Older patients are at higher risk of chemotherapy-induced toxicity, raising interest in less toxic anti-HER2 regimens for older persons with HER2-positive (HER2+) metastatic breast cancer (MBC).
This ...phase II study randomized (1:1) patients with HER2+ MBC, aged 70+ or frail 60+, to first line chemotherapy with metronomic oral cyclophosphamide (M) + Trastuzumab (T) and Pertuzumab (P) or TP alone. T-DM1 was offered in case of progression.
In total, 39 and 41 patients were randomized to TP and TPM arm respectively. Median follow-up is 54.0 months. 24-month PFS was 18.7% (95% CI 8.2–32.4) and 28.7% (95% CI 15.8–43.0), respectively. A total of 49 (61.3%) patients died of whom 37 (75.5%) from disease progression; number of deaths per arm was 27 (69.2%) for TP and 22 (53.7%) for TPM. There was no significant difference in OS between the two arms (median OS TP vs TPM: 32.1 vs 37.5 months, p 0.25). Among the 40 patients who have started T-DM1 after disease progression on TP/TPM, PFS rate at 6 months after start of T-DM1 was 43.6% (95% CI: 27.7–58.5) and grade 3 or higher AE occurred in 18 pts (45%).
Metronomic chemotherapy-based dual blockade (TPM), followed by T-DM1 after progression, provides an active and relatively well tolerated treatment option in an older/frail HER2+ MBC population, with a median survival of over 3 years. Nevertheless, the majority of this older/frail population died from breast cancer, highlighting the need for well tolerated and efficacious treatments in these patients.
•HER2+ metastatic breast cancer in older persons represents an important challenge.•Dual anti-HER2 therapy with metronomic chemotherapy is effective and safe.•Efficacy of second line T-DM1 is similar to the general breast cancer population.•Despite comorbidities, most older/frail patients die from breast cancer.
ClinicalTrials.gov Identifier: NCT01597414.
Treatment of patients with residual disease after neoadjuvant chemotherapy for breast cancer is an unmet clinical need. We hypothesised that tumour subclones showing expansion in residual disease ...after chemotherapy would contain mutations conferring drug resistance.
We studied oestrogen receptor and/or progesterone receptor-positive, HER2-negative tumours from 42 patients in the EORTC 10994/BIG 00-01 trial who failed to achieve a pathological complete response. Genes commonly mutated in breast cancer were sequenced in pre and post-treatment samples.
Oncogenic driver mutations were commonest in PIK3CA (38% of tumours), GATA3 (29%), CDH1 (17%), TP53 (17%) and CBFB (12%); and amplification was commonest for CCND1 (26% of tumours) and FGFR1 (26%). The variant allele fraction frequently changed after treatment, indicating that subclones had expanded and contracted, but there were changes in both directions for all of the commonly mutated genes.
We found no evidence that expansion of clones containing recurrent oncogenic driver mutations is responsible for resistance to neoadjuvant chemotherapy. The persistence of classic oncogenic mutations in pathways for which targeted therapies are now available highlights their importance as drug targets in patients who have failed chemotherapy but provides no support for a direct role of driver oncogenes in resistance to chemotherapy. CLINICALTRIALS.GOV: EORTC 10994/BIG 1-00 Trial registration number NCT00017095.
IBC (inflammatory breast cancer) is a rare but very aggressive form of breast cancer with a particular phenotype. The molecular mechanisms responsible for IBC remain largely unknown. In particular, ...genetic and epigenetic alterations specific to IBC remain to be identified. MicroRNAs, a class of small noncoding RNAs able to regulate gene expression, are deregulated in breast cancer and may therefore serve as tools for diagnosis and prediction. This study was designed to determine miRNA expression profiling (microRNAome) in IBC. Quantitative RT‐PCR was used to determine expression levels of 804 miRNAs in a screening series of 12 IBC compared to 31 non‐stage‐matched non‐IBC and 8 normal breast samples. The differentially expressed miRNAs were then validated in a series of 65 IBC and 95 non‐IBC. From a set of 18 miRNAs of interest selected from the screening series, 13 were differentially expressed with statistical significance in the validation series of IBC compared to non‐IBC. Among these, a 5‐miRNA signature comprising miR‐421, miR‐486, miR‐503, miR‐720 and miR‐1303 was shown to be predictive for IBC phenotype with an overall accuracy of 89%. Moreover, multivariate analysis showed that this signature was an independent predictor of poor Metastasis‐Free Survival in non‐IBC patients.
What's new?
Inflammatory breast cancer (IBC) is a very aggressive type of breast cancer that most often originates from ductal epithelial cells and rapidly invades and blocks lymphoid vessels. To identify new diagnostic and causative leads in this disease, the authors performed a global expression profiling of microRNAs. They found 13 out of 804 miRNAs were differentially expressed in IBC compared to non‐IBC tumors. Among the 13 miRNAs, a 5‐miRNA signature was highly predictive of IBC, thus raising the hope for a new diagnostic and prognostic marker in this deadly disease.
Breast cancer in the elderly Crivellari, Diana; Aapro, Matti; Leonard, Robert ...
Journal of clinical oncology,
2007-May-10, Letnik:
25, Številka:
14
Journal Article
Recenzirano
Screening and adjuvant postoperative therapies have increased survival among women with breast cancer. These tools are seldom applied in elderly patients, although the usually reported incidence of ...breast cancer is close to 50% in women 65 years or older, reaching 47% after 70 years in the updated Surveillance, Epidemiology, and End Results (SEER) database. Elderly breast cancer patients, even if in good medical health, were frequently excluded from adjuvant clinical trials. Women age 70 years who are fit actually have a median life expectancy of 15.5 years, ie, half of them will live much longer and will remain exposed for enough time to the potentially preventable risks of a relapse and specific death. In the last few years, a new concern about this issue has developed. Treatment now faces two major end points, as in younger women: to improve disease-free survival in the early stages, and to palliate symptoms in advanced disease. However, in both settings, the absolute benefit of treatment is critical because protecting quality of life and all its related aspects (especially functional status and independence), is crucial in older persons who have more limited life expectancy. Furthermore, the new hormonal compounds (aromatase inhibitors) and chemotherapeutic drugs (capecitabine, liposomal doxorubicin), are potentially less toxic than and equally as effective as older more established therapies. These new treatments bring new challenges including higher cost, and defining their benefit in elderly breast cancer must include an analysis of the cost/benefit ratio. These issues emphasize the urgent need to develop and support clinical trials for this older population of breast cancer patients both in the adjuvant and metastatic settings, a move that will take us from a prejudiced, age-based medicine to an evidence-based medicine.
Several studies suggest that surgical excision of the primary tumor improves survival among patients with stage IV breast cancer at diagnosis. Exclusive locoregional radiotherapy (LRR) is an ...alternative form of locoregional treatment (LRT) in this setting. We retrospectively studied the impact of LRT on the survival of breast cancer patients with synchronous metastases.
Among 18,753 breast cancer patients treated in our institution between 1980 and 2004, 598 patients (3.2%) had synchronous metastasis at diagnosis. Demographic data, tumor characteristics, metastatic sites, and treatments were prospectively recorded. The impact of LRT on overall survival (OS) was evaluated by multivariate analysis including known prognostic factors.
Among 581 eligible patients, 320 received LRT (group A), and 261 received no LRT (group B). LRT consisted of exclusive LRR in 249 patients (78%), surgery of the primary tumor with adjuvant LRR in 41 patients (13%), and surgery alone in 30 patients (9%). With a median follow-up time of 39 months, the 3-year OS rates were 43.4% and 26.7% in group A and group B (P =.00002), respectively. The association between LRT and improved survival was particularly marked in women with visceral metastases. LRT was an independent prognostic factor in multivariate analysis (hazard ratio HR = 0.70; 95% CI, 0.58 to 0.85; P = .0002). The adjusted HR for late death (>or= 1 year) was 0.76 (95% CI, 0.61 to 0.96; P = .02).
In our experience, LRT, consisting mainly of exclusive LRR, was associated with improved survival in breast cancer patients with synchronous metastases. Exclusive LRR may thus represent an active alternative to surgery.
Patients with metastatic breast cancer (MBC) represent a heterogeneous group, with large differences in outcomes from individual patients. VE-cadherin, an endothelial-specific cadherin, was shown to ...promote tumour proliferation and angiogenesis. Soluble VE-cadherin has been recently associated to breast cancer progression. This study was designed to investigate the prognosis significance of soluble VE-cadherin in hormone-refractory MBC.
Between 2004 and 2007, 150 patients with a fully documented history of hormone-refractory MBC were included in the prospective SEMTOF study. Serum concentrations of VE-cadherin were measured at inclusion for 141 patients and 6 weeks after the beginning of chemotherapy, using a sandwich enzyme immunoassay.
The presence of high levels of serum VE-cadherin was significantly correlated to a shorter progression-free (PFS) and overall survival (OS). In a multivariate analysis along with clinical and biologic prognostic parameters, high serum VE-cadherin level was an independent adverse prognostic variable for PFS (median PFS 9.7 (IC95: 8; 11.9) vs 5.8 (IC95: 4.1; 8) months P=0.0008) and OS (median OS 34 (IC95: 26.6; 47.1) vs 14.8 (IC95: 9.3; 21.4) months P=0.0007). Moreover, VE-cadherin decrease during chemotherapy was also associated with good prognosis.
Serum VE-cadherin levels correlate to poorer survival in patients with hormone-refractory MBC. As sVE-cadherin reflects tumour angiogenesis, this could have therapeutic implications for antiangiogenic treatment.
The management of elderly patients with cancer is a therapeutic challenge and a public health problem. Definitive chemoradiotherapy (CRT) is an accepted standard treatment for patients with locally ...advanced esophageal cancer who cannot undergo surgery. However, there are few reports regarding tolerance to CRT in elderly patients. We previously reported results for CRT in patients aged ≥75 years. Following this first phase II trial, we propose to conduct a phase I/II study to evaluate the combination of carboplatin and paclitaxel, with concurrent RT in unresectable esophageal cancer patients aged 75 years or older.
This prospective multicenter phase I/II study will include esophageal cancer in patients aged 75 years or older. Study procedures will consist to determinate the tolerated dose of chemotherapy (Carboplatin, paclitaxel) and of radiotherapy (41.4-45 and 50.4 Gy) in the phase I. Efficacy will be assessed using a co-primary endpoint encompassing health related quality of life and the progression-free survival in the phase II with the dose recommended of CRT in the phase I. This geriatric evaluation was defined by the French geriatric oncology group (GERICO).
This trial has been designed to assess the tolerated dose of CRT in selected patient aged 75 years or older.
Clinicaltrials.gov ID: NCT02735057 . Registered on 18 March 2016.
The prospective multicenter COMET trial followed a cohort of 306 consecutive metastatic breast cancer patients receiving bevacizumab and paclitaxel as first-line chemotherapy. This study was intended ...to identify and validate reliable biomarkers to better predict bevacizumab treatment outcomes and allow for a more personalized use of this antiangiogenic agent. To that end, we aimed to establish risk scores for survival prognosis dichotomization based on classic clinico-pathological criteria combined or not with single nucleotide polymorphisms (SNPs). The genomic DNA of 306 patients was extracted and a panel of 13 SNPs, covering seven genes previously documented to be potentially involved in drug response, were analyzed by means of high-throughput genotyping. In receiver operating characteristic (ROC) analyses, the hazard model based on a triple-negative cancer phenotype variable, combined with specific SNPs in VEGFA (rs833061), VEGFR1 (rs9582036) and VEGFR2 (rs1870377), had the highest predictive value. The overall survival hazard ratio of patients assigned to the poor prognosis group based on this model was 3.21 (95% CI (2.33–4.42); p < 0.001). We propose that combining this pharmacogenetic approach with classical clinico-pathological characteristics could markedly improve clinical decision-making for breast cancer patients receiving bevacizumab-based therapy.
Summary Background TP53 has a crucial role in the DNA damage response. We therefore tested the hypothesis that taxanes confer a greater advantage than do anthracyclines on breast cancers with mutated ...TP53 than in those with wild-type TP53. Methods In an open-label, phase 3 study, women (age <71 years) with locally advanced, inflammatory, or large operable breast cancers were randomly assigned in a 1:1 ratio to either a standard anthracycline regimen (six cycles of intravenous fluorouracil 500 mg/m2 , epirubicin 100 mg/m2 , and cyclophosphamide 500 mg/m2 every 21 days FEC100, or fluorouracil 600 mg/m2 , epirubicin 75 mg/m2 , cyclophosphamide 900 mg/m2 tailored FEC starting on day 1 and then every 21 days) or a taxane-based regimen (three cycles of docetaxel 100 mg/m2 , intravenously infused over 1 h on day 1 every 21 days, followed by three cycles of intravenous epirubicin 90 mg/m2 and docetaxel 75 mg/m2 on day 1 every 21 days T-ET) at 42 centres in Europe. Randomisation was by use of a minimisation method that stratified patients by institution and initial tumour stage. The primary endpoint was progression-free survival (PFS) according to TP53 status. Analysis was by intention to treat. This is the final analysis of this trial. The study is registered with ClinicalTrials.gov , number NCT00017095. Findings 928 patients were enrolled in the FEC group and 928 in the T-ET group. TP53 status was not assessable for 183 (20%) patients in the FEC group and 204 (22%) patients in the T-ET group mainly because of low tumour-cell content in the biopsy. 361 primary endpoint events were recorded in the FEC group and 314 in the T-ET group. In patients with TP53 -mutated tumours, 5-year PFS was 59·5% (95% CI 53·4–65·1) in the T-ET group (n=326) and 55·3% (49·2–60·9) in the FEC group (n=318; hazard ratio 0·84, 98% CI 0·63–1·14; p=0·17). In patients with TP53 wild-type tumours, 5-year PFS was 66·8% (95% CI 61·4–71·6) in the T-ET group (n=398) and 64·7% (59·6–69·4) in the FEC group (n=427; 0·89, 98% CI 0·68–1·18; p=0·35). For all patients, irrespective of TP53 status, 5-year PFS was 65·1% (95% CI 61·6–68·3) in the T-ET group and 60·8% (57·3–64·2) in the FEC group (0·85, 98% CI 0·71–1·02; p=0·035). At the sites using FEC100 versus T-ET, the most common grade 3 or 4 adverse events were febrile neutropenia (75 9% of 803 vs 173 21% of 809, respectively), and neutropenia (653 81% vs 730 90%, respectively). At the sites using tailored FEC versus T-ET, the most common grade 3 or 4 adverse events were febrile neutropenia (ten 8% of 118 vs 26 22% of 116, respectively), and neutropenia (100 85% vs 115 99%, respectively). Two patients died of toxicity during or within 30 days of chemotherapy completion and without disease relapse (one in each group). Interpretation Although TP53 status was prognostic for overall survival, it was not predictive of preferential sensitivity to taxanes. TP53 status tested by use of the yeast assay in this patient population cannot be used to select patients for an anthracycline-based chemotherapy versus a taxane-based chemotherapy. Funding US National Cancer Institute, La Ligue Nationale Contre le Cancer, European Union, Pharmacia, and Sanofi-Aventis.
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