scholarly journals Targeted Therapy Modulates the Secretome of Cancer-Associated Fibroblasts to Induce Resistance in HER2-Positive Breast Cancer

2021 ◽  
Vol 22 (24) ◽  
pp. 13297
Author(s):  
Melani Luque ◽  
Marta Sanz-Álvarez ◽  
Andrea Santamaría ◽  
Sandra Zazo ◽  
Ion Cristóbal ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Conditioned Medium ◽  
Metastatic Breast ◽  
Breast Cancer Cell Lines ◽  
Cancer Associated Fibroblasts ◽  
Tumour Stroma ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Essential Components ◽  
Positive Breast Cancer

The combination of trastuzumab plus pertuzumab plus docetaxel as a first-line therapy in patients with HER2-positive metastatic breast cancer has provided significant clinical benefits compared to trastuzumab plus docetaxel alone. However, despite the therapeutic success of existing therapies targeting HER2, tumours invariably relapse. Therefore, there is an urgent need to improve our understanding of the mechanisms governing resistance, so that specific therapeutic strategies can be developed to provide improved efficacy. It is well known that the tumour microenvironment (TME) has a significant impact on cancer behaviour. Cancer-associated fibroblasts (CAFs) are essential components of the tumour stroma that have been linked to acquired therapeutic resistance and poor prognosis in breast cancer. For this reason, it would be of interest to identify novel biomarkers in the tumour stroma that could emerge as therapeutic targets for the modulation of resistant phenotypes. Conditioned medium experiments carried out in our laboratory with CAFs derived from HER2-positive patients showed a significant capacity to promote resistance to trastuzumab plus pertuzumab therapies in two HER2-positive breast cancer cell lines (BCCLs), even in the presence of docetaxel. In order to elucidate the components of the CAF-conditioned medium that may be relevant in the promotion of BCCL resistance, we implemented a multiomics strategy to identify cytokines, transcription factors, kinases and miRNAs in the secretome that have specific targets in cancer cells. The combination of cytokine arrays, label-free LC-MS/MS quantification and miRNA analysis to explore the secretome of CAFs under treatment conditions revealed several up- and downregulated candidates. We discuss the potential role of some of the most interesting candidates in generating resistance in HER2-positive breast cancer.

scholarly journals Real-world effectiveness of post-trastuzumab emtansine treatment in patients with HER2-positive, unresectable and/or metastatic breast cancer: a retrospective observational study (KBCSG-TR 1917)

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Takahiro Nakayama ◽  
Tetsuhiro Yoshinami ◽  
Hiroyuki Yasojima ◽  
Nobuyoshi Kittaka ◽  
Masato Takahashi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Observational Study ◽  
Real World ◽  
Metastatic Breast ◽  
Trastuzumab Emtansine ◽  
Her2 Positive ◽  
The Real ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

Abstract Background Trastuzumab emtansine (T-DM1) is a second-line standard therapy for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Evidence regarding post–T-DM1 treatments is currently lacking. We evaluated the effectiveness of post–T-DM1 drug therapy in patients with HER2-positive, unresectable and/or metastatic breast cancer. Methods In this multicenter, retrospective, observational study, real-world clinical data of female patients with HER2-positive breast cancer who had a history of T-DM1 treatment were consecutively collected from five sites in Japan. We investigated the effectiveness of post–T-DM1 therapy by evaluating the real-world progression-free survival (rwPFS), time to treatment failure (TTF), overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR). Tumor response was assessed by investigators according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) guidelines. Subgroup and exploratory analyses according to background factors were also undertaken. Results Of the 205 patients who received T-DM1 treatment between 1 January 2014 and 31 December 2018, 128 were included in this study. Among the 128 patients analyzed, 105 (82%) patients received anti-HER2 therapy and 23 (18%) patients received regimens without anti-HER2 therapy. Median (95% confidence interval [CI]) rwPFS, TTF, and OS were 5.7 (4.8–6.9) months, 5.6 (4.6–6.4) months, and 22.8 (18.2–32.4) months, respectively. CBR and ORR (95% CI) were 48% (38.8–56.7) and 23% (15.1–31.4), respectively. Cox-regression analysis showed that an ECOG PS score of 0, a HER2 immunohistochemistry score of 3+, recurrent type, ≥12 month duration of T-DM1 therapy, and anti-HER2 therapy were independent variables for rwPFS. An exploratory subgroup analysis of regimens after T-DM1 showed that those with anti-HER2 therapy had a median rwPFS of 6.3 and those without anti-HER2 therapy had a median rwPFS of 4.8 months. Conclusions In the real-world setting in Japan, several post–T-DM1 regimens for patients with unresectable and/or metastatic HER2-positive breast cancer, including continuation of anti-HER2 therapy, showed some effectiveness; however, this effectiveness was insufficient. Novel therapeutic options are still needed for further improvement of PFS and OS in later treatment settings. Trial registration UMIN000038296; registered on 15 October 2019.

Trastuzumab deruxtecan in previously treated HER2-positive metastatic breast cancer: Plain language summary of the DESTINY-Breast01 study

2021 ◽  
Author(s):  
Shanu Modi
Keyword(s):  
Breast Cancer ◽  
Adverse Events ◽  
Metastatic Breast ◽  
Common Adverse Event ◽  
The Body ◽  
Plain Language ◽  
Her2 Positive ◽  
Serious Adverse Events ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

This is a summary of the article discussing the results of the DESTINY-Breast01 study originally published in the New England Journal of Medicine. The DESTINY-Breast01 study is a clinical study in participants with a type of breast cancer called HER2-positive breast cancer. The participants in the study received a treatment called trastuzumab deruxtecan, also known as T-DXd. The purpose of this summary is to help you understand the results of the DESTINY-Breast01 study. T-DXd is currently available as a treatment for adults with HER2-positive breast cancer that cannot be removed by surgery, also called unresectable, or that has spread, also called metastatic. In the DESTINY-Breast01 study, all the participants had HER2-positive breast cancer that was metastatic or unresectable. All participants were required to have had previous treatment for their HER2-positive breast cancer with another treatment, called trastuzumab emtansine or T-DM1. All the participants received T-DXd every 3 weeks. Part 1 was done to learn how T-DXd acted in the body, and to choose a dose to give to all the participants in Part 2. In Part 2, 184 participants received T-DXd at 5.4 mg/kg and the results showed that T-DXd reduced tumor growth. Up to 60.9% of the participants had their tumors shrink or disappear, with a treatment response that lasted for nearly 15 months on average. The participants lived with their cancer for around 16 months before it got worse. During the study, 183 out of 184 participants had side effects, known as adverse events. The most common adverse event was nausea. There were 42 participants (22.8%) who had serious adverse events, including lung toxicity. These results suggest that T-DXd could be a treatment option for people with metastatic HER2-positive breast cancer who have already been treated with T-DM1. Additional studies will provide more information and results about T-DXd. ClinicalTrials.gov NCT number: NCT03248492 To read the full Plain Language Summary of this article, click on the View Article button above and download the PDF. Link to original article here .

scholarly journals Trastuzumab in combination with AT-101 induces cytotoxicity and apoptosis in Her2 positive breast cancer cells

2020 ◽  
Vol 16 (3) ◽  
pp. 4485-4495
Author(s):  
Gulcan Bulut ◽  
Harika Atmaca ◽  
Burcak Karaca
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Breast Cancer Cells ◽  
Breast Cancer Cell Lines ◽  
Her2 Positive ◽  
Protein Levels ◽  
Her2 Positive Breast Cancer ◽  
Synergistic Cytotoxicity ◽  
Positive Breast Cancer

Aim: AT-101 is a polyphenolic compound with potent anti-apoptotic effects in various cancers. In this study, the possible synergistic cytotoxic and apoptotic effect of trastuzumab/AT-101 combination was investigated in HER2-positive breast cancer cell lines. Materials & methods: SKBR-3, MDA-MB-453 and MCF-10A cell lines were treated with a trastuzumab/AT-101 combination. Synergistic cytotoxicity and apoptosis effects were shown and then PI3K and Akt protein levels were studied. Result: The trastuzumab/AT-101 combination induced synergistic cytotoxicity and apoptosis in both breast cancer cells but not in MCF-10A cells. Combination treatment induced cytotoxicity via inhibiting PI3K/AKT but not the MAPK/ERK pathway. Conclusion: The trastuzumab/AT-101 combination may be a good candidate for patients with trastuzumab-resistant Her2-positive breast cancer and inhibition of the PI3K/AKT pathway may be one of the underlying mechanisms.

QOL-enhancing surgery for patients with HER2-positive metastatic breast cancer

2018 ◽  
Vol 9 (2) ◽  
pp. 151-154
Author(s):  
Masaya Kai ◽  
Makoto Kubo ◽  
Hitomi Kawaji ◽  
Kanako Kurata ◽  
Hitomi Mori ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Systemic Therapy ◽  
Primary Tumour ◽  
Metastatic Breast ◽  
Stage Iv ◽  
Her2 Positive ◽  
Tumour Control ◽  
Her2 Positive Breast Cancer ◽  
Stage Iv Breast Cancer ◽  
Positive Breast Cancer

The role of the resection of primary tumour in stage IV breast cancer is unclear. Systemic therapy is recommended to prolong the survival and improve the quality of life (QOL). However, even if the systemic therapy is effective to control distant metastasis, sometimes the local lesion worsens, especially in the aggressive subtypes such as HER2-positive breast cancer. In uncontrollable tumours, the wound bed can bleed, weep and get infected, leading to dismal QOL. Our study describes two cases of patients with HER2-positive stage IV breast cancer who underwent palliative mastectomy which resulted in improvement of QOL. Local tumour control through palliative mastectomy can be beneficial for symptomatic aggressive patients with HER2-positive breast cancer to improve their QOL.

scholarly journals New Therapeutic Strategies in Advanced Nonoperable or Metastatic HER2-positive Breast Cancer

2021 ◽  
Vol 81 (06) ◽  
pp. 666-678
Author(s):  
Diana Lüftner ◽  
Matthias Peipp
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Treatment Options ◽  
Metastatic Breast ◽  
Antibody Engineering ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
The Us ◽  
Positive Breast Cancer

AbstractDespite therapeutic gains in the treatment of HER2-positive (HER2: human epidermal growth factor receptor 2) advanced/metastatic breast cancer, there remains an urgent need for more effective treatment options. At present, there is no definitive approved standard therapy beyond second-line treatment. One of the major challenges is overcoming treatment resistance. Depending on the underlying resistance mechanism, different strategies are being pursued for new innovative treatment concepts in HER2-positive breast cancer. Specifically designed antibodies for targeted therapy are one important focus to successfully meet these challenges. Trastuzumab deruxtecan (T-DXd, DS-8201a), an optimised antibody drug conjugate (ADC) is in clinical trials, showing promising outcomes in patients with advanced, nonoperable or metastatic HER2-positive breast cancer who had already undergone intensive prior treatment. Based on this data, T-DXd has already been approved in the US and Japan for HER2-positive advanced nonoperable and metastatic breast cancer – in the US after at least two prior anti-HER2 targeted treatment lines and in Japan after prior chemotherapy. T-DXd represents successful “antibody engineering”. Since the beginning of the year, T-DXd has also been approved in Europe as monotherapy for inoperable or metastatic HER2-positive breast cancer in patients who are pretreated with at least two anti-HER2 directed therapies. This paper presents strategies for improving treatment options in advanced nonoperable and metastatic HER2-positive breast cancer, with the development of T-DXd as an example.

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