Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer.

Background: The phase III MONALEESA-2 study demonstrated significantly prolonged progression-free survival (PFS) and a manageable toxicity profile for first-line ribociclib plus letrozole versus placebo plus letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Here, we report updated efficacy and safety data, together with exploratory biomarker analyses, from the MONALEESA-2 study. Patients and methods: A total of 668 postmenopausal women with HR+, HER2- recurrent/metastatic breast cancer were randomized (1 : 1; stratified by presence/absence of liver and/or lung metastases) to ribociclib (600 mg/day; 3-weeks-on/1-week-off; 28-day treatment cycles) plus letrozole (2.5 mg/day; continuous) or placebo plus letrozole. The primary end point was locally assessed PFS. The key secondary end point was overall survival (OS). Other secondary end points included overall response rate (ORR) and safety. Biomarker analysis was an exploratory end point. Results: At the time of the second interim analysis, the median duration of follow-up was 26.4 months. Median PFS was 25.3 months [95% confidence interval (CI) 23.0-30.3] for ribociclib plus letrozole and 16.0 months (95% CI 13.4-18.2) for placebo plus letrozole (hazard ratio 0.568; 95% CI 0.457-0.704; log-rank P = 9.63 × 10-8). Ribociclib treatment benefit was maintained irrespective of PIK3CA or TP53 mutation status, total Rb, Ki67, or p16 protein expression, and CDKN2A, CCND1, or ESR1 mRNA levels. Ribociclib benefit was more pronounced in patients with wild-type versus altered receptor tyrosine kinase genes. OS data remain immature, with 116 deaths observed; 50 in the ribociclib arm and 66 in the placebo arm (hazard ratio 0.746; 95% CI 0.517-1.078). The ORR was 42.5% versus 28.7% for all patients treated with ribociclib plus letrozole versus placebo plus letrozole, respectively, and 54.5% versus 38.8%, respectively, for patients with measurable disease. Safety results, after a further 11.1 months of follow-up, were comparable with those reported at the first analysis, with no new or unexpected toxicities observed, and no evidence of cumulative toxicity. Conclusions: The improved efficacy outcomes and manageable tolerability observed with first-line ribociclib plus letrozole are maintained with longer follow-up, relative to letrozole monotherapy. Clinical trials number: NCT01958021.

Carbonic anhydrase IX is a predictive marker of doxorubicin resistance in early-stage breast cancer independent of HER2 and TOP2A amplification.

BACKGROUND: In early-stage breast cancer, adjuvant chemotherapy is associated with significant systemic toxicity with only a modest survival benefit. Therefore, there is considerable interest in identifying predictive markers of response to therapy. Doxorubicin, one of the most common drugs used to treat breast cancer, is an anthracycline chemotherapeutic agent, a class of drugs known to be affected by hypoxia. Accordingly, we examined whether expression of the endogenous hypoxia marker carbonic anhydrase IX (CA IX) is predictive of outcome in early-stage breast cancer patients treated with doxorubicin. METHODS: We obtained 209 early-stage pre-treatment surgically-resected breast tumours from patients, who received doxorubicin in their chemotherapeutic regimen and had >10 years of follow-up. Immunohistochemistry was used to detect CA IX, and we used fluorescence in situ hybridisation to detect both human epidermal growth factor receptor (HER2) and DNA topoisomerase II-alpha (TOP2A) gene amplification. RESULTS: Carbonic anhydrase IX intensity was significantly correlated with progression-free survival (PFS) and overall survival (OS) in patients receiving 300 mg m(-2) of doxorubicin (HR=1.82 and 3.77; P=0.0014 and 0.010, respectively). There was a significant, inverse correlation between CA IX score and oestrogen receptor expression, but no significant correlations were seen with either HER2 or TOP2A ratio. CONCLUSION: We demonstrate that CA IX expression is correlated with worse PFS and OS for breast cancer patients treated with doxorubicin, independent of HER2 or TOP2A gene amplification. This study provides evidence that using CA IX to detect hypoxia in surgically-resected breast tumours may be of clinical use in choosing an appropriate chemotherapy regimen.

Impact of lapatinib plus trastuzumab versus single-agent lapatinib on quality of life of patients with trastuzumab-refractory HER2+ metastatic breast cancer.

BACKGROUND: Progression-free survival (PFS) was significantly longer for the lapatinib plus trastuzumab (L+T) arm than for L alone in a phase III, randomized, open-label study of women with human epidermal growth factor receptor 2 positive metastatic breast cancer who had documented progression on at least one T-containing regimen in the metastatic setting. This analysis focused on impact of treatments on health-related quality of life (HRQOL). METHODS: HRQOL was assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire. Changes from baseline and time to deterioration were analyzed in the intent-to-treat population. RESULTS: Differences between the treatment arms in adjusted mean change from baseline favored the L+T arm, ranging from 0.0 to 4.1 (FACT-B), 1.0-4.0 [Functional Assessment of Cancer Therapy-General (FACT-G)], and 0.5-2.7 (Trial Outcome Index). Most differences were not statistically significant, except for FACT-G at week 12 (delta = 4.0, P = 0.037). Similar results were found in a sensitivity analysis that included HRQOL records up to patient withdrawal from original randomized treatment. The longer time to HRQOL deterioration in the L+T arm was not statistically significant (FACT-B hazard ratio, 0.82; 95% confidence interval 0.56-1.20). CONCLUSION: The addition of lapatinib to trastuzumab prolonged PFS while improving or maintaining near-term HRQOL, suggesting a meaningful clinical benefit to patients.

Single-agent lapatinib for HER2-overexpressing advanced or metastatic breast cancer that progressed on first- or second-line trastuzumab-containing regimens.

BACKGROUND: This phase II study evaluated the efficacy and safety of lapatinib in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer that progressed during prior trastuzumab therapy. PATIENTS AND METHODS: Women with stage IIIB/IV HER2-overexpressing breast cancer were treated with single-agent lapatinib 1250 or 1500 mg once daily after protocol amendment. Tumor response according to RECIST was assessed every 8 weeks. HER2 expression was assessed in tumor tissue by immunohistochemistry and FISH. RESULTS: Seventy-eight patients were enrolled in the study. Investigator and independent review response rates [complete response (CR) or partial response (PR)] were 7.7% and 5.1%, and clinical benefit rates (CR, PR, or stable disease for >or=24 weeks) were 14.1% and 9.0%, respectively. Median time to progression was 15.3 weeks by independent review, and median overall survival was 79 weeks. The most common treatment-related adverse events were rash (47%), diarrhea (46%), nausea (31%), and fatigue (18%). CONCLUSIONS: Single-agent lapatinib has clinical activity with manageable toxic effects in HER2-overexpressing breast cancer that progressed on trastuzumab-containing therapy. Studies of lapatinib-based combination regimens with chemotherapy and other targeted therapies in metastatic and earlier stages of breast cancer are warranted.

Analysis of dermatologic events in patients with cancer treated with lapatinib.

PURPOSE: Dermatologic events (DEs) in patients with cancer treated with lapatinib, a small-molecule dual tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR [ErbB1]) and HER2 (ErbB2), were characterized. PATIENTS AND METHODS: Nine clinical trials of metastatic cancer were included in this analysis. Lapatinib was administered at doses ranging from 1000 to 1500 mg/day as monotherapy (n=928) or in combination with paclitaxel or capecitabine (n=491). Patients not treated with lapatinib comprised the control group. Dermatologic events included hand-foot syndrome, rash, hair disorder, dry skin, pruritus/urticaria, skin disorder, skin infection, and nail disorder; DEs were characterized based on type, time to onset, severity, duration, and required interventions. RESULTS: Fifty-eight percent of patients treated with lapatinib monotherapy, 74% treated with lapatinib plus paclitaxel or capecitabine, and 53% in the control group developed DEs. Among patients receiving lapatinib monotherapy, 55% experienced grade 1/2 DEs, 3% had grade 3 DEs, and no grade 4 DEs were observed. The most common DE was rash (43%); all other events occurred in

A phase II study of lapatinib monotherapy in chemotherapy-refractory HER2-positive and HER2-negative advanced or metastatic breast cancer.

BACKGROUND: The efficacy and tolerability of the epidermal growth factor receptor/human epidermal growth factor receptor type 2 (HER2) tyrosine kinase inhibitor lapatinib in refractory metastatic breast cancer were assessed. PATIENTS AND METHODS: In a phase II, open-label study, patients with previously treated HER2-positive (n = 140) or HER2-negative (n = 89) metastatic breast cancer received once-daily oral lapatinib 1500 mg/day. RESULTS: Most (76%) patients had received four or more lines of prior therapy. The response rate in the HER2-positive cohort was 4.3% by investigator assessment and 1.4% by independent assessment. Both assessments established that approximately 6% of HER2-positive patients derived clinical benefit from lapatinib, being progression free for >/=6 months. No objective tumor responses occurred in the HER2-negative cohort. Independent review assessments of median time to progression and median progression-free survival were similar in the HER2-positive and HER2-negative cohorts (9.1 and 7.6 weeks, respectively). All responders exhibited HER2 overexpression (3+ by immunohistochemistry), and five of six responders were HER2 amplified by FISH. Lapatinib-related adverse events, including diarrhea (54%), rash (30%), and nausea (24%), were primarily mild to moderate in severity. CONCLUSIONS: Lapatinib monotherapy had modest clinical activity in HER2-positive metastatic breast cancer that progressed on prior trastuzumab regimens. No apparent clinical activity was observed in chemotherapy-refractory, HER2-negative disease.

Human recombinant erythropoietin (rEpo) has no effect on tumour growth or angiogenesis.

Tumour hypoxia has been shown to increase mutation rate, angiogenesis, and metastatic potential, and decrease response to conventional therapeutics. Improved tumour oxygenation should translate into increased treatment response. Exogenous recombinant erythropoietin (rEpo) has been recently shown to increase tumour oxygenation in a mammary carcinoma model. The mechanism of this action is not yet understood completely. The presence of Epo and its receptor (EpoR) have been demonstrated on several normal and neoplastic tissues, including blood vessels and various solid tumours. In addition, rEpo has been shown in two recent prospective, randomized clinical trials to negatively impact treatment outcome. In this study, we attempt to characterize the direct effects of rEpo on tumour growth and angiogenesis in two separate rodent carcinomas. The effect of rEpo on R3230 rat mammary adenocarcinomas, CT-26 mouse colon carcinomas, HCT-116 human colon carcinomas, and FaDu human head and neck tumours, all of which express EpoR, was examined. There were no differences in tumour growth or proliferation (measured by Ki-67) between placebo-treated and rEpo-treated tumours. In the mammary window chamber, vascular length density (VLD) measurements in serial images of both placebo-treated and Epo-treated rats revealed no difference in angiogenesis between the Epo-treated tumours and placebo-treated tumours at any time point. These experiments are important because they suggest that the recent clinical detriment seen with the use of Epo is not due to its tumour growth effects or angiogenesis. These studies also suggest that further preclinical studies need to examine rEpo's direct tumour effects in efforts to improve the therapeutic benefits of Epo in solid tumour patients.

Ultrasound guided pO2 measurement of breast cancer reoxygenation after neoadjuvant chemotherapy and hyperthermia treatment.

The objective of this study was to determine whether neoadjuvant chemotherapy in combination with hyperthermia (HT) would improve oxygenation in locally advanced breast tumours. The study describes a new optimized ultrasound guided technique of pO2 measurement using Eppendorf polarographic oxygen probes in 18 stage IIB-III breast cancer patients. Prior to treatment, tumour hypoxia (median pO2<10 mmHg) was present in 11/18 patients (average median pO2=3.2 mmHg). Seven patients had well oxygenated tumours (median pO2 of 48.3 mmHg). Eight patients with hypoxic tumours prior to treatment had a significant improvement (p=0.0008) in tumour pO2 after treatment (pO2 increased to 19.2 mmHg). In three patients, tumours remained hypoxic (average median pO2=4.5 mmHg). The advantages of the ultrasound guided pO2 probe are in the accuracy of the Eppendorf electrode placement in tumour tissue, the ability to monitor electrode movement through the tumour tissue during the measurement and the ability to avoid electrode placement near or in large blood vessels by using colour Doppler imaging. The results of this preliminary study suggest that the combination of neoadjuvant chemotherapy and hyperthermia improves oxygenation in locally advanced breast tumours that are initially hypoxic.

Tamoxifen inhibits angiogenesis in estrogen receptor-negative animal models.

Inhibition of tumor angiogenesis is a therapeutic strategy that can inhibit tumor growth and metastases. The aim of this study was to determine whether the estrogen receptor (ER) ligand drug tamoxifen has antiangiogenic effects. We used three different models of angiogenesis, including measurement of microvessel densities in murine tumors, ex vivo aortic ring assays, and corneal pocket assays. ER-negative fibrosarcoma tumors in tamoxifen-treated ovariectomized rats had significantly less vessel formation compared with untreated animals (median microvessel density, 53.6 versus 94.3 counts/per x 200 field; P = 0.002). Rat aortic rings treated with tamoxifen at several different concentrations demonstrated significantly less vascular sprouting than control rings (P = 0.0001). Corneal pocket assays performed in tamoxifen-treated rats compared with control and estrogen-treated rats demonstrated decreased vascular length (0.88 mm versus 1.26 mm versus 1.47 mm; P = 0.022) and vessel area (21% versus 34% versus 47%; P = 0.018). These three animal models all showed significant inhibition of angiogenesis by tamoxifen and suggest a possible contributory mechanism of ER-independent manipulation by tamoxifen in the treatment and prevention of breast cancer. These studies raise the question as to whether or not newer ER ligand drugs might possess even more potent antiangiogenic effects, which in turn could lead to the broadening of the clinical usefulness of these compounds in a number of diseases. More importantly, these studies suggest that the antiangiogenic effects of tamoxifen are due, in part, to ER-independent mechanisms.

Combining prostate specific antigen with cancer and gland volume to predict more reliably pathological stage: the influence of prostate specific antigen cancer density.

The serum prostate specific antigen (PSA) level was determined in 311 men with documented prostate cancer (stages T1cN0, T2N0 and T3N0) before bilateral pelvic lymphadenectomy and radical retropubic prostatectomy. The prostates were whole mounted, serially sectioned, and examined for cancer volume, capsular perforation, seminal vesicle invasion, lymph node involvement, Gleason grade, nuclear grade and nuclear deoxyribonucleic acid content. Median serum PSA level was significantly different between cancers that were organ confined, those that had capsular perforation or seminal vesicle invasion and those with positive lymph nodes (p < 0.001). Median serum PSA level was also significantly different between tumors with Gleason scores of less than 6 and those with higher Gleason scores (p < 0.001), and between tumors with greater than 30% of poorly differentiated cancer (Gleason primary grades 4 and 5) and those with 30% or less poorly differentiated cancer (p < 0.001). Bivariate analysis revealed that the strongest correlations of serum PSA level were with cancer volume (r = 0.56), per cent of poorly differentiated cancer (r = 0.42), positive surgical margins (r = 0.39) and pathological stage (r = 0.38), for all p < 0.001. Multivariate analysis showed that cancer volume was the major contributor to serum PSA level. The derivative, PSA-cancer density (serum PSA times cancer volume divided by prostate volume), accounted for the effects of prostate volume and cancer volume on serum PSA. PSA-cancer density showed a significant correlation with pathological stage (r = 0.56), Gleason score (r = 0.53) and per cent of poorly differentiated cancer (r = 0.49, for all p < 0.001), and these correlations were significantly stronger than serum PSA level alone or PSA density (serum PSA divided by prostate volume; volume determined from tissue specimens) for all variables. These results indicate that preoperative serum PSA level has significant predictive value in determining tumor burden and pathological stage, and this predictive value is increased by accounting for cancer and gland volume with PSA-cancer density.

A clinical comparison of Grason Stadler insert earphones and TDH-50P standard earphones.

Recent investigations have reported numerous advantages of insert earphones. However, no data have been reported regarding Grason Stadler (GS) insert earphones. The purpose of this investigation was to compare results obtained using the GS insert earphone to those obtained using a standard earphone on pure-tone thresholds, ipsilateral effective masking levels, and an estimate of interaural attenuation. Twenty-seven normal-hearing listeners participated. Pure-tone thresholds and ipsilateral effective masking levels obtained were not significantly different for the two transducers. However, the GS insert earphones yielded significantly greater interaural attenuation.