21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer.

BACKGROUND: The recurrence score based on the 21-gene breast-cancer assay has been clinically useful in predicting a chemotherapy benefit in hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary lymph-node-negative breast cancer. In women with positive lymph-node disease, the role of the recurrence score with respect to predicting a benefit of adjuvant chemotherapy is unclear. METHODS: In a prospective trial, we randomly assigned women with hormone-receptor-positive, HER2-negative breast cancer, one to three positive axillary lymph nodes, and a recurrence score of 25 or lower (scores range from 0 to 100, with higher scores indicating a worse prognosis) to endocrine therapy only or to chemotherapy plus endocrine (chemoendocrine) therapy. The primary objective was to determine the effect of chemotherapy on invasive disease-free survival and whether the effect was influenced by the recurrence score. Secondary end points included distant relapse-free survival. RESULTS: A total of 5083 women (33.2% premenopausal and 66.8% postmenopausal) underwent randomization, and 5018 participated in the trial. At the prespecified third interim analysis, the chemotherapy benefit with respect to increasing invasive disease-free survival differed according to menopausal status (P = 0.008 for the comparison of chemotherapy benefit in premenopausal and postmenopausal participants), and separate prespecified analyses were conducted. Among postmenopausal women, invasive disease-free survival at 5 years was 91.9% in the endocrine-only group and 91.3% in the chemoendocrine group, with no chemotherapy benefit (hazard ratio for invasive disease recurrence, new primary cancer [breast cancer or another type], or death, 1.02; 95% confidence interval [CI], 0.82 to 1.26; P = 0.89). Among premenopausal women, invasive disease-free survival at 5 years was 89.0% with endocrine-only therapy and 93.9% with chemoendocrine therapy (hazard ratio, 0.60; 95% CI, 0.43 to 0.83; P = 0.002), with a similar increase in distant relapse-free survival (hazard ratio, 0.58; 95% CI, 0.39 to 0.87; P = 0.009). The relative chemotherapy benefit did not increase as the recurrence score increased. CONCLUSIONS: Among premenopausal women with one to three positive lymph nodes and a recurrence score of 25 or lower, those who received chemoendocrine therapy had longer invasive disease-free survival and distant relapse-free survival than those who received endocrine-only therapy, whereas postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy. (Funded by the National Cancer Institute and others; RxPONDER ClinicalTrials.gov number, NCT01272037.).

Updated recommendations regarding the management of older patients with breast cancer: a joint paper from the European Society of Breast Cancer Specialists (EUSOMA) and the International Society of Geriatric Oncology (SIOG).

Breast cancer is increasingly prevalent in older adults and is a substantial part of routine oncology practice. However, management of breast cancer in this population is challenging because the disease is highly heterogeneous and there is insufficient evidence specific to older adults. Decision making should not be driven by age alone but should involve geriatric assessments plus careful consideration of life expectancy, competing risks of mortality, and patient preferences. A multidisciplinary taskforce, including members of the European Society of Breast Cancer Specialists and International Society of Geriatric Oncology, gathered to expand and update the previous 2012 evidence-based recommendations for the management of breast cancer in older individuals with the endorsement of the European Cancer Organisation. These guidelines were expanded to include chemotherapy toxicity prediction calculators, cultural and social considerations, surveillance imaging, genetic screening, gene expression profiles, neoadjuvant systemic treatment options, bone-modifying drugs, targeted therapies, and supportive care. Recommendations on geriatric assessment, ductal carcinoma in situ, screening, primary endocrine therapy, surgery, radiotherapy, adjuvant systemic therapy, and secondary breast cancer were updated.

Systemic Therapy in Older Patients With High-Risk Disease.

Adjuvant systemic treatments for older patients with breast cancer require constant dose or schedule adjustments of standards established for younger ones. This is mainly due to frailty that increases according to age (40%-50% of signals in all comers after age 70 years) and remains difficult to spot or diagnose accurately and therefore is often overlooked. Older patients are at higher risk to develop side effects whether under chemotherapy, optimized endocrine treatment, or targeted therapies. Pharmacokinetic reflects poorly functional reserves that reduce with aging and is therefore misleading. The demonstration of significant long-term benefits provided by adjuvant treatments is challenged by life expectancy, driven by multimorbidity status that increases with age, competing with cancer outcome. When geriatric assessment is incorporated into the multidisciplinary team, treatment decision process shows 30%-50% changes, de-escalating initial age-agnostic treatment choices in two of three cases. Finally, expectations from treatment vary over the years: In older ones, although not being exclusive, there is a general shift of preference for protecting functionality, cognitive functions, and independence, as summarized in quality of life that many systemic adjuvant treatment may jeopardize. These provocative considerations show importance to pay more attention to expectations expressed by older patients to limit gaps between what is thought by health care professionals as right, often on the basis of dose intensity models strongly engrained in oncology and that older patients may assess counterintuitively differently. The most achieved molecular testing to identify high-risk luminal tumors should be combined with determinant geriatric factors to bring relevant global information in the adjuvant setting for older patients.

Individualizing Surveillance Mammography for Older Patients After Treatment for Early-Stage Breast Cancer: Multidisciplinary Expert Panel and International Society of Geriatric Oncology Consensus Statement.

IMPORTANCE: There is currently no guidance on how to approach surveillance mammography for older breast cancer survivors, particularly when life expectancy is limited. OBJECTIVE: To develop expert consensus guidelines that facilitate tailored decision-making for routine surveillance mammography for breast cancer survivors 75 years or older. EVIDENCE: After a literature review of the risk of ipsilateral and contralateral breast cancer events among breast cancer survivors and the harms and benefits associated with mammography, a multidisciplinary expert panel was convened to develop consensus guidelines on surveillance mammography for breast cancer survivors 75 years or older. Using an iterative consensus-based approach, input from clinician focus groups, and critical review by the International Society for Geriatric Oncology, the guidelines were refined and finalized. FINDINGS: The literature review established a low risk for ipsilateral and contralateral breast cancer events in most older breast cancer survivors and summarized the benefits and harms associated with mammography. Draft mammography guidelines were iteratively evaluated by the expert panel and clinician focus groups, emphasizing a patient's risk for in-breast cancer events, age, life expectancy, and personal preferences. The final consensus guidelines recommend discontinuation of routine mammography for all breast cancer survivors when life expectancy is less than 5 years, including those with a history of high-risk cancers; consideration to discontinue mammography when life expectancy is 5 to 10 years; and continuation of mammography when life expectancy is more than 10 years. Individualized, shared decision-making is encouraged to optimally tailor recommendations after weighing the benefits and harms associated with surveillance mammography and patient preferences. The panel also recommends ongoing clinical breast examinations and diagnostic mammography to evaluate clinical findings and symptoms, with reassurance for patients that these practices will continue. CONCLUSIONS AND RELEVANCE: It is anticipated that these expert guidelines will enhance clinical practice by providing a framework for individualized discussions, facilitating shared decision-making regarding surveillance mammography for breast cancer survivors 75 years or older.

Population pharmacokinetics and exploratory pharmacodynamics of ifosfamide according to continuous or short infusion schedules: an n = 1 randomized study.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * The optimal infusion duration for ifosfamide remains to be determined. * No differences according to time of infusion have been identified in traditional pharmacokinetic endpoints, such as area under the curve. * The impact on pharmacodynamics has never been modelled or correlated with pharmacokinetics. WHAT THIS STUDY ADDS: * The pharmacokinetics and pharmacodynamics of ifosfamide and its main metabolites can both be modelled with no influence of infusion duration. * Pharmacodynamic modelling (renal and haematological toxicity) allows further simulations of new schedules with favourable toxicity profiles. AIMS: To model the pharmacokinetics and pharmacodynamics of ifosfamide and its key metabolites. The pharmacodynamic parameters included were renal toxicity and myelosuppression measured using urinary beta(2)-microglobulin (BMG) and absolute neutrophil count (ANC), respectively. METHODS: Seventeen patients were enrolled into an n = 1 randomized trial during two consecutive cycles of ifosfamide 9 g m(-2) during each cycle given by a 3 h or 72 h infusion. Data were analyzed using NONMEM. RESULTS: Ifosfamide and metabolite concentration-time profiles were described by a one-compartment open-model with auto-induction of clearance. BMG and ANC time-courses were related to ifosfamide concentration via indirect response models. CONCLUSIONS: This modelling allowed the simulation of weekly schedules of flat doses with favourable myelotoxic profiles.

Life-threatening sepsis associated with adjuvant doxorubicin plus docetaxel for intermediate-risk breast cancer.

CONTEXT: Adjuvant chemotherapy with new cytotoxic agents for breast cancer must be properly assessed for toxicity. OBJECTIVE: To describe adverse events associated with adjuvant chemotherapy for breast cancer, which led to premature termination of a clinical trial. DESIGN, SETTING, AND PATIENTS: We conducted a prospective randomized multicenter study (Reposant sur des Arguments Pronostiques et Predictifs [RAPP]-01) to compare the effectiveness of 2 chemotherapy regimens. Patients (women aged 18-70 years) had primary unilateral breast cancer and either a moderate number of positive axillary lymph nodes (< or =3) or no positive axillary lymph nodes (N0), but were at a high risk of relapse. Patients were treated at 11 French cancer referral centers from June 1999 through January 2003. Primary prophylaxis for febrile neutropenia was not recommended in the study protocol. INTERVENTIONS: Doxorubicin, 50 mg/m2, plus docetaxel, 75 mg/m2, or doxorubicin, 60 mg/m2, plus cyclophosphamide, 600 mg/m2, given postoperatively for 4 courses. MAIN OUTCOME MEASURES: The main end point was the disease-free survival rate at 5 years, as estimated using the Kaplan-Meier product limit method. Secondary end points included safety, which is the focus of this article, and overall survival. RESULTS: A total of 627 women were enrolled. Median follow-up is currently too short (24 months) to analyze the primary end point. The trial was terminated prematurely when 2 deaths related to drug toxicity and 1 case of perforative peritonitis occurred among patients with febrile neutropenia, all in the doxorubicin-docetaxel group. The incidence of febrile neutropenia was significantly higher with the doxorubicin-docetaxel regimen (40.8%) than with the doxorubicin-cyclophosphamide regimen (7.1%) (P<.001). CONCLUSIONS: A high risk of life-threatening complications associated with the doxorubicin-docetaxel regimen was found in this open-label controlled trial. The doxorubicin-docetaxel combination should not be considered as an alternative to the doxorubicin-cyclophosphamide regimen outside carefully designed studies that include primary prophylaxis for febrile neutropenia.

Impact of liposomal doxorubicin-based adjuvant chemotherapy on autonomy in women over 70 with hormone-receptor-negative breast carcinoma: A French Geriatric Oncology Group (GERICO) phase II multicentre trial.

RATIONALE: Breast cancer is a disease of ageing. Functional independence in elderly patients, measured with the Katz activities of daily living (ADL) scale, predicts overall survival and the need for welfare support. Few prospective studies have examined the feasibility of adjuvant chemotherapy and its impact on autonomy in women over 70 years of age with high-risk breast cancer. This multicentre phase II trial was designed to assess the impact of adjuvant anthracycline-based chemotherapy on these patients' autonomy. DESIGN AND METHODS: In a two-stage Fleming design, women aged ≥70 years with histologically proven hormone-receptor-negative early breast cancer and a significant risk of recurrence (pN+ or "high risk" pN0) received 4 cycles of nonpegylated liposomal doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) every 3 weeks postoperatively, on an outpatient basis. The primary endpoint was the change in the ADL score during chemotherapy. Secondary endpoints include comprehensive geriatric, quality-of-life and acceptability assessments, tolerability, and long-term outcome. The results for the primary endpoint and other scales at completion of adjuvant chemotherapy are reported here, while long-term follow-up is not yet complete. RESULTS: Forty patients (median age 75 [70-82]) were enrolled between February 2006 and November 2007. Chemotherapy had no deleterious impact on ADL, cognition, mental status, or the frequency of comorbidities. In contrast, the number of patients at risk of malnutrition, based on the Mini Nutritional Assessment, more than doubled between baseline and the end of chemotherapy, rising from 15% to 38%. Quality-of-life deteriorated in terms of social and role functioning, likely owing to fatigue, loss of appetite, nausea and vomiting. Treatment acceptability was good. The main adverse effect was neutropenia, 15% of the patients experiencing febrile neutropenia. No cardiac toxicity or toxic deaths occurred. CONCLUSION: This study demonstrates the feasibility of an adjuvant chemotherapy regimen combining nonpegylated liposomal doxorubicin and cyclophosphamide in fit elderly women <85 years with breast cancer. Although chemotherapy had an impact on social and role functioning, autonomy was not impaired and toxicity was acceptable. Special attention should be paid to nutritional status before and after treatment.

[Breast cancer in the elderly]. / Le cancer du sein de la femme âgée.

Breast cancer is the most commonly diagnosed cancer and leading cause of cancer mortality in women worldwide. The elderly comprise a large part of the breast cancer population, and there are important specific considerations for this population. Late diagnosis and substandard local and systemic therapies are frequent, which is only partially "compensated" by a more indolent tumour behaviour due to the increasing likelihood according to age of potentially hormone sensitive tumour status. Endocrine treatment remains a key component of systemic treatment in both advanced and early setting. However chemotherapy is a valid option, with interest strengthened by proven efficacy in adjuvant setting for aggressive phenotypes, better management of side effects and attempts to develop predictive index for toxicity. The recently reported laboratory studies on potential mechanisms for resistance to endocrine therapies that involve crosstalk between growth factor signalling pathways and hormonal receptors stimulate also new therapeutic approaches.

Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the ANGIOTAX Study.

PURPOSE: The objective of this phase II trial was to assess the efficacy and toxicity of weekly paclitaxel for patients with metastatic or unresectable angiosarcoma. PATIENTS AND METHODS: Thirty patients were entered onto the study from April 2005 through October 2006. Paclitaxel was administered intravenously as a 60-minute infusion at a dose of 80 mg/m(2) on days 1, 8, and 15 of a 4-week cycle. The primary end point was the nonprogression rate after two cycles. RESULTS: The progression-free survival rates after 2 and 4 months were 74% and 45%, respectively. With a median follow-up of 8 months, the median time to progression was 4 months and the median overall survival was 8 months. The progression-free survival rate was similar in patients pretreated with chemotherapy and in chemotherapy-naïve patients (77% v 71%). Three patients with locally advanced breast angiosarcoma presented partial response, which enabled a secondary curative-intent surgery with complete histologic response in two cases. One toxic death occurred as a result of a thrombocytopenia episode. Six patients presented with grade 3 toxicities and one patient presented with a grade 4 toxicity. Anemia and fatigue were the most frequently reported toxicities. CONCLUSION: Weekly paclitaxel at the dose schedule used in the current study was well tolerated and demonstrated clinical benefit.

Adjuvant chemotherapy in elderly patients with breast cancer: where are we?

PURPOSE OF REVIEW: Breast cancer in elderly patients is a major health concern that will only increase in the future. For early-stage breast cancer, adjuvant chemotherapy may be indicated in this patient group following adequate local treatment and before possible hormone therapy. This review summarizes the current knowledge and provides guidelines for the use of adjuvant chemotherapy in elderly patients with breast cancer. RECENT FINDINGS: Most data are extracted from large multicenter trials with upper age limits of 65 or 70 years. Only one multicenter randomized study investigated the potential benefit of an adjuvant anthracycline-based chemotherapy regimen added to endocrine treatment after the age of 65 years. Retrospective analyses from international group databases show the same potential absolute benefit derived from adjuvant chemotherapy in elderly compared with younger patients, however. This benefit must be weighed against life expectancy and tolerability of chemotherapy. SUMMARY: Limited confidence of medical oncologists with cytotoxic chemotherapy administration to the elderly and a lack of both prospective studies and shared guidelines for decision making in this subpopulation are the main factors responsible for the limited use of adjuvant chemotherapy in elderly patients with breast cancer. Fortunately this contrasts with an increasing awareness among clinicians, who should learn to integrate absolute benefit, life expectancy, and tolerance of chemotherapy in their clinical decisions. Discrimination on the basis of older age alone is no longer acceptable.

Safety and efficacy of ET-743: the French experience.

Initial evidence of clinical benefit with ecteinascidin-743 (ET-743) in patients with sarcoma was provided during a Phase I pharmacokinetic study in which 52 patients received ET-743 at doses of 50-1800 micrograms/m2 as a 24 h continuous infusion every 3 weeks. Neutropenia and thrombocytopenia were the dose-limiting toxicities; liver toxicity (a severe but transient and reversible increase in transaminase concentrations) was not treatment limiting. In conjunction with results obtained with ET-743 in a compassionate-use program, these indications of activity in heavily pretreated patients with sarcoma prompted initiation of a French multicenter Phase II study of ET-743 in this population. From February 1999 to January 2001, 54 patients with advanced anthracycline-pretreated soft-tissue sarcoma (STS) received ET-743 at a dose of 1500 micrograms/m2 every 3 weeks by continuous 24 h infusion. The main histological subtype was leiomyosarcoma (37%); the majority of primary tumors were visceral (24%) or uterine (19%) sarcomas. In this Phase II population (> or = 25% negative prognostic or predictive factors of response to chemotherapy; > or = 50% anthracycline- and ifosfamide-resistant), safety data were comparable to those obtained in the Phase I and compassionate-use studies. Asymptomatic and reversible neutropenia and transaminitis (grade 3/4) were the most frequent toxicities (approximately 60% of patients); febrile neutropenia was infrequent (< 10%). No mucositis, alopecia, cardiac or neurotoxicity was observed. Two severe cases of rhabdomyolysis occurred. Side effects were non-cumulative, reversible and manageable. Of 52 evaluable patients, three (6%) achieved a long-lasting (8-13 months) partial response, four (8%) achieved a minor response (25-50% tumor reduction) and 22 (42%) achieved disease stabilization. With a 13-month median follow-up, median survival was almost 11 months. Progression-free survival at 6 months was 26.5% and the overall survival rate at 12 months was almost 50%. The response rate was uninfluenced by tumor metastatic site, size or anthracycline sensitivity status. These results, combined with the lack of cumulative toxicity, confirm the role of ET-743 in the treatment of advanced STS.