Gabriella Mariani

2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial

BACKGROUND Trastuzumab--a humanised monoclonal antibody against HER2--has been shown to improve disease-free survival after chemotherapy in women with HER2-positive early breast cancer. We investigated the drugs effect on overall survival after a median follow-up of 2 years in the Herceptin Adjuvant (HERA) study. METHODS HERA is an international multicentre randomised trial that compared 1 or 2 years of trastuzumab treatment with observation alone after standard neoadjuvant or adjuvant chemotherapy in women with HER2-positive node positive or high-risk node negative breast cancer. 5102 women participated in the trial; we analysed data from 1703 women who had been randomised for treatment with trastuzumab for 1 year and 1698 women from the control group, with median follow-up of 23.5 months (range 0-48 months). The primary endpoint of the trial was disease-free survival. Here, we assess overall survival, a secondary endpoint. Analyses were done on an intent-to-treat basis. This trial is registered with the European Clinical Trials Database, number 2005-002385-11. FINDINGS 97 (5.7%) patients randomised to observation alone and 58 (3.4%) patients randomised to 1 year of treatment with trastuzumab were lost to follow-up. 172 women stopped trastuzumab prematurely. 59 deaths were reported for trastuzumab and 90 in the control group. The unadjusted hazard ratio (HR) for the risk of death with trastuzumab compared with observation alone was 0.66 (95% CI 0.47-0.91; p=0.0115). 218 disease-free survival events were reported with trastuzumab compared with 321 in the control group. The unadjusted HR for the risk of an event with trastuzumab compared with observation alone was 0.64 (0.54-0.76; p<0.0001). INTERPRETATION Our results show that 1 year of treatment with trastuzumab after adjuvant chemotherapy has a significant overall survival benefit after a median follow-up of 2 years. The emergence of this benefit after only 2 years reinforces the importance of trastuzumab in the treatment of women with HER2-positive early breast cancer.

Gene Expression Profiles in Paraffin-Embedded Core Biopsy Tissue Predict Response to Chemotherapy in Women With Locally Advanced Breast Cancer

PURPOSE We sought to identify gene expression markers that predict the likelihood of chemotherapy response. We also tested whether chemotherapy response is correlated with the 21-gene Recurrence Score assay that quantifies recurrence risk. METHODS Patients with locally advanced breast cancer received neoadjuvant paclitaxel and doxorubicin. RNA was extracted from the pretreatment formalin-fixed paraffin-embedded core biopsies. The expression of 384 genes was quantified using reverse transcriptase polymerase chain reaction and correlated with pathologic complete response (pCR). The performance of genes predicting for pCR was tested in patients from an independent neoadjuvant study where gene expression was obtained using DNA microarrays. RESULTS Of 89 assessable patients (mean age, 49.9 years; mean tumor size, 6.4 cm), 11 (12%) had a pCR. Eighty-six genes correlated with pCR (unadjusted P < .05); pCR was more likely with higher expression of proliferation-related genes and immune-related genes, and with lower expression of estrogen receptor (ER) -related genes. In 82 independent patients treated with neoadjuvant paclitaxel and doxorubicin, DNA microarray data were available for 79 of the 86 genes. In univariate analysis, 24 genes correlated with pCR with P < .05 (false discovery, four genes) and 32 genes showed correlation with P < .1 (false discovery, eight genes). The Recurrence Score was positively associated with the likelihood of pCR (P = .005), suggesting that the patients who are at greatest recurrence risk are more likely to have chemotherapy benefit. CONCLUSION Quantitative expression of ER-related genes, proliferation genes, and immune-related genes are strong predictors of pCR in women with locally advanced breast cancer receiving neoadjuvant anthracyclines and paclitaxel.

Trastuzumab as adjuvant systemic therapy for HER2-positive breast cancer.

Trastuzumab has an established role for the treatment of HER2-positive early-stage breast cancer because of the success of this agent in the adjuvant setting. Several key questions about the value of trastuzumab for the treatment of breast cancer, however, still need to be answered. Various differences in patient characteristics and treatment regimens were present in the randomized trials discussed in this Review; therefore, the details of trastuzumab use need clarification. For example, the optimum timing, the ideal administration schedule, and the appropriate length of treatment are not known. Cardiotoxicity is major concern even though the results of all randomized trials have shown that the degree of cardiotoxicity with trastuzumab is acceptable—the incidence of cardiac damage caused by trastuzumab ranged from 0.4% to 4.1% in the different trials (cumulative incidence of congestive heart failure, New York Heart Association class 3–4). Current data do not support the use of trastuzumab for more than 1 year. The analysis of 2-year treatment with trastuzumab is expected to be available in 2009.

Selumetinib Plus Docetaxel Compared With Docetaxel Alone and Progression-Free Survival in Patients With KRAS-Mutant Advanced Non-Small Cell Lung Cancer: The SELECT-1 Randomized Clinical Trial.

Importance There are no specifically approved targeted therapies for the most common genomically defined subset of non–small cell lung cancer (NSCLC), KRAS-mutant lung cancer. Objective To compare efficacy of the mitogen-activated protein kinase kinase (MEK) inhibitor selumetinib + docetaxel with docetaxel alone as a second-line therapy for advanced KRAS-mutant NSCLC. Design, Setting, and Participants Multinational, randomized clinical trial conducted at 202 sites across 25 countries from October 2013 through January 2016. Of 3323 patients with advanced NSCLC and disease progression following first-line anticancer therapy tested for a KRAS mutation, 866 were enrolled and 510 randomized. Primary reason for exclusion was ineligibility. The data cutoff date for analysis was June 7, 2016. Interventions Patients were randomized 1:1; 254 to receive selumetinib + docetaxel and 256 to receive placebo + docetaxel. Main Outcomes and Measures Primary end point was investigator assessed progression-free survival. Secondary end points included overall survival, objective response rate, duration of response, effects on disease-related symptoms, safety, and tolerability. Results Of 510 randomized patients (mean age, 61.4 years [SD, 8.3]; women, 207 [41%]), 505 patients (99%) received treatment and completed the study (251 received selumetinib + docetaxel; 254 received placebo + docetaxel). At the time of data cutoff, 447 patients (88%) had experienced a progression event and 346 deaths (68%) had occurred. Median progression-free survival was 3.9 months (interquartile range [IQR], 1.5-5.9) with selumetinib + docetaxel and 2.8 months (IQR, 1.4-5.5) with placebo + docetaxel (difference, 1.1 months; hazard ratio [HR], 0.93 [95% CI, 0.77-1.12]; P = .44). Median overall survival was 8.7 months (IQR, 3.6-16.8) with selumetinib + docetaxel and 7.9 months (IQR, 3.8-20.1) with placebo + docetaxel (difference, 0.9 months; HR, 1.05 [95% CI, 0.85-1.30]; P = .64). Objective response rate was 20.1% with selumetinib + docetaxel and 13.7% with placebo + docetaxel (difference, 6.4%; odds ratio, 1.61 [95% CI, 1.00-2.62]; P = .05). Median duration of response was 2.9 months (IQR, 1.7-4.8; 95% CI, 2.7-4.1) with selumetinib + docetaxel and 4.5 months (IQR, 2.3-7.3; 95% CI, 2.8-5.6) with placebo + docetaxel. Adverse events of grade 3 or higher were more frequent with selumetinib + docetaxel (169 adverse events [67%] for selumetinib + docetaxel vs 115 adverse events [45%] for placebo + docetaxel; difference, 22%). Conclusions and Relevance Among patients with previously treated advanced KRAS-mutant non–small cell lung cancer, addition of selumetinib to docetaxel did not improve progression-free survival compared with docetaxel alone. Trial Registration clinicaltrials.gov: NCT01933932

Axillary lymph node dissection versus no dissection in patients with T1N0 breast cancer: A randomized clinical trial (INT09/98)

Although axillary surgery is still considered to be a fundamental part of the management of early breast cancer, it may no longer be necessary either as treatment or as a guide to adjuvant treatment. The authors conducted a single‐center randomized trial (INT09/98) to determine the impact of avoiding axillary surgery in patients with T1N0 breast cancer and planning chemotherapy based on biological factors of the primary tumor on long‐term disease control.

Locally advanced breast cancer treated with primary chemotherapy: comparison between magnetic resonance imaging and pathologic evaluation of residual disease.

Aims and Background We evaluated the response of locally advanced breast cancer to induction chemotherapy using MRI techniques. The size and vitality of any residual pathologic tissue was quantified by means of morphologic and dynamic analysis. A curve derived from the dynamic parameters shows the uptake intensity with respect to the time elapsed since administration, which is related to vascularization and therefore indirectly reflects the angiogenesis of malignant tissue. Methods and Study Design A group of 30 patients were examined with MRI for staging purposes before undergoing treatment and subsequently to assess the response to treatment. Alterations in size and dynamic parameters were closely monitored. Results The overall accuracy was 90%, the sensitivity 96%, the specificity 75%, the positive predictive value 92.5% and the negative predictive value 66%. Interestingly, analysis of the dynamic curves made it possible to obtain additional information regarding the angiogenetic activity of the residual tumor. Conclusions Evaluation of the response to treatment by means of conventional imaging and clinical examination can be particularly difficult because of the fibrosis induced by cytotoxic drugs or the small volume of residual disease. The additional information supplied by MRI could therefore allow a more conservative surgical approach in selected cases of optimal response to treatment, as well as a much more accurate follow-up. Furthermore, the variation in dynamic parameters according to the vitality of residual disease could in the future become a useful tool for monitoring the effectiveness of anti-angiogenetic drugs.

Biologic and clinical effects of continuous infusion interleukin-2 in patients with non-small cell lung cancer

Background. Interleukin‐2 (IL‐2) has shown antitumor activity in some neoplasms, such as melanoma and renal carcinoma, but toxicity derived from bolus administration is significant, particularly at the cardiorespiratory level.

Combination of Chemotherapy and Recombinant Alpha-Interferon in Advanced Non-Small Cell Lung Cancer Multicentric Randomized FONICAP Trial Report

Background. Preclinical data suggested that alphainterferon (IFN) may potentiate chemotherapy cytotoxicity.

Safety of everolimus plus exemestane in patients with hormone-receptor–positive, HER2–negative locally advanced or metastatic breast cancer progressing on prior non-steroidal aromatase inhibitors: primary results of a phase IIIb, open-label, single-arm, expanded-access multicenter trial (BALLET)

BACKGROUND This European phase IIIb, expanded-access multicenter trial evaluated the safety of EVE plus EXE in a patient population similar to BOLERO-2. PATIENTS AND METHODS Post-menopausal women aged ≥18 years with hormone receptor-positive, human epidermal growth factor-receptor-2-negative advanced breast cancer (ABC) recurring/progressing during/after prior non-steroidal aromatase inhibitors were enrolled. The primary objective was safety of EVE plus EXE based on frequency of adverse events (AEs), and serious AEs (SAEs). The secondary objective was to evaluate AEs of grade 3/4 severity. RESULTS The median treatment duration was 5.1 months [95% confidence interval (CI) 4.8-5.6] for EVE and 5.3 months (95% CI 4.8-5.6) for EXE. Overall, 2131 patients were included in the analysis; 81.8% of patients experienced EVE- or EXE-related or EVE/EXE-related AEs (investigator assessed); 27.2% were of grade 3/4 severity. The most frequently reported non-hematologic AEs were (overall %, % EVE-related) stomatitis (52.8%; 50.8%) and asthenia (22.8%; 14.6%). The most frequently reported hematologic AEs were (overall %, % EVE-related) anemia (14.4%; 8.1%) and thrombocytopenia (5.9%; 4.6%). AE-related treatment discontinuations were higher in elderly (≥70 years) versus non-elderly patients (23.8% versus 13.0%). The incidence of EVE-related AEs in both elderly and non-elderly patients appeared to be lower in first-line ABC versus later lines. The incidence of AEs (including stomatitis/pneumonitis) was independent of BMI status (post hoc analysis). Overall, 8.5% of patients experienced at least one EVE-related SAE. Of the 121 on-treatment deaths (5.7%), 66 (3.1%) deaths were due to disease progression and 46 (2.2%) due to AEs; 4 deaths were suspected to be EVE-related. CONCLUSIONS This is the largest ever reported safety dataset on a general patient population presenting ABC treated with EVE plus EXE and included a sizeable elderly subset. Although the patients were more heavily pretreated, the safety profile of EVE plus EXE in BALLET was consistent with BOLERO-2. CLINICAL TRIAL REGISTRATION EudraCT Number: 2012-000073-23.

Clinical and pharmacokinetic study of sunitinib and docetaxel in women with advanced breast cancer.

BACKGROUND This exploratory study examined the pharmacokinetics, safety, and antitumor activity of sunitinib plus docetaxel in patients with HER-2-negative advanced breast cancer. PATIENTS AND METHODS Patients with HER-2-negative disease who had received prior adjuvant anthracycline-based therapy received docetaxel (75 mg/m(2)) on day 1 of each 3-week cycle followed by sunitinib (37.5 mg/day for 2 weeks on Schedule 2/1) starting on day 2 (day 3 on cycle 2). RESULTS Twenty-two patients were enrolled. No clinically significant drug-drug interactions were observed. The most common non-hematologic AE (any grade) was fatigue/asthenia. Grade 4 neutropenia occurred in 20/22 patients (91%; n = 7 had neutropenic fever). The safety profile was similar to each agent given individually. 14/19 (73.7%) evaluable patients had a PR and 5/19 (26.3%) had SD. CONCLUSIONS Sunitinib plus docetaxel on Schedule 2/1 did not result in any clinically significant drug-drug interactions. This combination was manageable and exhibited antitumor activity.