Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study.

BACKGROUND: Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer at the second interim analysis, however follow-up was limited. Here, we present results of the prespecified primary outcome analysis and an additional follow-up analysis. PATIENTS AND METHODS: This global, phase III, open-label trial randomized (1 : 1) 5637 patients to adjuvant ET for ≥5 years ± abemaciclib for 2 years. Cohort 1 enrolled patients with ≥4 positive axillary lymph nodes (ALNs), or 1-3 positive ALNs and either grade 3 disease or tumor ≥5 cm. Cohort 2 enrolled patients with 1-3 positive ALNs and centrally determined high Ki-67 index (≥20%). The primary endpoint was IDFS in the intent-to-treat population (cohorts 1 and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety. RESULTS: At the primary outcome analysis, with 19 months median follow-up time, abemaciclib + ET resulted in a 29% reduction in the risk of developing an IDFS event [hazard ratio (HR) = 0.71, 95% confidence interval (CI) 0.58-0.87; nominal P = 0.0009]. At the additional follow-up analysis, with 27 months median follow-up and 90% of patients off treatment, IDFS (HR = 0.70, 95% CI 0.59-0.82; nominal P < 0.0001) and DRFS (HR = 0.69, 95% CI 0.57-0.83; nominal P < 0.0001) benefit was maintained. The absolute improvements in 3-year IDFS and DRFS rates were 5.4% and 4.2%, respectively. Whereas Ki-67 index was prognostic, abemaciclib benefit was consistent regardless of Ki-67 index. Safety data were consistent with the known abemaciclib risk profile. CONCLUSION: Abemaciclib + ET significantly improved IDFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer, with an acceptable safety profile. Ki-67 index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Overall, the robust treatment benefit of abemaciclib extended beyond the 2-year treatment period.

Final efficacy and updated safety results of the randomized phase III BEATRICE trial evaluating adjuvant bevacizumab-containing therapy in triple-negative early breast cancer.

BACKGROUND: The purpose of this analysis was to assess the long-term impact of adding bevacizumab to adjuvant chemotherapy for early triple-negative breast cancer (TNBC). METHODS: Patients eligible for the open-label randomized phase III BEATRICE trial had centrally confirmed triple-negative operable primary invasive breast cancer (pT1a-pT3). Investigators selected anthracycline- and/or taxane-based chemotherapy for each patient. After definitive surgery, patients were randomized 1:1 to receive ≥4 cycles of chemotherapy alone or with 1 year of bevacizumab (5 mg/kg/week equivalent). Stratification factors were nodal status, selected chemotherapy, hormone receptor status, and type of surgery. The primary end point was invasive disease-free survival (IDFS; previously reported). Secondary outcome measures included overall survival (OS) and safety. RESULTS: After 56 months' median follow-up, 293 of 2591 randomized patients had died. There was no statistically significant difference in OS between treatment arms in either the total population (hazard ratio 0.93, 95% confidence interval [CI] 0.74-1.17; P = 0.52) or pre-specified subgroups. The 5-year OS rate was 88% (95% CI 86-90%) in both treatment arms. Updated IDFS results were consistent with the primary IDFS analysis. Five-year IDFS rates were 77% (95% CI 75-79%) with chemotherapy alone versus 80% (95% CI 77-82%) with bevacizumab. From 18 months after first study dose to study end, new grade ≥3 adverse events occurred in 4.6% and 4.5% of patients in the two arms, respectively. CONCLUSION: Final OS results showed no significant benefit from bevacizumab therapy for early TNBC. Late-onset toxicities were rare in both groups. Five-year OS and IDFS rates suggest that the prognosis for patients with TNBC is better than previously thought. CLINICALTRIALS.GOV: NCT00528567.

A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4).

Background: Phosphatidylinositol 3-kinase (PI3K) pathway activation in preclinical models of breast cancer is associated with tumor growth and resistance to anticancer therapies, including paclitaxel. Effects of the pan-Class I PI3K inhibitor buparlisib (BKM120) appear synergistic with paclitaxel in preclinical and clinical models. Patients and methods: BELLE-4 was a 1:1 randomized, double-blind, placebo-controlled, adaptive phase II/III study investigating the combination of buparlisib or placebo with paclitaxel in women with human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer with no prior chemotherapy for advanced disease. Patients were stratified by PI3K pathway activation and hormone receptor status. The primary endpoint was progression-free survival (PFS) in the full and PI3K pathway-activated populations. An adaptive interim analysis was planned following the phase II part of the study, after ≥125 PFS events had occurred in the full population, to decide whether the study would enter phase III (in the full or PI3K pathway-activated population) or be stopped for futility. Results: As of August 2014, 416 patients were randomized to receive buparlisib (207) or placebo (209) with paclitaxel. At adaptive interim analysis, there was no improvement in PFS with buparlisib versus placebo in the full (median PFS 8.0 versus 9.2 months, hazard ratio [HR] 1.18), or PI3K pathway-activated population (median PFS 9.1 versus 9.2 months, HR 1.17). The study met protocol-specified criteria for futility in both populations, and phase III was not initiated. Median duration of study treatment exposure was 3.5 months in the buparlisib arm versus 4.6 months in the placebo arm. The most frequent adverse events with buparlisib plus paclitaxel (≥40% of patients) were diarrhea, alopecia, rash, nausea, and hyperglycemia. Conclusions: Addition of buparlisib to paclitaxel did not improve PFS in the full or PI3K pathway-activated study population. Consequently, the trial was stopped for futility at the end of phase II.

Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA).

BACKGROUND: Pertuzumab (P) combined with trastuzumab (H)-based chemotherapy improves efficacy in early and advanced HER2-positive breast cancer. We assessed the tolerability, with particular focus on cardiac safety, of H and P with chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer. PATIENTS AND METHODS: In this multicenter, open-label phase II study, patients with operable, locally advanced, or inflammatory breast cancer were randomized 1 : 1 : 1 to receive six neoadjuvant cycles q3w (Arm A: 5-fluorouracil, epirubicin, cyclophosphamide [FEC] + H + P ×3 → docetaxel [T] + H + P ×3; Arm B: FEC ×3 → T + H + P ×3; Arm C: T + carboplatin + H [TCH]+P ×6). pCR was assessed at surgery and adjuvant therapy given to complete 1 year of H. RESULTS: Two hundred twenty-five patients were randomized. During neoadjuvant treatment, two patients (2.7%; Arm B) experienced symptomatic left ventricular systolic dysfunction (LVSD) and 11 patients (Arm A: 4 [5.6%]; Arm B: 4 [5.3%]; Arm C: 3 [3.9%]) had declines in left ventricular ejection fraction of ≥10% points from baseline to <50%. Diarrhea was the most common adverse event. pCR (ypT0/is) was reported for 61.6% (Arm A), 57.3% (Arm B), and 66.2% (Arm C) of patients. CONCLUSION: The combination of P with H and standard chemotherapy resulted in low rates of symptomatic LVSD.

Effect of neoadjuvant chemotherapy on low-density lipoprotein (LDL) receptor and LDL receptor-related protein 1 (LRP-1) receptor in locally advanced breast cancer

Low-density lipoprotein (LDL) receptors are overexpressed in most neoplastic cell lines and provide a mechanism for the internalization and concentration of drug-laden nanoemulsions that bind to these receptors. The aim of the present study was to determine whether the administration of standard chemotherapeutic schemes can alter the expression of LDL and LDL receptor-related protein 1 (LRP-1) receptors in breast carcinoma. Fragments of tumoral and normal breast tissue from 16 consecutive volunteer women with breast cancer in stage II or III were obtained from biopsies before the beginning of neoadjuvant chemotherapy and after chemotherapy, from fragments excised during mastectomy. Tissues were analyzed by immunohistochemistry for both receptors. Because complete response to treatment was achieved in 4 patients, only the tumors from 12 were analyzed. Before chemotherapy, there was overexpression of LDL receptor in the tumoral tissue compared to normal breast tissue in 8 of these patients. LRP-1 receptor overexpression was observed in tumors of 4 patients. After chemotherapy, expression of both receptors decreased in the tumors of 6 patients, increased in 4 and was unchanged in 2. Nonetheless, even when chemotherapy reduced receptors expression, the expression was still above normal. The fact that chemotherapy does not impair LDL receptors expression supports the use of drug carrier systems that target neoplastic cells by the LDL receptor endocytic pathway in patients on conventional chemotherapy.

Effect of neoadjuvant chemotherapy on low-density lipoprotein (LDL) receptor and LDL receptor-related protein 1 (LRP-1) receptor in locally advanced breast cancer.

Low-density lipoprotein (LDL) receptors are overexpressed in most neoplastic cell lines and provide a mechanism for the internalization and concentration of drug-laden nanoemulsions that bind to these receptors. The aim of the present study was to determine whether the administration of standard chemotherapeutic schemes can alter the expression of LDL and LDL receptor-related protein 1 (LRP-1) receptors in breast carcinoma. Fragments of tumoral and normal breast tissue from 16 consecutive volunteer women with breast cancer in stage II or III were obtained from biopsies before the beginning of neoadjuvant chemotherapy and after chemotherapy, from fragments excised during mastectomy. Tissues were analyzed by immunohistochemistry for both receptors. Because complete response to treatment was achieved in 4 patients, only the tumors from 12 were analyzed. Before chemotherapy, there was overexpression of LDL receptor in the tumoral tissue compared to normal breast tissue in 8 of these patients. LRP-1 receptor overexpression was observed in tumors of 4 patients. After chemotherapy, expression of both receptors decreased in the tumors of 6 patients, increased in 4 and was unchanged in 2. Nonetheless, even when chemotherapy reduced receptors expression, the expression was still above normal. The fact that chemotherapy does not impair LDL receptors expression supports the use of drug carrier systems that target neoplastic cells by the LDL receptor endocytic pathway in patients on conventional chemotherapy.

Uptake by breast carcinoma of a lipidic nanoemulsion after intralesional injection into the patients: a new strategy for neoadjuvant chemotherapy.

OBJECTIVE: Previously we showed that after intravenous injection a lipidic nanoemulsion concentrates in breast carcinoma tissue and other solid tumors and may carry drugs directed against neoplastic tissues. Use of the nanoemulsion decreases toxicity of the chemotherapeutic agents without decreasing the anticancer action. Currently, the hypothesis was tested whether the nanoemulsion concentrates in breast carcinoma tissue after locoregional injection. METHODS: Three different techniques of injection of the nanoemulsion were tested in patients scheduled for surgical treatment: G1 (n=4) into the mammary tissue 5 cm away from the tumor; G2 (n=4) into the peritumoral mammary tissue; G3 (n=6) into the tumoral tissue. The nanoemulsion labeled with radioactive cholesteryl oleate was injected 12 h before surgery; plasma decay of the label was determined from blood samples collected over 24 h and the tissue fragments excised during the surgery were analyzed for radioactivity uptake. RESULTS: Among the three nanoemulsion injection techniques, G3 showed the greatest uptake (data expressed in c.p.m/g of tissue) by the tumor (44,769+/-54,749) and by the lymph node (2356+/-2966), as well as the greatest concentration in tumor compared to normal tissue (844+/-1673). In G1 and G2, uptakes were, respectively, tumor: 60+/-71 and 843+/-1526; lymph node: 263+/-375 and 102+/-74; normal tissue: 139+/-102 and 217+/-413. CONCLUSIONS: Therefore, with intralesional injection of the nanoemulsion, a great concentration effect can be achieved. This injection technique may be thus a promising approach for drug-targeting in neoadjuvant chemotherapy in breast cancer treatment.

A phase II trial of fractionated vinorelbine/doxorubicin as first-line therapy for advanced breast cancer.

In western countries breast cancer is still the leading cause of death of women. Very promising results have been obtained by combining vinorelbine and doxorubicin, two of the most active drugs in metastatic breast cancer. However, despite the activity reported, this combination has shown a 10% rate of grade 2-4 cardiac toxicity, mainly due to the total cumulative doses of anthracycline delivered. The aim of this study was to divide the total dose of doxorubicin into two administrations on days 1 and 8, in order to cut down its toxicity while maintaining the same activity. Fifty-two chemotherapy naïve patients with metastatic breast cancer entered into the study and were treated with vinorelbine 25 mg/m2 plus doxorubicin 25 mg/m2 both on days 1 and 8 every three weeks. Fifty-one patients were eligible and evaluable for toxicity while 47 of them were evaluable for activity. Haematological toxicity was predominantly related to neutropenia, with grade 3/4 in 16% of cycles. Non-haematological toxicity was represented by alopecia grade 3 (which affected 65% of the patients), local phlebitis and severe constipation. No clinically significant cases of neuropathy or cardiac dysfunction were seen. With regard to activity, 38 out of 47 patients (80%) responded to therapy, nine of them achieving complete responses (19%). Median response duration was 16 months and the median overall survival was 22.7 months. We conclude that the fractionated administration of vinorelbine and doxorubicin is associated with excellent haematological and non-haematological tolerability (especially as regards cardiac toxicity), coupled with high levels of activity comparable to those observed using regimens based on unfractionated administration of treatment.

Visible-band testbed projector with a replicated diffractive optical element.

Raytheon has designed, fabricated, and tested a diffractive-optical-element-based (DOE-based) testbed projector for direct and indirect visual optical applications. By use of a low-cost replicated DOE surface from Rochester Photonics Corporation for color correction the projector optics bettered the modular transfer function of an equivalent commercial camera lens. The testbed demonstrates that a practical DOE-based optical system is suitable for both visual applications (e.g., head-mounted displays) and visual projection (e.g., tactical sensors). The need for and the proper application of DOE's in visual optical systems, the nature and the performance of the projector optical design, and test results are described.

Phase II trial of weekly i.v. vinorelbine as a single agent in first-line advanced breast cancer chemotherapy. The Latin-American experience.

This study investigated the therapeutic effect of single-agent i.v. weekly Navelbine (vinorelbine), a semisynthetic vinca alkaloid, in women who had received no prior treatment for locally advanced or metastatic breast cancer. Of 68 patients entered into the study, 63 were adequate inclusions, assessable for toxicity and response by WHO criteria; the 5 patients who were not evaluated were excluded from analysis because they were found not to meet the eligibility criteria of the study. Navelbine was given as a weekly 30 mg/m2 short i.v. (20 minutes) infusion; treatment was continued until disease progression. The overall response rate was 44% (complete response 8%, partial response 36%). The response rate according to target was lymph nodes, 62.9%; liver, 50.0%; lung, 50.0%; skin, 37.5%; and primary tumor, 30.8%. The median duration of response was 17.9 weeks (range: 7-52 weeks). The median time to treatment failure was 12.9 weeks, and the median survival was 50.3 weeks. The 63 eligible patients received 501 cycles. The mean dose intensity was 76%. At least one episode of WHO grade 3/4 granulocytopenia was seen in 46% of the patients (13.6% of cycles). Significant nausea/vomiting was seen in only 5% of patients corresponding to 1% of cycles. Only 5% of patients developed WHO grade 3-4 constipation and grade 3 peripheral neuropathy was observed in 1.6% of patients. Alopecia was rare (6.3% of patients), and other side effects were uncommon. This study confirms that Navelbine has major single-agent antitumor activity as frontline therapy in advanced breast cancer. Given its excellent tolerance profile and low morbidity, it should be recommended for inclusion in first-line combination chemotherapy regimens.

Breast cancer control programme in developing countries.

Breast cancer is a very important health problem in developing countries, where its incidence has increased in the last decades. Mortality rates due to breast cancer have also increased, and the main reason for this is late diagnosis. The authors demonstrate that organizing programmes for early breast cancer detection is possible by making use of simple resources. A set of tiered interventions is proposed, stratified in levels of complexity: Level 1--Identification of abnormal breast by health professionals; Level 2--Medical assistance to women whose breast is considered abnormal, in order to diagnose and treat benign diseases and recognize suspect cases of cancer; Level 3--Management of the women with suspected or diagnosed breast cancer by a multidisciplinary team. Therefore, a proposal for wide action for breast cancer control in developing countries is presented.

PIP: The incidence of breast cancer is increasing and is a major cause of death in women worldwide. This may be explained, in part, by the growing percentage of older women who constitute the main age group with increased risk for breast cancer development. This article reports on the authors' efforts to correct two misconceptions about breast cancer and to address the public health issues in developing countries. The misconceptions are that breast cancer is not a relevant public health problem and that a health program would require high technology and be very costly. In developing countries, the female mortality rates are increasing, as is the incidence of breast cancer. Late diagnosis is believed to be a significant mortality factor. Existing diagnostic techniques used are clinical examinations, either physical or self-exam, and instrumental examination. Clinical methods are reasonably sensitive, inexpensive, and simple. Cultural aspects and taboos can be a problem. Choice of what methods or combination of methods to use in a health care program is determined by the level of medical experience, local economy, and cultural constraints. Health education plays an important role in any prevention program. Three levels are suggested in a program. Level 1 aims to educate the entire population serviced. Level 2 tries to assist women during diagnosis and treatment of benign nodules. Level 3 is for the care of suspected or confirmed cancer patients. The authors make seven recommendations for establishing a breast cancer preventive program.

Tissue carcinoembryonic antigen in the prognosis of early invasive breast cancer.

Twenty-five patients with stage II ductal breast carcinoma followed up for ten years were studied for the presence of tissue carcinoembryonic antigen (CEA). Overall expression of CEA was 60%. The ten year survival rate was significantly higher for patients with CEA-negative tumours (70%) than for patients with CEA-positive tumours (27%), while the difference between the survival rate of patients with (30%) or without (53%) lymph node involvement did not reach significance. Among the 10 patients with lymph node involvement, CEA-negative patients had a better outcome. These results suggest that there is a correlation between the presence of tissue CEA and the prognosis of the disease, and that CEA status might possibly be more important than lymph node involvement, at least within stage II breast carcinomas.

Medida vascular no carcinoma da mama.Estudo mamografico quantitativo. / Vascular measurement in brest cancer Quantitative mammographic study

O padrao vascular das mamas apreciado pela mamografia foi estudado quantitativamente entre 1978 e 1982. Assim, a vascularizacao mamaria em 10 portadoras de carcinoma (Grupo A) foi comparada com a existente em 10 pacientes com displasia (Grupo B). A idade media foi de 47,1 e 45 anos para os grupos A e B, respectivamente. O total de mensuracoes nas 40 mamas foi de 4.000, escolhidas ao acaso. O diametro medio dos vasos nas mamas carcinomatosas foi de 1,60 +/- 0,11 milimetros, ao passo que o da glandula contralateral foi de 0,72 +/- 0, 12 milimetros, dados estatisticamente diferentes. O diametro medio dos vasos nas pacientes com displasia apresentou-se estatisticamente igual nas glandulas direita a esquerda, isto e, 0,71 +/- 0,08 e 0,68 +/- 0,10 milimetros, respectivamente. Comparou-se o diametro medio dos vasos nas mamas das enfermas com displasia (0,69 +/- 0,09 milimetros) com o correspondente das 10 glandulas normais em portadoras de carcinoma (0,73 +/- 0,11 milimetros).Nao houve diferenca estatistica nos dados encontrados, sugerindo que o aumento da vascularizacao em mamas carcinomatosas resulta de fator local

Estudo clinico e laboratorial de pacientes climatericas (fase pos-menopausica) submetidas ao LIR-1660. / Clinical and laboratorial study of climacteric patients (post-menopausal phase) submitted to LIR 1660

Trinta pacientes na pos-menopausa fisiologica foram tratadas com LIR-1660 na dosagem de 100 mg/dia durante 20 dias. Atraves do indice menopausal de Kupperman, da dosagem de FSH, LH prolactina, estradiol e da colpocitologia hormonal observaram-se as modificacoes apos o tratamento. Pode-se concluir ser a droga eficaz no controle dos sintomas neurovegetativos, mas nao determina alteracoes nas concentracoes sanguineas dos hormonios estudados e na colpocitologia hormonal. Em nenhum caso foi observado efeitos colaterais e galactorreia

Estudo clinico de nova medicacao (LIR-1660) na sindrome climaterica (fase pos-menopausica) / Clinical study of a new drug (LTR-1660) in the climateric syndrome (post-menopausal phase)

Os autores estudaram 20 pacientes climatericas na fase pos-menopausica fisiologica, pertencentes a Secao de Climaterio da Clinica Ginecologica da FMUSP (Hospital das Clinicas - Servico do Prof. Carlos Alberto Salvatore), cujas idades oscilaram de 44 a 60 anos. A estas pacientes foi administrado LIR-1660 na dosagem de 100 mg por dia, via oral, por 20 dias consecutivos. Os resultados relacionados aos sintomas vasomotores foram satisfatorios em 80% dos casos e regulares em 20%; em nenhum caso observou-se efeito colateral a droga. Concluem os autores da eficacia desta substancia, e que a mesma representa uma boa alternativa terapeutica nas pacientes climatericas

Nova medicacao nao estrogenica no tratamento da sindrome climaterica. / A new non-hormonal steroid drug in the treatment of climacteric syndrome

Os autores avaliaram, em 20 pacientes menopausadas, uma nova medicacao a base de ciclofenil e diazepam. O criterio de diagnostico da sindrome climaterica e do controle de eficacia foi feito atraves do indice de Kuppermann no pre e pos-tratamento. Devido aos excelentes resultados obtidos os autores concluem que a nova medicacao representa uma opcao eficaz para o adequado controle da sintomatologia climaterica