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A combined analysis of two large studies found that the addition of trastuzumab to chemotherapy with doxorubicin and cyclophosphamide plus paclitaxel improved the outcome among women with operable HER2-positive breast cancer. An analysis of two large studies found that the addition of trastuzumab to chemotherapy with doxorubicin and cyclophosphamide plus paclitaxel improved the outcome among women with operable HER2-positive breast cancer. Trastuzumab, a monoclonal antibody targeting the extracellular domain of the HER2 protein, was approved in 1998 as a first-line treatment in combination with paclitaxel for HER2-positive metastatic breast cancer. 1 The benefit of this approach in patients with metastatic disease and the poor prognosis of HER2-positive breast cancer 2 , 3 motivated the National Cancer Institute (NCI) to sponsor two trials of adjuvant treatment with trastuzumab, led by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the North Central Cancer Treatment Group (NCCTG). NSABP trial B-31, which began accrual in February 2000, compares four cycles of doxorubicin and cyclophosphamide followed by . . .

Trastuzumab targets the extracellular domain of the HER2 protein. Adding trastuzumab to chemotherapy for patients with early-stage, HER2-positive breast cancer reduces the risk of recurrence and death, but is associated with cardiac toxicity. We investigated the long-term benefits and risks of adjuvant trastuzumab on breast cancer recurrence and cause-specific mortality. We did a collaborative meta-analysis of individual patient data from randomised trials assessing chemotherapy plus trastuzumab versus the same chemotherapy alone. Randomised trials that enrolled women with node-negative or node-positive, operable breast cancer were included. We collected individual patient-level data on baseline characteristics, dates and sites of first distant breast cancer recurrence and any previous local recurrence or second primary cancer, and the date and underlying cause of death. Primary outcomes were breast cancer recurrence, breast cancer mortality, death without recurrence, and all-cause mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, oestrogen receptor (ER) status, and trial yielded first-event rate ratios (RRs). Seven randomised trials met the inclusion criteria, and included 13 864 patients enrolled between February, 2000, and December, 2005. Mean scheduled treatment duration was 14·4 months and median follow-up was 10·7 years (IQR 9·5 to 11·9). The risks of breast cancer recurrence (RR 0·66, 95% CI 0·62 to 0·71; p<0·0001) and death from breast cancer (0·67, 0·61 to 0·73; p<0·0001) were lower with trastuzumab plus chemotherapy than with chemotherapy alone. Absolute 10-year recurrence risk was reduced by 9·0% (95% CI 7·4 to 10·7; p<0·0001) and 10-year breast cancer mortality was reduced by 6·4% (4·9 to 7·8; p<0·0001), with a 6·5% reduction (5·0 to 8·0; p<0·0001) in all-cause mortality, and no increase in death without recurrence (0·4%, –0·3 to 1·1; p=0·35). The proportional reduction in recurrence was largest in years 0–1 after randomisation (0·53, 99% CI 0·46 to 0·61), with benefits persisting through years 2–4 (0·73, 0·62 to 0·85) and 5–9 (0·80, 0·64 to 1·01), and little follow-up beyond year 10. Proportional recurrence reductions were similar irrespective of recorded patient and tumour characteristics, including ER status. The more high risk the tumour, the larger the absolute reductions in 5-year recurrence (eg, 5·7% [95% CI 3·1 to 8·3], 6·8% [4·7 to 9·0], and 10·7% [7·7 to 13·6] in N0, N1–3, and N4+ disease). Adding trastuzumab to chemotherapy for early-stage, HER2-positive breast cancer reduces recurrence of, and mortality from, breast cancer by a third, with worthwhile proportional reductions irrespective of recorded patient and tumour characteristics. Cancer Research UK, UK Medical Research Council.

In postmenopausal women with oestrogen receptor-positive early breast cancer, 5 years of adjuvant tamoxifen substantially reduces 15-year recurrence and mortality; aromatase inhibitor treatment (AIT) is even more effective. We assess the effects of further AIT among women recurrence-free after at least 5 years of endocrine therapy. We conducted individual patient data meta-analyses of 12 randomised trials, including 22 031 women who had completed at least 5 years of tamoxifen, AIT, or tamoxifen then AIT, comparing subsequent AIT versus no further adjuvant therapy. Primary outcomes were recurrence of invasive breast cancer (local, distant, or new contralateral), breast cancer mortality, mortality from other causes, and all-cause mortality. Intention-to-treat analyses (irrespective of allocation adherence and stratified by age, nodal status, and trial, and censored at death from unrelated causes) yielded event rate ratios (RRs). Allocation to AIT versus no further treatment reduced recurrence rates by 27% (RR 0·73 [95% CI 0·67–0·80], p<0·0001). This reduction was greater after previous tamoxifen alone than after some previous AIT, and greater in trials of 5 years of AIT versus no further AIT than in trials of 2–3 years of AIT versus no further AIT. After some previous AIT, allocation to 5 further years of AIT (with median 8·1 years [IQR 6·0–10·0] follow-up after trial treatments diverged) reduced both recurrence (RR 0·71 [0·61–0·81], p<0·0001; risk from year 5 to year 15 after diagnosis 11·6% vs 15·2%) and distant recurrence (RR 0·73 [0·61–0·88], p=0·0010; 6·6% vs 8·6%); breast cancer mortality was reduced non-significantly (RR 0·90 [0·70–1·15], p=0·40; 4·4% vs 5·0%). Tumour characteristics had no definite effects on the proportional recurrence reductions from year 5 to year 15, so the absolute recurrence reduction with 10 years vs 5 years AIT was greater for node-positive (risk 16·3% vs 20·1%) than for node-negative disease (9·1% vs 11·8%). Allocation to 5 further years of AIT increased 5-year bone fracture risk (RR 1·35 [1·13–1·61], p=0·0009; 4·6% vs 3·4%). Non-adherence to allocated treatment was widespread (39·0% further AIT vs 37·6% placebo in the placebo-controlled trials). Allocation to 5 further years of AIT reduced subsequent distant recurrence rates by about a quarter despite substantial non-adherence. Longer follow-up would have been needed to help assess directly any effects on mortality. Cancer Research UK and Breast Cancer Research Foundation.

ER and HER2 are critical drivers of breast cancer biology and can interact when co-expressed, but less data describe the impact of ER/HER2 co-expression on clinical disease characteristics. We studied the impact of ER and HER2 (co)-expression in a cohort of 1,187 patients with invasive breast cancer and compared disease characteristics among different groups according to ER and HER2 status. Age, tumor size, grade, nodal status, TNM stage, and metastatic sites were compared and significance determined using the appropriate t tests. All p values were two-tailed. Compared to ER-negative/HER2-negative disease as the control group, ER expression was associated with older age, smaller tumors, lower grade, earlier TNM stage, and increased bone involvement in de novo metastasis, while HER2 had no significant impact on these characteristics. ER and HER2 co-expression was associated with lower grade and higher bone involvement in de novo metastasis, reflecting a retained impact for ER. HER2 impact on ER-positive disease was reflected by younger age, higher grade and TNM stage, and increased frequency of visceral involvement in de novo metastasis. Within the ER-positive/HER2-positive group, triple positive breast cancer (ER+/PgR+/HER2+) was associated with younger age compared to ER+/PgR−/HER2+ disease (mean age of 50.8 vs. 56 years, p  = 0.0226). PgR was also associated with younger age in ER+/HER2− disease with a mean age of 57.6 years in ER+/PgR+/HER2− disease vs. 63.4 years in ER+/PgR−/HER2− disease ( p  < 0.0001). In conclusion, ER has a profound impact on breast cancer characteristics, including a retained impact when co-expressed with HER2. Similarly, HER2 dramatically modulates ER-positive breast cancer making it more aggressive. PgR association with young age may be related to hormonal levels of the premenopausal state, with HER2 providing an earlier growth advantage in triple positive disease, suggesting a specific dependence for this subset on high estrogen levels.

Fulvestrant, which degrades ER, is used after AI failure in metastatic breast cancer but resistance develops quickly. We hypothesized that using everolimus to inhibit mTOR, a key signaling pathway in endocrine resistance, may delay fulvestrant resistance in patients and thus improve its efficacy. We conducted a phase II trial of combined fulvestrant and everolimus in postmenopausal women with disease progression or relapse after an AI. Primary endpoint was time to progression (TTP) and secondary endpoints included objective response rate, clinical benefit rate (CBR), safety, and biomarker correlates. Tumor blocks were collected and biopsy of accessible tumor was done for future biomarker analysis. Of 33 patients enrolled two were ruled ineligible after enrollment and were excluded from study analysis, for a total of 31 evaluable patients. Median age was 54 years (range 45–85). Prior therapy included tamoxifen (81 %), chemotherapy (71 %), with 26 % of patients having received 3 or more endocrine agents. Median TTP was 7.4 months (95 % CI 1.9–12.1) with an objective response rate of 13 % and CBR of 49 %. Of particular note, 32 % of patients exhibited de novo resistance to study treatment with disease progression as their best response. Most common adverse events (AEs) were elevated AST (87 %) and ALT (77 %), anemia (74 %), hyperglycemia (71 %), and hypercholesterolemia (68 %). Prominent clinical toxicities were mucositis (58 %), weight loss (48 %), and rash (42 %). Most AEs were grade 1 or 2 and largely reversible with infrequent need for everolimus dose reduction. To conclude, everolimus plus fulvestrant is effective after AI failure in heavily pretreated metastatic ER-positive breast cancer and has manageable toxicity. Further study of this combination is warranted in randomized studies. Since not all patients experience benefit, and in view of potential toxicities, biomarker examination is critical to help select patients most likely to benefit from this strategy in future studies.

ER and HER2 are critical drivers of breast cancer biology and can interact when co-expressed, but less data describe the impact of ER/HER2 co-expression on clinical disease characteristics. We studied the impact of ER and HER2 (co)-expression in a cohort of 1,187 patients with invasive breast cancer and compared disease characteristics among different groups according to ER and HER2 status. Age, tumor size, grade, nodal status, TNM stage, and metastatic sites were compared and significance determined using the appropriate t tests. All p values were two-tailed. Compared to ER-negative/HER2-negative disease as the control group, ER expression was associated with older age, smaller tumors, lower grade, earlier TNM stage, and increased bone involvement in de novo metastasis, while HER2 had no significant impact on these characteristics. ER and HER2 co-expression was associated with lower grade and higher bone involvement in de novo metastasis, reflecting a retained impact for ER. HER2 impact on ER-positive disease was reflected by younger age, higher grade and TNM stage, and increased frequency of visceral involvement in de novo metastasis. Within the ER-positive/ HER2-positive group, triple positive breast cancer (ER+/ PgR+/HER2+) was associated with younger age compared to ER+/PgR--/HER2+ disease (mean age of 50.8 vs. 56 years, p = 0.0226). PgR was also associated with younger age in ER+/HER2- disease with a mean age of 57.6 years in ER+/PgR+/HER2--disease vs. 63.4 years in ER+/PgR--/HER2--disease (p < 0.0001). In conclusion, ER has a profound impact on breast cancer characteristics, including a retained impact when co-expressed with HER2. Similarly, HER2 dramatically modulates ER-positive breast cancer making it more aggressive. PgR association with young age may be related to hormonal levels of the premenopausal state, with HER2 providing an earlier growth advantage in triple positive disease, suggesting a specific dependence for this subset on high estrogen levels. Keywords Breast cancer * Estrogen receptor * Progesterone receptor * Human epidermal growth factor receptor * Co-expression * Triple positive breast cancer

Breast cancer can metastasize at any time during its course, but timing of systemic relapse cannot be predicted by traditional TNM staging. Characteristics of distant recurrence within the first 3 years of diagnosis may identify a group of patients who could benefit from novel strategies to prevent systemic relapse. Of 1,089 patients with breast cancer treated at our institution between January 2007 and May 2011, we identified 76 with de novo metastases (on presentation) and 40 with systemic relapse after a median follow up of 2.2 years. Compared to relapse, de novo metastatic disease was more likely to be grade 1 or 2 (43.1 vs. 18.4 %, p  = 0.032), estrogen receptor (ER) positive (69.7 vs. 47.5 %, p  = 0.019), progesterone receptor (PgR) positive (56.6 vs. 32.5 %, p  = 0.014), and HER2-positive (27.5 vs. 10.3 %, p  = 0.035). In the 815 patients with stage I–III disease who were at risk of systemic relapse, univariate analyses were performed for age, tumor size, grade, ER, PgR, HER2, lymph nodes, and TNM stage. A multivariate Cox regression model was built using step-wise model selection and identified 4 covariates that were significantly associated with risk of early relapse: stage-III ( p  < 0.001), grade-III ( p  = 0.002), PgR-negative status ( p  = 0.014), and HER2-negative status ( p  = 0.033). A risk-score was developed based on the linear combination of these covariates and time-dependent predictive curves were used to evaluate the predictive accuracy of the proposed risk-score. The highest risk-score group had a 1, 2, and 3-year relapse probabilities of 11.5, 41.2, and 52.5 %, respectively. The corresponding 1, 2, and 3-year relapse probabilities for the overall population were 1.2, 4.4, and 6.3 %, respectively. Our proposed model can be used to select patients at high-risk of early relapse who could benefit from enrollment on clinical trials with novel therapies designed for this group.

Targeting growth factor and survival pathways may delay endocrine-resistance in estrogen receptor-positive breast cancer. A pilot Phase II study adding sorafenib to endocrine therapy in 11 patients with metastatic estrogen receptor-positive breast cancer was conducted. Primary end point was response by RECIST after 3 months of sorafenib. Secondary end points included safety, time to progression and biomarker modulation. The study closed early owing to slow accrual. Eight out of 11 patients had progressive disease on study entry and three had stable disease. Of the ten evaluable patients, seven experienced stable disease (70%) and three experienced progressive diseas (30%), with a median time to progression of 6.1 months (8.4 months in the seven patients on tamoxifen). The serum samples demonstrated a significant reduction in VEGF receptor 2 and PDGF receptor-α. Microarray analysis identified 32 suppressed genes, no induced genes and 29 enriched Kyoto Encyclopedia of Genes and Genomes pathways. The strategy of adding a targeted agent to endocrine therapy upon resistance may be worthwhile testing in larger studies.

Fulvestrant, which degrades ER, is used after AI failure in metastatic breast cancer but resistance develops quickly. We hypothesized that using everolimus to inhibit mTOR, a key signaling pathway in endocrine resistance, may delay fulvestrant resistance in patients and thus improve its efficacy. We conducted a phase II trial of combined fulvestrant and everolimus in postmenopausal women with disease progression or relapse after an AI. Primary endpoint was time to progression (TTP) and secondary endpoints included objective response rate, clinical benefit rate (CBR), safety, and biomarker correlates. Tumor blocks were collected and biopsy of accessible tumor was done for future biomarker analysis. Of 33 patients enrolled two were ruled ineligible after enrollment and were excluded from study analysis, for a total of 31 evaluable patients. Median age was 54 years (range 45-85). Prior therapy included tamoxifen (81%), chemotherapy (71%), with 26% of patients having received 3 or more endocrine agents. Median TTP was 7.4 months (95% CI 1.9-12.1) with an objective response rate of 13% and CBR of 49%. Of particular note, 32% of patients exhibited de novo resistance to study treatment with disease progression as their best response. Most common adverse events (AEs) were elevated AST (87%) and ALT (77%), anemia (74%), hyperglycemia (71%), and hypercholesterolemia (68%). Prominent clinical toxicities were mucositis (58%), weight loss (48%), and rash (42%). Most AEs were grade 1 or 2 and largely reversible with infrequent need for everolimus dose reduction. To conclude, everolimus plus fulvestrant is effective after AI failure in heavily pretreated metastatic ER-positive breast cancer and has manageable toxicity. Further study of this combination is warranted in randomized studies. Since not all patients experience benefit, and in view of potential toxicities, biomarker examination is critical to help select patients most likely to benefit from this strategy in future studies.