected grade 3-5 adverse events (AE) including: febrile neutropenia, infection, sensory/motor neuropathy, and mucositis. Secondary endpoints included objective response rate, disease control rate, PFS, overall survival (OS), quality of life (QoL), and pharmacoeconomics. The study was registered prospectively with ClinicalTrials.gov, number NCT01131195 on May 25, 2010. RESULTS: Between September 2010 and December 2012, 147 patients were included at 22 centers. The incidence of primary endpoint-defining AEs was similar in arm A (25 % [18/71]; 95 % CI 15-35 %) and arm B (24 % [16/68]; 95 % CI 13-34 %; P = 0.96). Objective response rates were 58 % (42/73; 95 % CI 0.46-0.69) and 50 % (37/74; 95 % CI 0.39-0.61) in arms A and B, respectively (P = 0.45). Median PFS was 10.3 months (95 % CI 8.7-11.3) in arm A and 8.5 months (95 % CI 6.5-11.9) in arm B (P = 0.90). Other secondary efficacy endpoints were not significantly different between study arms. The only statistically significant differences in QoL were less hair loss and less numbness in arm B. Treatment costs between the two arms were equivalent. CONCLUSION: This trial failed to meet its primary endpoint of a reduced rate of prespecified grade 3-5 AEs with metronomic bevacizumab, cyclophosphamide and capecitabine.

Patient-reported outcomes with adjuvant exemestane versus tamoxifen in premenopausal women with early breast cancer undergoing ovarian suppression (TEXT and SOFT): a combined analysis of two phase 3 randomised trials.

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.

Cross-sectional study of self-reported physical activity, eating habits and use of complementary medicine in breast cancer survivors.

BACKGROUND: Besides conventional adjuvant therapies, many breast cancer survivors engage in various activities like exercise, diet and complementary and alternative medicine (CAM) in order to improve their prognosis. Little is known about specific interests and willingness to participate in institutional programs (e.g. exercise classes). METHODS: We conducted a cross-sectional study in patients with early breast cancer assessing current physical activity (PA, e.g. 30 minutes brisk walking), attention to eating habits ("diet"), use of CAM, and interest in learning more about these fields. Patients indicating interest in PA counselling received a voucher for a free instruction by a certified physiotherapist. Data were analysed for factors predictive for engagement in the three fields using a stepwise multivariate logistic approach. RESULTS: Of 342 consecutive patients, 232 (69%) reported to be physically active more than once per week, 299 (87%) paying special attention to nutrition (in most cases fruits, "balanced diet", low fat), and 159 (46%) use of CAM (vitamins, special teas, homeopathy, herbal medicine, mistletoe). Factors predictive for PA were use of CAM, higher age, and fewer worries about the future. Swiss nationality at birth, physical activity and higher education were predictive for diet; whereas physical activity, higher education and lower age were predictive for use of CAM. No associations between any of the above variables and breast cancer characteristics were found. Around half of the patients reported interest in receiving more information and willingness to attend special counselling. Of 166 vouchers, only 7 (4%) were eventually utilized. CONCLUSIONS: A high proportion of breast cancer survivors report PA, following a specific diet and use of CAM. There were no disease related factors associated with such pursuits, but an association between patient related factors and these fields was observed suggesting general health awareness in some patients. Around half of the patients were interested in more information and indicated willingness to participate in institutional programs. Impact on disease specific and general health including health economic aspects warrants further research.

Eribulin as first-line treatment in older patients with advanced breast cancer: A multicenter phase II trial [SAKK 25/14].

INTRODUCTION: Standard-dose eribulin mesylate (1.4 mg/m2 d1 + 8) achieves clinical benefit rates of 26%-52% in patients with metastatic breast cancer (mBC). <10% of patients in the registration trial were ≥ 70 years old; dose reductions were common in these older patients. MATERIALS AND METHODS: This single-arm phase II trial explored the efficacy of reduced starting dosing of first-line eribulin at 1 mg/m2 d1 + 8 q3 weeks in patients with mBC aged ≥70 years. The primary endpoint was a disease control rate (DCR) ≥55%. The secondary endpoints were objective response (OR), progression-free survival (PFS), overall survival (OS), and patient-reported neurotoxicity. RESULTS: Overall, 77 patients were accrued; their median age was 76 years and Eastern Cooperative Oncology Group performance status was 0-1 in 90%. The DCR was 40% (90% confidence interval [CI]: 31-50); therefore, the primary endpoint was not reached. The overall response rate was 22% (95%CI: 13-33), median PFS 5.4 months (95%CI: 4.5-7.7), and median OS 16.1 months (95%CI: 13.5-26.9). Dose modifications were necessary in 35% of patients. In nine patients, more than fifteen cycles were given; 48 patients (62%) experienced at least one grade 3 toxicity. Median patient-reported neurotoxicity scores remained stable for at least fifteen cycles. The main reason for treatment discontinuation was disease progression (57%). DISCUSSION: We report the first prospective data on first-line eribulin in older patients. The reduced starting dose of 1.1 mg/m2 was safe, with prolonged treatment and DC achieved in a considerable proportion of patients (but less than the 55% assumed), without cumulative neurotoxicity. The reduced dose was apparently within the range of the minimal effective dose, as shown by the efficacy lack in patients requiring further dose reductions. Thus, our results do not support the approach of a reduced starting dose for older patients.

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

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.[Media: see text].