scholarly journals RAB5A expression is a predictive biomarker for trastuzumab emtansine in breast cancer

2021 ◽  
Author(s):  
Olav Engebraten ◽  
Christina Yau ◽  
Kristian Berg ◽  
Elin Borgen ◽  
Oystein Garred ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Intracellular Transport ◽  
Kinase Inhibitors ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Cytotoxic Agents ◽  
Endocytic Trafficking ◽  
Trastuzumab Emtansine ◽  
Her2 Positive

PURPOSE: Targeted therapeutics strongly depends on validated biomarkers in order to select patients most likely to benefit from the treatment. HER2 serves as a predictive biomarker for HER2-targeted tyrosine kinase inhibitors and monoclonal antibodies. HER2 may, however, also be utilized as a transport gate for delivery of cytotoxic agents into the cell, such as for HER2-targeted antibody drug conjugates (ADCs; e.g. trastuzumab emtansine (T-DM1)). The predictive biomarkers for such ADCs may be more complex, also reflecting the intracellular transport. METHODS: Five HER2-positive breast and ovarian cancer cell lines were evaluated with respect to T-DM1 sensitivity and correlated to the expression levels of proteins involved in endocytic trafficking including RAB4A, RAB5A and RAB11A, with possible impact on ADC pharmacology. The results were confirmed in a clinical cohort consisting of patients from the adaptive breast cancer clinical trial I-SPY2 where pathological complete response (pCR) was correlated to the RNA expression level of RAB4A, RAB5A and RAB11A. A subset of the clinical KAMILLA trial including 19 patients was used as a verification cohort where semi-quantitative IHC of RAB5A was correlated to progression free survival (PFS). RESULTS: The early endosome marker RAB5A, was found to correlate positively to T-DM1 sensitivity in the cell line panel. Correlation between RAB5A expression and T-DM1 sensitivity (pCR) was confirmed in patients treated with trastuzumab emtansine/pertuzumab in the I-SPY2 trial, but not in the trastuzumab/paclitaxel control arm. The clinical correlation was verified in the patients from the KAMILLA trial where semi- quantitative RAB5A IHC staining correlated significantly positive to PFS. CONCLUSION: The present results indicate that RAB5A is a predictive biomarker for T-DM1 and outline, for the first time, proteins involved in endocytic trafficking as predictive biomarkers for ADCs.

scholarly journals RAB5A expression is a predictive biomarker for trastuzumab emtansine in breast cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Olav Engebraaten ◽  
Christina Yau ◽  
Kristian Berg ◽  
Elin Borgen ◽  
Øystein Garred ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Transport ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Cytotoxic Agents ◽  
Trastuzumab Emtansine ◽  
Targeted Therapeutics ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Drug Conjugates

AbstractHER2 is a predictive biomarker for HER2-targeted therapeutics. For antibody–drug conjugates (ADCs; e.g., trastuzumab emtansine (T-DM1)), HER2 is utilized as a transport gate for cytotoxic agents into the cell. ADC biomarkers may therefore be more complex, also reflecting the intracellular drug transport. Here we report on a positive correlation between the early endosome marker RAB5A and T-DM1 sensitivity in five HER2-positive cell lines. Correlation between RAB5A expression and T-DM1 sensitivity is confirmed in breast cancer patients treated with trastuzumab emtansine/pertuzumab in the I-SPY2 trial (NCT01042379), but not in the trastuzumab/paclitaxel control arm. The clinical correlation is further verified in patients from the KAMILLA trial (NCT01702571). In conclusion, our results suggest RAB5A as a predictive biomarker for T-DM1 response and outline proteins involved in endocytic trafficking as predictive biomarkers for ADCs.

scholarly journals Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer

Cells ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 321 ◽  
Author(s):  
Sobhani ◽  
D’Angelo ◽  
Pittacolo ◽  
Roviello ◽  
Miccoli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Targeted Therapies ◽  
Randomized Clinical Trials ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Her2 Positive ◽  
Retinoblastoma Tumor

Breast Cancer (BC) is the second most common type of cancer worldwide and displays the highest cancer-related mortality among women worldwide. Targeted therapies have revolutionized the way BC has been treated in recent decades, improving the life expectancies of millions of women. Among the different molecular pathways that have been of interest for the development of targeted therapies are the Cyclin-Dependent Kinases (CDK). CDK inhibitors are a class of molecules that already exist in nature and those belonging to the Cyclin dependent kinase inhibitors family INK4 that specifically inhibit CDK4/6 proteins. CDK4/6 inhibitors specifically block the transition from the G1 to the S phase of the cell cycle by dephosphorylation of the retinoblastoma tumor suppressor protein. In the past four years, the CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, received their first FDA approval for the treatment of Hormone Receptor (HR)-positive and Human Epidermal growth factor Receptor 2 (HER2)-negative breast cancer after showing significant improvements in progression-free survival in the PALOMA-1, MONALEESA-2 and the MONARCH-2 randomized clinical trials, respectively. After the encouraging results from these clinical trials, CDK4/6 inhibitors have also been investigated in other BC subtypes. In HER2-positive BC, a combination of CDK4/6 inhibitors with HER2-targeted therapies showed promise in preclinical studies and their clinical evaluation is ongoing. Moreover, in triple-negative BC, the efficacy of CDK4/6 inhibitors has been investigated in combination with other targeted therapies or immunotherapies. This review summarizes the molecular background and clinical efficacy of CDK4/6 inhibitors as single agents or in combination with other targeted therapies for the treatment of BC. Future directions for ongoing clinical trials and predictive biomarkers will be further debated.

scholarly journals Breast Cancer Treatment and Antibody Drug Conjugates: Beyond T-DM1

2021 ◽  
Vol 9 (8) ◽  
Author(s):  
Mony Ung ◽  
Jean Lacaze ◽  
Eleonora Maio ◽  
Florence Dalenc
Keyword(s):  
Breast Cancer ◽  
Anticancer Agents ◽  
Bystander Effect ◽  
Cytotoxic Agents ◽  
Clinical Activity ◽  
Trastuzumab Emtansine ◽  
Her2 Positive ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Antibody–drug conjugates (ADCs) are a new class of anticancer agents that combine cytotoxic agents attached by a linker to a monoclonal antibody. These engineered drugs can selectively deliver a cytotoxic payload to targeted cancer cells and the local microenvironment (bystander effect), thereby increasing activity and reducing off-target toxicity. The association of ADCs with other anti-cancer therapies is therefore promising. Trastuzumab-emtansine was the first approved ADC in breast cancer (BC), specifically for the management of human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. New ADCs are in development in BC. Some have shown meaningful clinical benefit and have been recently approved, such as trastuzumab deruxtecan in HER2-positive trastuzumab emtansine (T-DM1) pretreated BC and Trop-2 guided sacituzumab govitecan in triple-negative BC. Trastuzumab deruxtecan also has potential clinical activity in HER2-low BC thanks to a bystander effect. In this article, we review the ADCs under development in advanced BC.

Early predictors of benefit to dual anti-PD1/HER2 inhibition: Biomarker analysis from phase 2 trial of pembrolizumab/trastuzumab in HER2-positive metastatic esophagogastric (mEG) cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4058-4058
Author(s):  
Steven Brad Maron ◽  
Walid Khaled Chatila ◽  
Henry S. Walch ◽  
Ryan Ptashkin ◽  
Shalom Sabwa ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Ct Scans ◽  
Her2 Positive ◽  
Phase 2 Trial ◽  
Biomarker Analysis ◽  
Pre Treatment ◽  
Pet Scans

4058 Background: Pembrolizumab and trastuzumab (P&T) and chemotherapy demonstrated 27 month mOS, 13 month mPFS, and 91% response rate in first-line HER2-positive mEG cancer irrespective of PD-L1 status (Janjigian Lancet Oncology 2020). Biomarkers including 89Zr-trastuzumab PET, blood, and tumor analysis were correlated with progression-free survival. Methods: Twenty-five patients received P&T once 3 weeks prior to addition of chemotherapy to P&T. Pre-treatment tumor biopsies, 89Zr-trastuzumab PET scans, serial plasma ctDNA (Guardant360, Redwood City, CA) and CT scans were performed. Tumor-matched DNA alterations were identified by correlating ctDNA and tissue-NGS variant calls. Pre-, on-, and post-treatment biopsies were analyzed using WES and IHC (HER2, PD-L1). Biomarkers were correlated with mPFS and 6-month PFS, the primary endpoint. Results: Of patients with tumor-matched mutations ctDNA at baseline, 12 of 16 had a decline in their maxVAF by week 3, corresponding to a mPFS of 14.7 (11.0-NR) vs 5.9 (95% CI 4.1-NR) months (p=0.009) and a mOS of 29.7 (95% CI 27.2-NR) vs 7.71 (95% CI 6.6-NR) months (p=0.006). 9 of 12 (75%) patients with decline in ctDNA at 3 weeks post-P&T achieved the 6-month PFS primary endpoint while the 4 patients with no decline in ctDNA all progressed in under 6-months. Similarly, 7 of 9 (78%) patients who had a decline in CT-measurements in all disease sites achieved the 6 month PFS primary endpoint, versus 10 of 16 (62.5%) of patients who did not respond in all sites (p=0.66), suggesting that ctDNA is superior to CT as an early predictive biomarker of response. Lack of ERBB2 amplification (amp) by NGS in ctDNA and/or tumor was associated with lack of response to P&T alone prior to addition of chemotherapy. Interestingly, no lesions from patients lacking ERBB2 ctDNA amp (n=3) responded to induction P&T by CT, while lesions from 3/9 patients lacking ERBB2 tissue amp responded to P&T by 3-week CT, suggesting intrapatient HER2 heterogeneity. Eight patients also underwent 89Zr-Trastuzumab PET scans prior to P&T and up to 5 lesions per disease site were measured on serial CT scans. All 15 lesions with intense uptake (SUVmax>10) responded to P&T, but only 9/24 lesions with SUVmax<10. All 4 patients who had at least 1 intense lesion achieved a post-P&T CT response and later 6+ month PFS. All 3 of 3 evaluable patients with intense uptake had baseline ctDNA ERBB2 amp. Conclusions: Patients with a decline in tumor-matched maxVAF after one dose of P&T were more likely to achieve durable PFS. Pre-treatment ctDNA ERBB2 amp and/or intense 89Zr-trastuzumab PET avidity are non-invasive predictive biomarkers of response to HER2-directed therapy. Evaluation of tumor immune environment digital spatial profiling is underway. Clinical trial information: NCT02954536.

scholarly journals Pertuzumab in Combination with Trastuzumab and Chemotherapy in the Treatment of HER2-Positive Metastatic Breast Cancer: Safety, Efficacy, and Progression Free Survival

2014 ◽  
Vol 8 ◽  
pp. BCBCR.S9032 ◽  
Author(s):  
Joseph J. Maly ◽  
Erin R. Macrae
Keyword(s):  
Breast Cancer ◽  
Kinase Inhibitors ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Preclinical Research ◽  
Her2 Positive ◽  
Cancer Management ◽  
Improved Outcomes ◽  
Breast Cancer Management ◽  
Computer Based

Tyrosine kinase inhibitors have revolutionized the oncology community and were pioneered by the use in HER2-targeted therapies. Improved outcomes were seen with the advent of trastuzumab, leading investigators to develop newer agents to target the HER2 pathway such as the novel monoclonal antibody pertuzumab. In this paper, we describe the attributes of pertuzumab including: mechanism of action, pharmacokinetics and metabolism, safety/cardiotoxicity, drug interactions, efficacy, and role in HER2-positive breast cancer management. Newly reviewed here versus previously published reviews on pertuzumab oriented therapy are data of pertuzumab monotherapy as it is used in combination with other anti-HER2 agents derived from preclinical research and ongoing clinical trials. Materials and Methods A computer based literature search was carried out using PubMed data reported at international meetings (ASCO) up to September 2013 were included.

scholarly journals New Therapeutics in HER2-Positive Advanced Breast Cancer: Towards a Change in Clinical Practices?

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1573 ◽  
Author(s):  
Essia Mezni ◽  
Cécile Vicier ◽  
Mathilde Guerin ◽  
Renaud Sabatier ◽  
François Bertucci ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Kinase Inhibitors ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
Advanced Breast ◽  
Clinical Practices ◽  
Her2 Positive ◽  
Development Of Resistance ◽  
Breast Cancer Subgroup

Over the last few decades, improved knowledge of oncogenic activation mechanisms of HER2 protein has led to the development of HER2 targeted therapies that are currently commonly used in HER2-positive advanced breast cancer, such as trastuzumab, lapatinib, pertuzumab, and ado-trastuzumab emtansine. The management of this breast cancer subgroup has thus been revolutionized and its prognosis has changed dramatically. Nevertheless, HER2-positive advanced breast cancer remains an incurable disease and resistance to conventional anti-HER2 drugs is almost unavoidable. Nowadays, biochemical and pharmaceutical advances are meeting the challenge of developing increasingly sophisticated therapies directed against HER2, including novel anti HER2 antibodies with increased affinity. New antibody-drug conjugates (ADC) with more advanced pharmacological properties, and dual targeting of epitopes via bispecific monoclonal antibodies are also emerging. In addition, more potent and more specific HER2 tyrosine kinase inhibitors have shown interesting outcomes and are under development. Finally, researchers’ interest in tumor microenvironment, particularly tumor-infiltrating lymphocytes, and the major role that signaling pathways, such as the PI3K/AKT/mTOR pathway, play in the development of resistance to anti-HER2 therapies have spurred the development of clinical trials evaluating innovative combinations of anti-HER2 with PD-1/PDL-1, CDK4/6 and PI3K inhibitors. However, several questions remain unresolved, like the optimal management of HER2-positive/HR-positive advanced breast cancer and the identification of predictive biomarkers to better define populations that can benefit most from these new therapies and approaches.

scholarly journals Predictive biomarkers in nonsmall cell carcinoma and their clinico-pathological association

2019 ◽  
Vol 08 (04) ◽  
pp. 250-254 ◽  
Author(s):  
Anurag Mehta ◽  
Nayana N. Sriramanakoppa ◽  
Poojan Agarwal ◽  
Gayatri Viswakarma ◽  
Smreti Vasudevan ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Stage Iv ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
First Line ◽  
Anaplastic Lymphoma ◽  
Biomarker Testing

Abstract Background: Lung cancer is the leading cause of cancer-related mortality worldwide. Genome-directed therapy is less toxic, prolongs survival and provides a better quality of life. Predictive biomarker testing, therefore, has become a standard of care in advanced lung cancers. The objective of this study was to relate clinical and pathological features, including response to targeted therapy (TT) and progression-free survival (PFS) with positive driver mutation. Materials and Methods: Archival data of nonsmall cell carcinoma patients with Stage IV disease were retrieved. Those who tested positive for one of the four biomarkers (epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK], MET, and ROS) were included. Patient demographics and clinical features were reviewed. Tumor histomorphology was correlated with oncological drivers. Treatment response, PFS, and overall survival were studied in three subcohorts of patients who received computed tomography (CT), CT followed by TT and those who received TT in the first line. Results: A total of 900 patients underwent biomarker evaluation of which 288 tested positive. Frequency of the four biomarkers observed was 26.6% (229/860), 6.6% (51/775), 6.6% (5/75), and 5.1% (3/59) for EGFR, ALK, MET, and ROS-1, respectively. The median PFS for EGFR-mutated cohort was 12 months, whereas it was 21 months for ALK protein overexpressing cases. Patients treated with first-line tyrosine kinase inhibitors performed better compared to those who were switched from chemotherapy to TT or those who received chemotherapy alone (P < 0.05). Conclusion: Biomarker testing has improved patient outcome. Genome-directed therapy accords best PFS with an advantage of nearly 10 months over cytotoxic therapy.

scholarly journals ASCO 2019: highlights in HER2-positive metastatic breast cancer

2019 ◽  
Vol 12 (4) ◽  
pp. 308-311 ◽  
Author(s):  
Rupert Bartsch ◽  
Elisabeth Bergen
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Brain Metastases ◽  
Kinase Inhibitors ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
High Rate ◽  
Phase Iii ◽  
Her2 Positive ◽  
Line Setting

Summary At the 2019 ASCO (American Society of Clinical Oncology) Annual Meeting, several interesting trial results were presented in the field of HER2-positive metastatic breast cancer. The end-of-study analysis of the pivotal CLEOPATRA trial indicated an overall survival of 57.1 months in patients receiving pertuzumab in addition to trastuzumab and docetaxel in the first-line setting. SOPHIA was the first phase III trial comparing the Fc-engineered antibody margetuximab plus chemotherapy by physician’s choice with trastuzumab plus chemotherapy in heavily pretreated patients; the novel antibody yielded a statistically significant albeit short prolongation of progression-free survival (PFS) over standard treatment. The phase III NALA trial compared the second-generation tyrosine-kinase inhibitors neratinib with lapatinib; both drugs were combined with capecitabine. In this study a clinically meaningful prolongation of PFS by 2.2 months was observed. In addition, the time to intervention for brain metastases was prolonged in the neratinib group and the cumulative incidence of brain metastases was lower as well. On the downside a high rate of grade 2 and 3 diarrhoea was observed.

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