Jacques Bonneterre

A phase two randomised trial of neratinib monotherapy versus lapatinib plus capecitabine combination therapy in patients with HER2+ advanced breast cancer

BACKGROUND The safety and efficacy of neratinib monotherapy were compared with that of lapatinib plus capecitabine in patients with human epidermal growth factor receptor-2-positive (HER2+), locally advanced/metastatic breast cancer and prior trastuzumab treatment. METHODS Patients received neratinib 240 mg/d continuously (n=117) or lapatinib 1250 mg/d continuously plus capecitabine 2000 mg/m(2) per day on days 1-14 of each 21-d cycle (n=116). The primary aim was to demonstrate non-inferiority of neratinib for progression-free survival (PFS). FINDINGS The non-inferiority of neratinib was not demonstrated when compared with lapatinib plus capecitabine (hazard ratio, 1.19; 95% confidence interval, 0.89-1.60; non-inferiority margin, 1.15). Median PFS for neratinib was 4.5 months versus 6.8 months for lapatinib plus capecitabine and median overall survival was 19.7 months versus 23.6 months. Objective response rate (neratinib, 29% versus lapatinib plus capecitabine, 41%; P=0.067) and clinical benefit rate (44% versus 64%; P=0.003) were lower for the neratinib arm but consistent with previously reported results. In both treatment arms, diarrhoea was the most frequently reported treatment-related adverse event of any grade (neratinib, 85% versus lapatinib plus capecitabine, 68%; P=0.002) and of grade 3/4 (28% versus 10%; P<0.001), but was typically managed with concomitant anti-diarrhoeal medication and/or study treatment modification. Importantly, neratinib had no significant skin toxicity. INTERPRETATION The results are considered as inconclusive since neither inferiority nor non-inferiority of treatment with neratinib versus lapatinib plus capecitabine could be demonstrated. The study confirmed relevant single-agent clinical activity and acceptable overall tolerability of neratinib in patients with recurrent HER2+ advanced breast cancer.

A randomized controlled phase II trial of a novel composition of paclitaxel embedded into neutral and cationic lipids targeting tumor endothelial cells in advanced triple-negative breast cancer (TNBC)

BACKGROUND EndoTAG-1, composed of paclitaxel embedded in liposomal membranes targeting tumor endothelial cells, was evaluated for safety and efficacy in advanced triple-negative breast cancer (TNBC). PATIENTS AND METHODS One hundred and forty patients were treated with weekly EndoTAG-1 (22 mg/m(2)) plus paclitaxel (70 mg/m(2)), twice weekly EndoTAG-1 (2× 44 mg/m(2)), or weekly paclitaxel (90 mg/m(2)) for greater than or equal to four cycles (3-week treatment + 1-week rest) or until progression/toxicity. Primary end point was progression-free survival (PFS) rate evaluated centrally after four cycles of therapy (week 16). The study was not powered for intergroup comparisons. RESULTS The PFS rate at week 16 was 59.1% [one-sided 95% CI: 45.6, ∞] on combination treatment, 34.2% [21.6, ∞] on EndoTAG-1, and 48.0% [30.5, ∞] on paclitaxel. Median PFS reached 4.2, 3.4, and 3.7 months, respectively. After complete treatment (week 41 analysis), median overall survival (OS) was 13.0, 11.9, and 13.1 months for the modified Intention-to-Treat (ITT) population and 15.1, 12.5, and 8.9 months for the per-protocol population, respectively. The clinical benefit rate was 53%, 31%, and 36% for the treatment groups. Safety analysis revealed known toxicities of the drugs with slight increases of grade 3/4 neutropenia on combination therapy. CONCLUSION Treatment of advanced TNBC with a combination of EndoTAG-1 and standard paclitaxel [Taxol® (Bristol-Myers Squibb GmbH), or equivalent generic formulation] was well tolerated and showed antitumor efficacy. The positive trend needs to be confirmed in a randomized phase III trial. STUDY REGISTRATION European Clinical Trials Database: EudraCT number 2006-002221-23. ClinicalTrials.gov identifier: NCT00448305.BACKGROUND EndoTAG-1, composed of paclitaxel embedded in liposomal membranes targeting tumor endothelial cells, was evaluated for safety and efficacy in advanced triple-negative breast cancer (TNBC). PATIENTS AND METHODS One hundred and forty patients were treated with weekly EndoTAG-1 (22 mg/m2) plus paclitaxel (70 mg/m2), twice weekly EndoTAG-1 (2× 44 mg/m2), or weekly paclitaxel (90 mg/m2) for greater than or equal to four cycles (3-week treatment + 1-week rest) or until progression/toxicity. Primary end point was progression-free survival (PFS) rate evaluated centrally after four cycles of therapy (week 16). The study was not powered for intergroup comparisons. RESULTS The PFS rate at week 16 was 59.1% [one-sided 95% CI: 45.6, ∞] on combination treatment, 34.2% [21.6, ∞] on EndoTAG-1, and 48.0% [30.5, ∞] on paclitaxel. Median PFS reached 4.2, 3.4, and 3.7 months, respectively. After complete treatment (week 41 analysis), median overall survival (OS) was 13.0, 11.9, and 13.1 months for the modified Intention-to-Treat (ITT) population and 15.1, 12.5, and 8.9 months for the per-protocol population, respectively. The clinical benefit rate was 53%, 31%, and 36% for the treatment groups. Safety analysis revealed known toxicities of the drugs with slight increases of grade 3/4 neutropenia on combination therapy. CONCLUSION Treatment of advanced TNBC with a combination of EndoTAG-1 and standard paclitaxel [Taxol® (Bristol-Myers Squibb GmbH), or equivalent generic formulation] was well tolerated and showed antitumor efficacy. The positive trend needs to be confirmed in a randomized phase III trial. STUDY REGISTRATION European Clinical Trials Database: EudraCT number 2006-002221-23. ClinicalTrials.gov identifier: NCT00448305.

Febrile neutropenia incidence and hematological toxicity with the FEC100-docetaxel regimen in the treatment of early-stage breast cancer

BACKGROUND Chemotherapy for the treatment of early-stage breast cancer (ESBC) patients improves survival outcomes. However, its most common acute toxicity is myelosuppression, which can reduce the delivered dose and compromise the survival benefit. Because FEC100-docetaxel (FEC100-D) is a common protocol for ESBC, we evaluated its febrile neutropenia (FN) incidence and the role of its hematological toxicity on the individual relative dose-intensity (RDI). PATIENTS AND METHODS It is a French single-center, observational, retrospective study. Patients received adjuvant/neoadjuvant FEC100-D treatment, without primary prophylaxis by granulocyte colony-stimulating factors (G-CSF). The neutrophil count the day before the planned chemotherapy cycle had to be over 1,500.mm(-3) for the treatment to be administered. Data collected included: date and dose of chemotherapy cycles, FN and high grade of hematological toxicity occurrence for each course, G-CSF prescription. RESULTS One thousand, seven hundred and fifty-seven cycles in 284 patients were delivered. FN was observed in 4.9% (n = 14) of the patients, without hospitalizations or deaths after. Grade 3-4 neutropenia occurred in 5.8% of the cycles, during the first cycle in 40% of cases. Seventeen percent of our patients received less than 85% of RDI. CONCLUSION The hematotoxicity of this treatment is acceptable. The risk of FN is low. No G-CSF primary prophylaxis is needed without additional risk factor.

The Quality of Life of Young Women with Nonmetastatic Breast Cancer and their Partners’: Specific Needs Require Development of Specific Questionnaires for Each of them

To the Editor: In developed countries, approximately 13% of women with breast cancer are younger than 45 years of age. Improved therapy in expectation of cure highlights these young women’s specific problems (1,2). These, like the wish to have children, are sometimes incompatible with the treatments. Furthermore, children’s education, family responsibilities, sexuality, marital relationship, body image, and professional activity are also sources of concern. Some studies seem to indicate that young women (< 45–50 years) have a worse quality of life and are more vulnerable to the negative effects of the disease than older ones (3–5). Patients are in search of social and emotional support which is most frequently provided by a member of the family and particularly the partner (6). Life and daily tasks can be upset. This correlates directly and ⁄ or indirectly with depression, anxiety and the physical state of health called ‘‘subjective burden’’ (7). The deterioration of the quality of life and sexual problems in women with breast cancer can affect the marital relationship. This can result in a break up of married life, especially if marital difficulties were present previously. On the other hand, it can bring the couple closer. Thus, it appears essential for women with breast cancer to involve their partner (8,9). The objectives of the study were to measure the impact of breast cancer on the quality of life of young women (< 45 years of age) with nonmetastatic disease and the quality of life of their partners; to study the convergent and ⁄ or divergent points between the patients and partners in the course of treatment; and to create specific tools to deal with these issues. The psychological, emotional, family, and social effects of cancer on the patient and her partner were analyzed by the verbatim of nondirective talks. Patients younger than 45 years of age at the time of the diagnosis, with nonmetastatic breast cancer, in treatment by chemotherapy and their partner ⁄ spouse took part. Each couple must have been living together for at least 6 months. Open conversations, without directive questions, were conducted by expert psychologists. From February 2007 to June 2008, 69 couples were interviewed: 24 during chemotherapy, 11 during Trastuzumab treatment, 15 during hormonotherapy and 19 during follow up. The patients’ median age was 39 (range: 27–52) and 41 (range: 28–60) for the partners. The couple per se and the psychological dimensions were specifically mentioned by, respectively, 79% and 78% of the participants. Family matters were raised by 64%, and 51% mentioned professional and physical repercussions. Forty three percent, 24%, and 12% spoke of, respectively, social, domestic, and economic spheres. However, spiritual and medical aspects were under represented (less than 5% of the participants). The analysis of the subjective quality of life of the patient compared with the partner’s showed significant differences in five areas: the patients spoke more often about the psychological, familial, physical, professional and social impact than their partners (p < 0.05) (Fig. 1). Globally, the subjective feelings were comparable between the treatment periods (chemotherapy, Trastuzumab, hormonal therapy, and follow up). Nevertheless, Address correspondence and reprint request to: Dr. Laurence Vanlemmens, MD, 3 rue Frederic Combemale, BP 307, F-59020 Lille Cedex, or e-mail: l-vanlemmens@o-lambret.fr. Proposed by Medical Centre Oscar Lambret Supported by the Institut National Contre le Cancer, Ligue Nationale Contre le Cancer, Roche, Novartis Pharma, and Sanofi-Aventis, France

Development of a technique to detect the activated form of the progesterone receptor and correlation with clinical and histopathological characteristics of endometrioid adenocarcinoma of the uterine corpus

OBJECTIVE Hormonal therapy is generally reserved for patients with endometrial cancers that fail cytotoxic chemotherapy, but there is a lack of sufficiently sensitive diagnostics to identify potential responders. We sought to develop a diagnostic technique to detect activated progesterone receptors (APR) in endometrial cancers using routine immunohistochemistry (IHC) and to correlate the presence of APR with other histopathological features and clinical disease stage. METHODS Seventy-two tumor block specimens from patients with endometrial cancer were processed with conventional IHC methods for estrogen receptor-α (ERα), progesterone receptor (PR) and Ki67, a marker of proliferation. Tumor specimens were analyzed for the PR nuclear distribution patterns in individual tumor cells: APR positive (APR(pos)) tumors were prospectively defined as any tumor with >5% countable malignant cells with an aggregated nuclear pattern. Tumor APR status was analyzed against other biomarkers including ERα expression, Ki67 and tumor grade. RESULTS Fifty-six of 72 samples were endometrioid. Twenty-six of 49 PR-positive endometrioid tumors (53%; 95% CI 39-67%) were APR(pos). Percent of ER(pos) cells correlated with % PR(pos) malignant cells (p=0.001, rho=0.44). APR positivity did not correlate with % PR(pos) cells in a given tumor, nor did it correlate with % Ki67 positivity; APR positivity was independent of disease stage and tumor grade (p=NS). CONCLUSIONS In this study, approximately half of endometrioid tumors were APR(pos). APR is independent of histopathological and other known risk factors. Refining conventional PR detection has the potential to prospectively identify patients with endometrial cancer who may benefit from anti-progestin therapy.

Tumour and cellular distribution of activated forms of PR in breast cancers: a novel immunohistochemical analysis of a large clinical cohort

Background The progesterone receptor (PR) is expressed by ∼70% of early breast tumours and is implicated in the progression of breast cancer. In cancerous tissues PR may be activated in the absence of a ligand, or when ligand concentrations are very low, resulting in aberrantly activated PR (APR). The presence of APR may indicate that patients with breast cancer are more likely to respond to antiprogestins. The aims of this study were to describe and classify the histological subnuclear morphology of active and inactive PR in archival breast cancer samples. Methods Archived tumour specimens from 801 women with invasive breast cancer were collected. Tissue samples (n=789) were analysed for PR isoforms A and B (PRA and PRB), Ki67 and estrogen receptors (ERα) status, using immunohistochemistry. Medical records were used to determine human epidermal growth factor 2 (HER2) status, tumour stage and grade. Results A total of 79% of tumours stained positive for either PRA or PRB, and of these 25% of PRA-positive and 23% of PRB-positive tumours had PR present in the activated form. APRA was associated with higher tumour grade (p=0.001). APRB was associated with a higher tumour grade (p=0.046) and a trend for a more advanced stage. Patients with PR-positive tumours treated with antiestrogens had better disease-free survival (DFS) than those with PR-negative tumours (p<0.0001). Cumulative progression rate and DFS were similar irrespective of APR status. Both APRA and APRB were independent of HER2, ERα and Ki67 expression. Conclusions APR had a binary mode of expression in the breast cancer specimens tested, allowing separation into two tumour subsets. APR is an independent target at the cellular and tumour level and may therefore be a suitable predictive marker for antiprogestins, such as onapristone. Using the described technique, a companion diagnostic is under development to identify APR in solid tumours.

P3-17-06: Final Results of a Controlled, Randomized 3-Arm Phase II Trial of EndoTAG”-1, a Cationic Liposomal Formulation of Paclitaxel Targeting Tumor Endothelial Cells, in Advanced Triple-Negative Breast Cancer (TNBC).

Background EndoTAG™-1 (ET) is an innovative therapy of paclitaxel (P) embedded in cationic liposomes displaying antitumor activity by targeting negatively charged activated endothelial cells of tumor vessels. Methods: 140 patients (pts) with locally relapsed (r) or metastatic (m) centrally verified TNBC were randomized to i.v. weekly ET (22mg/m2 ) plus P (70mg/m2) (ET+P), biweekly ET alone (44mg/m2) or weekly P (90mg/m2) in a 2:2:1 ratio. Pts had ≤ 1 prior chemotherapy (CT) for r or m disease and ≥ 6 months (mo) after taxane. A cycle (cy) comprised 3 weeks(w) of therapy and 1 w rest. Pts were treated for a minimum of 4 cy or until disease progression/unacceptable toxicity. Primary endpoint was progression-free survival (PFS) rate at week 16 based on blinded central imaging and local assessment. Secondary endpoints included median overall survival (mOS), tumor response (RECIST), Quality of Life (QoL) and safety. The study was not powered for intergroup comparisons. Results: Pts baseline characteristics were overall well distributed. Appr. 80% of all pts were treated 1st line for r or m TNBC. Results of PFS rates at week 16 are shown in table. Based on central review, median PFS at week 16 was 4.2 mo for ET+P [95% CI: 3.5−9.1], 3.4 on ET [2.0−3.8] and 3.7 on P [1.9−6.7]. Antitumor activity was highest for ET+P with a clinical benefit rate (complete response (CR) + partial response (PR) + stable disease (SD) ≥6 mo at data cut off date of week 41) of 53% (26/49 evaluable pts), 31% (15/49) on ET and 36% (9/25) on P. The best overall response (CR, PR, SD at any time) on ET+P was 80% (39/49), on ET 65% (32/49) and 68% (17/25) on P. Analysis of median OS is shown in table. Analysis of the not predefined subgroup (centrally TNBC + ECOG 0/1 + first line population) showed an impressive median OS of 17.8 mo for ET+P. No differences were reported for QoL. No additional toxicities to those known for ET and P were observed except uncomplicated grade 3/4 neutropenia in the ET + P arm. Conclusions: At cut-off date week 41, the final analysis demonstrated ET+P as a promising combination compared to single agent arms. ET+P was well tolerated. These data will be the basis for a confirmatory phase III study. Acknowlegments: B. Glasschroeder, U. Elsasser Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-17-06.