Heat shock protein 90 (Hsp90) facilitates maturation and stability of HER2. Combining an Hsp90 inhibitor and trastuzumab has demonstrated anti-tumor effects in patients with HER2+ breast cancer. ...Adults with measurable, locally advanced or metastatic HER2+ breast cancer and prior trastuzumab treatment were enrolled in a phase 2 trial employing weekly 300 mg/m
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retaspimycin HCl, a potent Hsp90 inhibitor, with 6 mg/kg trastuzumab every 3 weeks. A Simon’s two-stage design determined trial expansion by dose-limiting toxicity (DLT) and response rates. Pharmacokinetics and electrocardiograms were evaluated. Twenty-six patients with median age 52.5 years (range 33–72) enrolled with a median of six prior chemotherapeutic regimens (range 2–20). On study, patients received a median of three treatment cycles (range 1–12). No DLTs were observed. Most adverse events (AEs) were grade 1 or 2; common treatment-related AEs included fatigue (46 %), nausea (31 %), and diarrhea (23 %). One patient had treatment-related serious AEs of grade 1 diarrhea and grade 3 hypokalemia. grade 3 transaminase elevation occurred in one patient (4 %) who also had metastatic liver disease. Sixteen patients (62 %) had stable disease, with a median on-study duration of 2.4 months (range 1.1–8.2). No confirmed responses were observed. Retaspimycin HCl at 300 mg/m² weekly in combination with trastuzumab was well tolerated and without significant toxicities. Modest clinical activity was observed, but did not meet criteria for trial expansion. The safety profile for patients on study raises the possibility of retaspimycin HCl underdosing that limited efficacy. Studies employing higher doses are ongoing.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Since the identification of the HER2 receptor amplification as an adverse prognostic factor that defined a special subtype of metastatic breast cancer, there has been a substantial improvement in ...survival of patients affected with this disease due to the development of anti-HER2 targeted therapies. The approval of trastuzumab and pertuzumab associated to a taxane in first line and subsequent treatment with the antibody-drug conjugate T-DM1 has certainly contributed to achieve these outcomes. The Tyrosine Kinase Inhibitor lapatinib was also approved in the basis of an improvement in progression free survival, becoming another commonly used treatment in combination with capecitabine. Inevitably, despite these therapeutic advances most patients progress on therapy due to primary or acquired resistance or because of an incorrect HER2 positivity assessment. Hence, it is crucial to correctly categorize HER2 amplified tumors and define mechanisms of resistance to design effective new treatment approaches. In addition, identifying biomarkers of response or resistance permits to tailor the therapeutic options for each patient sparing them from unnecessary toxicity as well as improving their outcomes. The aim of this review is to examine new strategies in development to treat HER2-positive metastatic breast cancer referring to the mechanisms of action of new drugs and new combinations including results reported so far.
•Trastuzumab and pertuzumab plus a taxane and T-DM1 have improved survival of HER2-positive metastatic breast cancer patients.•Most HER2-positive metastatic breast cancer patients progress on therapy.•Correctly categorizing HER2 amplified tumors and defining mechanisms of resistance is crucial.•New anti-HER2 treatments and combinations are currently in development.•Identifying biomarkers of response or resistance permits to tailor therapeutic options.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
HER2-positive metastatic breast cancer is incurable and new treatments are needed. Addition of atezolizumab to trastuzumab emtansine might potentiate anticancer immunity and enhance the HER2-targeted ...cytotoxic activity of trastuzumab emtansine. We aimed to test this combination in HER2-positive advanced breast cancer that had progressed after previous treatment with trastuzumab and a taxane.
The KATE2 study is a randomised, double-blind, placebo-controlled, phase 2 study at 68 centres from nine countries across Asia, Australia, North America, and western Europe. Eligible patients were adults (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and centrally confirmed, measurable, HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. Patients were randomly assigned (2:1) either trastuzumab emtansine (3·6 mg/kg of bodyweight) plus atezolizumab (1200 mg) or trastuzumab emtansine plus placebo; all study drugs were administered by intravenous infusion every 3 weeks. Randomisation was done via an interactive voice and web response system using a permuted block scheme (block size of six) and was stratified by PD-L1 status, world region, and liver metastases. Patients, investigators, and study team members were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02924883, and the study has been completed.
Between Sept 26, 2016, and Aug 7, 2017, 330 patients were screened for the study, of whom 202 were randomly allocated either atezolizumab (n=133) or placebo (n=69). At the recommendation of the independent data monitoring committee, treatment assignment was unmasked on Dec 11, 2017, due to futility and the numerically higher frequency of adverse events among patients assigned atezolizumab. This date was set as the clinical cutoff for the primary analysis. Median follow-up was 8·5 months (IQR 6·1–11·5) for patients assigned atezolizumab and 8·4 months (5·3–11·1) for those assigned placebo. Median progression-free survival was 8·2 months (95% CI 5·8–10·7) for patients assigned atezolizumab versus 6·8 months (4·0–11·1) for those assigned placebo (stratified hazard ratio 0·82, 95% CI 0·55–1·23; p=0·33). The most common grade 3 or worse adverse events were thrombocytopenia (17 13% among 132 patients who received atezolizumab vs three 4% among 68 who received placebo), increased aspartate aminotransferase (11 8% vs two 3%), anaemia (seven 5% vs 0), neutropenia (six 5% vs three 4%), and increased alanine aminotransferase (six 5% vs two 3%). Serious adverse events occurred in 43 (33%) of 132 patients who received atezolizumab and 13 (19%) of 68 patients who received placebo. One patient who received atezolizumab died due to a treatment-related adverse event (haemophagocytic syndrome).
Addition of atezolizumab to trastuzumab emtansine did not show a clinically meaningful improvement in progression-free survival and was associated with more adverse events. Further study of trastuzumab emtansine plus atezolizumab is warranted in a subpopulation of patients with PD-L1-positive, HER2-positive advanced breast cancer.
F Hoffman-La Roche.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Breast cancer deaths in western countries are falling due to screening and adjuvant therapy, but the treatment of metastatic breast cancer (MBC) has not shown comparable advances. The most ...active single agents are taxanes, which extend both disease-free and overall survival. However, opportunities remain for improving outcome. Nanoparticle technology is proving a valuable addition to the pharmaceutical armamentarium, particularly in oncology. Its use to bind paclitaxel to human albumin (nanoparticle albumin-bound paclitaxel; nab -paclitaxel; Abraxane®) ensures solubility of the taxane without the use of solvents and minimizes the risk of hypersensitivity reactions without premedication. The homogeneous colloidal suspension created allows rapid dispersal of unbound drug and linear pharmacokinetics. Albumin-mediated transport of paclitaxel across the endothelium facilitates uptake of drug, and a degree of tumour selectivity is achieved by the albumin-binding propensity of SPARC (Secreted Protein Acidic Rich in Cysteine), a substance expressed on and around many breast tumours. Clinical trials in first- and second-line MBC show that nab -paclitaxel is both more effective than solvent-based taxanes and associated with less severe neutropenia. Sensory neuropathy occurs but improves rapidly when compared with that caused by conventional taxanes. A clinical development programme is investigating nab -paclitaxel in the adjuvant and neoadjuvant settings. The low incidence of neutropenia makes nab -paclitaxel a good candidate for combination with other cytotoxics. It is also being assessed when given with biologic agents such as trastuzumab and bevacizumab.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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•Polymorphic microbiomes can be involved in carcinogenesis and response to treatment.•Firmicutes, Actinobacteria, Proteobacteria and Bacteroides are common phyla in breast ...milk.•Microbiome composition differs between healthy and breast cancer tissue.•Breast and gut microbiome impact breast cancer features and response to treatment.•Estrogen-metabolizing gut bacteria and their potential role in breast carcinogenesis are presented.
Disturbance of the microbial balance of a habitat can have detrimental effects on the health of the individual and, in addition, polymorphic microbiomes were recently suggested as emerging cancer hallmarks. Modern sequencing and metagenomics techniques have allowed characterization of intratumoral microbiome composition even in tissues such as the breast. We conducted a comprehensive literature review on different aspects related to the microbial landscape of the breast tissue and breast tumors, as well as its relation to systemic therapy. Emerging data suggest varying microbiome composition intratumorally compared to the normal breast tissue and other tumor types. Differences in the microbes present in normal breast and cancerous lesions of the breast have also been described, as well as potential correlation between microbiome composition and breast cancer subtype and stage. The interplay between gut and breast microbiome is not well understood although bacterial allocation through mesenteric lymph nodes has been suggested as a possible pathway. Moreover, gut bacteria with estrogen metabolizing properties are of special interest in the context of breast cancer and available knowledge and reported studies are hereby described. The relationship of gut microbiome and cancer therapy is another aspect of interest and available data are presented. Notwithstanding, the field of microbiome in the context of breast cancer is starting to evolve and a number of questions arise, with the gut-breast-cancer therapy axis in the center.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In hormone receptor-positive, HER2-negative early stage breast cancer, cyclin-dependent kinases 4 and 6 (CDK4/6) inhibition in combination with endocrine therapy could represent an alternative to ...multiagent chemotherapy. We aimed to evaluate the biological and clinical activity of neoadjuvant ribociclib plus letrozole in the luminal B subtype of early stage breast cancer.
CORALLEEN is a parallel-arm, multicentre, randomised, open-label, phase 2 trial completed across 21 hospitals in Spain. We recruited postmenopausal women (≥18 years) with stage I–IIIA hormone receptor-positive, Eastern Cooperative Oncology Group Performance Status 0–1, HER2-negative breast cancer and luminal B by PAM50 with histologically confirmed, operable primary tumour size of at least 2 cm in diameter as measured by MRI. Patients were randomly assigned (1:1) using a web-based system and permuted blocks of 25 to receive either six 28-days cycles of ribociclib (oral 600 mg once daily for 3 weeks on, 1 week off) plus daily letrozole (oral 2·5 mg/day) or four cycles of doxorubicin (intravenous 60 mg/m2) and cyclophosphamide (intravenous 600 mg/m2) every 21 days followed by weekly paclitaxel (intravenous 80 mg/m2) for 12 weeks. The total duration of the neoadjuvant therapy was 24 weeks. Randomisation was stratified by tumour size and nodal involvement. Samples were prospectively collected at baseline (day 0), day 15, and surgery. The primary endpoint was to evaluate the proportion of patients with PAM50 low-risk-of-relapse (ROR) disease at surgery in the modified intention-to-treat population including all randomly assigned patients who received study drug and had a baseline and at least one post-baseline measurement of ROR score. The PAM50 ROR risk class integrated gene expression data, tumour size, and nodal status to define prognosis. This trial was registered at ClinicalTrials.gov, NCT03248427.
Between July 27, 2017 to Dec 7, 2018, 106 patients were enrolled. At baseline, of the 106 patients, 92 (87%) patients had high ROR disease (44 85% of 52 in the ribociclib and letrozole group and 48 89% of 54 in the chemotherapy group) and 14 (13%) patients had intermediate-ROR disease (eight 15% and six 11%). Median follow-up was 200·0 days (IQR 191·2–206·0). At surgery, 23 (46·9%; 95% CI 32·5–61·7) of 49 patients in the ribociclib plus letrozole group and 24 (46·1%; 32·9–61·5) of 52 patients in the chemotherapy group were low-ROR. The most common grade 3–4 adverse events in the ribociclib plus letrozole group were neutropenia (22 43% of 51 patients) and elevated alanine aminotransferase concentrations (ten 20%). The most common grade 3–4 adverse events in the chemotherapy group were neutropenia (31 60% of 52 patients) and febrile neutropenia (seven 13%). No deaths were observed during the study in either group.
Our results suggest that some patients with high-risk, early stage, hormone receptor-positive, HER2-negative breast cancer could achieve molecular downstaging of their disease with CDK4/6 inhibitor and endocrine therapy.
Novartis, Nanostring, Breast Cancer Research Foundation-AACR Career Development Award.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•ctDNA as prognostic biomarker in early breast cancer is controversial.•We conducted a systematic review and meta-analysis to elucidate this question.•ctDNA (baseline and after neoadjuvant therapy) ...related to worse survival.•ctDNA status at baseline was not associated to pCR.•These results may help to tailor neoadjuvant treatment in early breast cancer.
Circulating tumor DNA (ctDNA) is increasingly being used as a biomarker in early breast cancer (EBC). We performed a systematic review and meta-analysis to investigate the prognostic value of ctDNA in patients with EBC treated with neoadjuvant therapy (NAT). We searched Medline, Web of Science and Embase for observational or interventional studies that included patients with EBC undergoing NAT, reported outcomes related to the predefined endpoints, and had full text articles available. Study selection followed the PRISMA guidelines and quality assessment the REMARK tool for biomarker studies. Primary endpoint was impact of ctDNA detection in different time points (baseline, on-treatment, and after NAT) on relapse-free survival (RFS) and overall survival (OS). Secondary endpoints included the association of ctDNA detection with pathologic complete response (pCR), and the positive and negative predictive value of ctDNA detection in predicting residual disease after NAT. From the 2908 studies initially identified, 11 met the eligibility criteria and were included in the meta-analysis. Detection of ctDNA, both at baseline and after completion of NAT, significantly associated to worse RFS (HR 4.22, 95% CI: 1.29–13.82 and HR 5.67, 95% CI: 2.73–11.75, respectively) and worse OS (HR 19.1, 95% CI: 6.9–53.04 and HR 4.00, 95% CI: 1.90–8.42, respectively). In contrast, detection of ctDNA did not associate with the probability of achieving a pCR. Our results suggest that ctDNA assessment during NAT for EBC merits further evaluation as a stratification risk factor in prospective trials, in order to better individualize patient’s treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Somatic mutations of ERBB2 and ERBB3 (which encode HER2 and HER3, respectively) are found in a wide range of cancers. Preclinical modelling suggests that a subset of these mutations lead to ...constitutive HER2 activation, but most remain biologically uncharacterized. Here we define the biological and therapeutic importance of known oncogenic HER2 and HER3 mutations and variants of unknown biological importance by conducting a multi-histology, genomically selected, 'basket' trial using the pan-HER kinase inhibitor neratinib (SUMMIT; clinicaltrials.gov identifier NCT01953926). Efficacy in HER2-mutant cancers varied as a function of both tumour type and mutant allele to a degree not predicted by preclinical models, with the greatest activity seen in breast, cervical and biliary cancers and with tumours that contain kinase domain missense mutations. This study demonstrates how a molecularly driven clinical trial can be used to refine our biological understanding of both characterized and new genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology.
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KISLJ, NUK, SBMB, UL, UM, UPUK
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