HER2-positive Cancer Research Articles

Neoadjuvant treatment strategies for HER2-positive breast cancer: cost-effectiveness and quality of life outcomes.

Achieving a pathologic complete response (pCR) with neoadjuvant therapy for HER2-positive breast cancer is associated with less recurrence and improved clinical outcomes compared to having residual cancer at surgery. However, recent data have demonstrated favorable outcomes for patients with residual HER2-positive cancer who received adjuvant trastuzumab emtansine (TDM-1). Therefore, we sought to determine the optimal chemotherapy/anti-HER2 treatment strategy. We created a decision-analytic model for patients with stage II-III HER2-positive cancer that incorporated utilities based on toxicity and recurrence. We separately modeled hormone receptor-negative (HR-) and positive (HR+) disease and calculated quality-adjusted life years (QALYs) and costs through 5years. Simulated patients received one of the following neoadjuvant treatments: three 'intensive' regimens (TCHP: docetaxel, carboplatin, trastuzumab, pertuzumab; THP + AC: taxol, trastuzumab, pertuzumab then doxorubicin and cyclophosphamide; THP: taxol, trastuzumab, pertuzumab) and two 'de-escalated' regimens (TH: taxol, trastuzumab; TDM-1) followed by adjuvant treatment based on pathologic response. Among 'intensive' neoadjuvant strategies, treatment with THP was more effective and less costly than TCHP or THP + AC. When 'de-escalated' strategies were included, TH became the most cost-effective. For HR-negative cancer, TH had 0.003 fewer quality-adjusted life years (QALYs) than THP but was less costly by $55,831, resulting in an incremental cost-effectiveness ratio of over $18M/QALY for THP, well above any threshold. For HR-positive cancer, neoadjuvant TH dominated the THP strategy. An adaptive-treatment strategy beginning with neoadjuvant THP or TH followed by tailoring post-operative therapy reduces treatment costs, and spares toxicity compared to more intensive chemotherapy regimens for women with HER2-positive breast cancer.

Antibody-modified magnetic nanoparticles as specific high-efficient cell-separation agents.

Separation of tumor cells is a promising approach that helps not only in early detection of cancer but also as an efficient tool that holds great importance in prohibiting cancer cell mutation, drug resistance to treatments, and in granting successful adjuvant therapies. As one of the highly efficient processes for the separation of single cells, tumor cells, and specific proteins from fresh whole blood, a magnetic iron oxide nanoparticle (IONP)-based immunomagnetic separation technique has been developed in this article. The synthesized IONPs were modified with antibodies (Abs) against human epithelial growth factor receptor 2 (HER2), which is overexpressed and/or amplified in about 15% of breast cancer patients with several types of human cancer cells. The prepared Ab-conjugated IONPs (Ab-IONPs) attach HER2-positive cancer cells exclusively and can serve as specific high-efficient single-cell separation agents. The results showed that the magnetic IONPs have been successfully attached to the Abs via 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide linkers. Maximum targeting efficiency of the Ab-IONP complex, which was 94.5 ± 0.8% for BT474 and 70.6 ± 0.4% for mixture of cells (BT474 and MCF7), was achieved with a minimum amount of Abs, to provide an economically efficient single-cell detection device.

A Novel HER2-Targeting Antibody 5G9 Identified by Large-Scale Trastuzumab-Based Screening Exhibits Potent Synergistic Antitumor Activity

Background: Pertuzumab is currently used in combination with trastuzumab as the first-line treatment for HER2-positive metastatic breast cancer. However, pertuzumab was originally developed independently from trastuzumab and was later incidentally found to have synergistic efficacy when combined with trastuzumab, it remains to be seen whether a more potent synergistic efficacy partner exists for trastuzumab. Methods: A trastuzumab-based functional assay was used to screen anti-HER2 antibodies harboring trastuzumab-synergistic antitumor activity. The lead candidate 5G9, in combination with trastuzumab, was further characterized for its bioactivities in cell proliferation, cell apoptosis, antigen-antibody endocytosis and HER2-mediated cell signaling pathway blocking. Finally, animal models were used to evaluate the in vivo synergistic antitumor efficacy of 5G9 in combination with trastuzumab. Findings: Compared to pertuzumab, 5G9 demonstrated more potent synergistic cell growth inhibitory activity when combined with trastuzumab (85% vs. 55%, P< 0.001). In addition, 5G9 exhibited a higher internalization rate than pertuzumab (20% vs. 9%, P< 0.05), and was able to further synergize with trastuzumab to promote antigen-antibody endocytosis. The internalination rate of the combination of 5G9 and trastuzumab was higher than the combination of pertuzumab and trastuzumab (35% vs. 14%, P< 0.001). In vivo animal studies demonstrated that 5G9 in combination with trastuzumab showed more potent synergistic antitumor efficacy than the combination of pertuzumab and trastuzumab. Interpretation: 5G9, together with trastuzumab, may provide a potential opportunity for more efficacious treatment of HER2-positive cancers. Funding Statement: Chunni Zhang was supported by grants from National Natural Science Foundation of China (no. 81472021 and no. 81672102) and from the State Key Laboratory of Analytical Chemistry for Life Science (no. 5431ZZXM1907). The research was funded in part by Biosion Incorporated. Declaration of Interests: Xiaoyao Hao, Shukai Xia and Jinyu Liu and Mingjiu Chen are employees of Biosion Inc.. The remaining authors declare no competing interests. Ethics Approval Statement: All animal studies were performed in accordance with Institutional Animal Care and Use Committee (IACUC) guidelines and approved by the Animal Ethical Committee.

Time-to-enhancement at ultrafast breast DCE-MRI: potential imaging biomarker of tumour aggressiveness.

This study was conducted in order to investigate whether there is a correlation between the time-to-enhancement (TTE) in ultrafast MRI and histopathological characteristics of breast cancers. Between January and August 2017, 274 consecutive breast cancer patients (mean age, 53.5years; range, 25-80years) who underwent ultrafast MRI and subsequent surgery were included for analysis. Ultrafast MRI scans were acquired using TWIST-VIBE or 4D TRAK-3D TFE sequences. TTE and maximum slope (MS) were derived from the ultrafast MRI. The repeated measures ANOVA, Mann-Whitney U test and Kruskal-Wallis H test were performed to compare the median TTE, MS and SER according to histologic type, histologic grade, ER/PR/HER2 positivity, level of Ki-67 and tumour subtype. For TTE calculation, intraclass correlation coefficient (ICC) was used to evaluate interobserver variability. The median TTE of invasive cancers was shorter than that of in situ cancers (p < 0.001). In invasive cancers, large tumours showed shorter TTE than small tumours (p = 0.001). High histologic/nuclear grade cancers had shorter TTE than low to intermediate grade cancers (p < 0.001 and p < 0.001). HER2-positive cancers showed shorter TTE than HER2-negative cancers (p = 0.001). The median TTE of cancers with high Ki-67 was shorter than that of cancers with low Ki-67 (p < 0.001). ICC between two readers showed moderate agreement (0.516). No difference was found in the median MS or SER values according to the clinicopathologic features. The median TTE of breast cancer in ultrafast MRI was shorter in invasive or aggressive tumours than in in situ cancer or less aggressive tumours, respectively. • Invasive breast tumours show a shorter TTE in ultrafast DCE-MRI than in situ cancers. • A shorter TTE in ultrafast DCE-MRI is associated with breast tumours of a large size, high histologic or nuclear grade, PR negativity, HER2 positivity and high Ki-67 level.

Oral Vinorelbine or Capecitabine Combined With Trastuzumab as Adjuvant Treatment for Patients With Lymph Node Negative, HER-2 Positive and Small Tumor Size Breast Cancer (ORCHID)

Oral Vinorelbine or Capecitabine Combined With Trastuzumab as Adjuvant Treatment for Patients With Lymph Node Negative, HER-2 Positive and Small Tumor Size Breast Cancer (ORCHID)

MiR-125a Induces HER2 Expression and Sensitivity to Trastuzumab in Triple-Negative Breast Cancer Lines.

The EGFR/HER2 signaling network is an effective therapeutic target for HER2-positive cancers, which are known for their aggressive biological course. Evidence indicates that the EGFR/HER2 network plays a role in the aggressive basal-like subtype as well. Here, we studied the potential role of miR-125a-3p as a modulator of the EGFR/HER2 pathway in basal-like breast cancer. Over-expression of miR-125a-3p reduced the migratory capability of MDA-MB-231 cells and led to an increase in the expression of ErbB2 transcript and protein. The induced ErbB2 responded to trastuzumab and underwent internalization and subsequent intra-lysosomal degradation. Trastuzumab treatment further reduced the migratory capability and induced the apoptosis of the cells. An in-vivo mouse model, which supported the in-vitro findings, showed a synergistic effect for miR-125a-3p and trastuzumab. Trastuzumab-treated miR-125a-3p-induced tumors were significantly smaller than control induced tumors. Our findings indicate that, in the basal-like subtype of breast cancer, miR-125a-3p may act as a tumor suppressor. miR-125a-3p induces an increase in the expression of ErbB2 that may render the cells suitable for treatment with anti-HER2 therapies.

Single Tumor Cells With Epithelial-Like Morphology Are Associated With Breast Cancer Metastasis.

Introduction: The identification of tumor cells that can be potential metastatic seeds would reach two key aims—prognosis of metastasis risk and appointment of the optimal adjuvant therapy to prevent metastatic disease. Single tumor cells (STCs) located out of multicellular structures can most likely demonstrate features that are needed to initiate metastasis.Methods: One-hundred-and-thirty-five patients with invasive breast carcinoma of no special type have been enrolled. Molecular subtypes of breast cancer were categorized according to St. Gallen recommendations. Hematoxylin and eosin staining was used to identify STCs with epithelial-like morphology (eSTCs) in breast tumors. Immunofluorescence staining was applied to evaluate stemness and epithelial–mesenchymal transition (EMT) in STCs. The correlation between STCs and recurrence and metastasis-free survival (MFS) was performed using the Kaplan–Meier method and the log-rank test.Results: Distant metastasis was more frequent in eSTC-positive than eSTC-negative patients (28.0% vs. 9.4%, p = 0.007). When tumor types were analyzed separately, distant metastasis tended to be more frequent in eSTC-positive than eSTC-negative patients for HER2-positive cancer [75.0% (3/4) vs. 12.5% (1/8), p = 0.066]. In luminal A [22.7% (5/22) vs. 10.0% (3/30), p = 0.259], luminal B [21.1% (4/19) vs. 6.7% (2/30), p = 0.189], and triple-negative [40.0% (2/5) vs. 11.8% (2/17), p = 0.209] cancers, distance metastasis was not associated with eSTCs. Median MFS was not reached in eSTC-positive and eSTC-negative patients. eSTC-positive patients had a higher risk of breast cancer metastasis [hazard ratio (HR) 3.57, 95% confidence interval (CI): 1.46–8.71; p = 0.001]. When tumor types were analyzed separately, a higher risk of breast cancer metastasis occurred only in HER2-positive patients (HR 8.49, 95% CI: 1.29–55.59; p = 0.016). Immunofluorescence analysis revealed mesenchymal-like STCs (mSTCs) and inter- and intra-tumor heterogeneity in STCs. There were breast tumors with either eSTCs or mSTCs and tumors with both types of STCs. Both eSTCs and mSTCs were represented by cells with different stem and/or EMT phenotypes.Conclusions: STCs with epithelial-like morphology contribute to breast cancer metastasis and represent an attractive model for studying mechanisms of metastatic seeding. The assessment of STCs in histological sections of breast tumors can be a simple and effective method for the prediction of metastasis risk.

Radiosensitization of HER2-positive esophageal cancer cells by pyrotinib.

Radiation therapy is a widely used treatment for esophageal cancer. However, radiation resistance might result in a poor prognosis. Overexpression of HER2 has been related to adaptive radiation resistance. Pyrotinib is a HER2 inhibitor that shows an anti-tumor effect in breast cancer. The present study aims to explore the influence of pyrotinib combined with radiotherapy on HER2-positive esophageal cancer cells and explore the underlying mechanism. We screened two cell lines (TE-1 and KYSE30) that highly express HER2 from several human esophageal cancer cell lines. Cells were treated with pyrotinib or/and radiation. Cell proliferation, cell cycle distribution, and cell migration were measured. The protein levels involved in cell cycle and DNA repair were measured by Western blot. Results showed that pyrotinib inhibited HER2 activation and exerted an anti-proliferative effect in TE-1 and KYSE30 cells. Furthermore, it enhanced the anti-proliferative effect of radiation in these two cell lines. These effects might be via inhibiting HER2 phosphorylation, inducing G0/G1 arrest, and reducing EMT and DNA repair. Our results indicated that pyrotinib sensitivitied HER2 positive esophageal cancer cells to radiation treatment through various mechanisms. These findings may provide a new therapeutic strategy for treating HER2 positive esophageal cancer.

Detection and destruction of HER2-positive cancer cells by Ultra Quenchbody-siRNA complex.

Ultra Quenchbody (UQ-body) is a biosensor that utilizes the quenching behavior of the fluorescent dye linked to the antibody V region. When the corresponding antigen is bound to the UQ-body, the fluorescence is restored and allows the detection of target molecules easily and sensitively. In this paper, we constructed UQ-bodies to sensitively detect the human epidermal growth factor receptor 2 (HER2) cancer marker in solution or on cancer cells, which was further used to kill the cancer cells. A synthetic Fab fragment of anti-HER2 antibody Fab37 with many Trp residues at hypervariable region was prepared and labeled with fluorescent dyes to obtain the UQ-bodies. The UQ-body could detect HER2 in solution at concentrations as low as 20 pM with an EC50 of 0.3 nM with a fourfold response. Fluorescence imaging of HER2-positive cells was successfully performed without any washing steps. To deliver small interfering RNA (siRNA) to cancer cells, a modified UQ-body with C-terminal 9R sequence was also prepared. HER2-positive cancer cells were effectively killed by polo-like kinase 1 siRNA intracellularly delivered by the UQ-body-9R. The novel approach employing siRNA-empowered UQ-body could detect and image the HER2 antigen easily and sensitively, and effectively kill the HER2-positive cancer cells.

Abstract P1-18-26: Risk of reduction of left ventricular ejection fraction with trastuzumab emtansine: A systematic review and meta-analysis of randomized controlled trials

Abstract Background: HER2 targeted therapies have significantly improved the prognosis of HER2 overexpressing cancers, in particular HER2-positive breast cancer. However, type-II cancer therapeutics-related cardiac dysfunction (CTRCD) characterized by a drop in left ventricular ejection fraction (LVEF) remains a significant adverse event for trastuszumab and other HER2 targeted therapies. Trastuzumab Emtansine (T-DM1) is a HER2 targeted antibody-drug conjugate consisting of anti-HER2 IgG1 antibody trastuzumab and a maytansine derivative microtubule inhibitor DM-1. Currently T-DM1 is approved for HER2-positive breast cancer both in the metastatic and in the adjuvant settings. We conducted a systematic review and meta-analysis of published phase 3 randomized controlled trials (RCTs) to determine the relative risk of reduction of LVEF with T-DM1 in comparison to other therapies in HER2-postive cancers. Methods: We conducted a systematic search at PUBMED, MEDLINE, EMBASE, and professional societies meeting abstracts as per PRISMA guidelines from inception until March 31st, 2019. Published phase 3 RCTs comparing T-DM1 with other therapies in patients with HER2-positive cancers and reporting the number of events of reduction in LVEF in both intervention and control arms were included in the final analysis. The primary meta-analytic approach was a random effects model using the Mantel-Haenszel (MH) method, and it was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was tested with I2 value and Cochran’s Q-test. Results: Five RCTs (EMILIA, GATSBY, KATHERINE, KRISTINE, and TH3RESA) randomizing 3802 patients (2080 in intervention arms and 1722 in control arms) with HER2-positive cancers were included in the final analysis. Four studies (EMILIA, KATHERINE, KRISTINE, and TH3RESA) were conducted in breast cancer patients, and one (GATSBY) was done in gastric/gastro-esophageal adenocarcinoma patients. GATSBY was a phase 2/3 study and rest were phase 3 RCTs. Patients in control arms received variable systemic therapies across trials, most of the studies used conventional HER2 targeting drugs (e.g. trastuzumab, lapatinib etc) with exception of GATSBY trial which only used taxanes. Dose of T-DM1 was usually 3.6 mg/kg every 3 weeks, except for GATSBY study where dose was 2.4 mg/kg every week. The pooled RR of any-grade reduction of LVEF was significantly lower in the T-DM1 group as compared to control at 0.58 (95% CI: 0.36-0.95, p = 0.03, I2 = 0). No publication bias was appreciated across all studies included in the final analysis. Conclusion: In our meta-analysis, the relative risk of reduction of LVEF was significantly lower in the T-DM1 containing regimens compared to other therapies in patients with HER2-positive cancers. It could be an area of research to identify the mechanism and to determine the clinical utility of this finding. Citation Format: Nusrat Jahan, Somedeb Ball, Lukman Tijani, Fred Hardwicke, Catherine Jones. Risk of reduction of left ventricular ejection fraction with trastuzumab emtansine: A systematic review and meta-analysis of randomized controlled trials [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-26.

Abstract P3-11-24: Relative risk of peripheral neuropathy with trastuzumab emtansine compared to taxane-based regimens in HER2-positive cancers: A systematic review and meta-analysis of published phase 3 randomized controlled trials

Abstract Background: Trastuzumab Emtansine (T-DM1) is a HER2-targeted antibody-drug conjugate consisting of anti-HER2 IgG1 antibody trastuzumab and maytansine derivative DM-1. The trastuzumab part of T-DM1 inhibits HER2 receptor signaling, mediates antibody-dependent cell-mediated cytotoxicity, and ensures selective delivery of DM-1 into HER2 overexpressing cells. DM-1 inhibits microtubules causing cell cycle arrest and apoptosis. Currently, T-DM1 is approved for HER2-positive breast cancer in the both metastatic and adjuvant settings. In different studies, peripheral neuropathy, in particular sensory peripheral neuropathy, has been reported as a significant adverse effect of T-DM1. We conducted a systematic review and meta-analysis of phase 3 randomized controlled trials (RCTs) using T-DM1 in the experimental arm and a taxane-based regimen in the control arm to determine the relative risk of peripheral neuropathy and peripheral sensory neuropathy associated with T-DM1 comparing to taxane-based regimens. Methods: We conducted a systematic search at PUBMED, MEDLINE, EMBASE databases and professional societies meeting abstracts as per PRISMA guidelines from inception until March 31st, 2019. Published phase 3 RCTs comparing T-DM1 with taxane-based regimens in patients with HER2-positive cancers and reporting number of events of peripheral neuropathy and peripheral sensory neuropathy in both the intervention and the control arms were included in the final analysis. The primary meta-analytic approach was a random effects model using the Mantel-Haenszel (MH) method, and it was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was tested with I2 value and Cochran’s Q-test. Results: Three RCTs (MARIANNE, GATSBY, and KRISTINE) randomizing 1857 participants (1174 in the T-DM1 arms and 683 in the control arms) were included in the final analysis. MARIANNE and KRISTINE were conducted in breast cancer patients, and GATSBY was done in gastric/gastro-esophageal junction adenocarcinoma patients. GATSBY was a phase 2/3 study and the rest were phase 3 RCTs. Trastuzumab was used along with taxanes in the control arm of MARIANNE and KRISTINE trials. Dose of T-DM1 was 3.6 mg/kg every 3 weeks in MARIANNE and KRISTINE trials; and 2.4 mg/kg every week in GATSBY trial. The characteristics of these trial are summarized in Table 1. The pooled RR of any grade peripheral neuropathy was significantly lower in the T-DM1 group compared to the taxane group (pooled RR:0.59, 95% CI: 0.39-0.89, P = 0.01, I2= 45%). The pooled RR for any grade sensory peripheral neuropathy was also significantly lower in the T-DM1 group compared to the taxane group (pooled RR:0.58, 95% CI: 0.46-0.74, P &amp;lt; 0.0001, I2=0%). Conclusion: Our meta-analysis demonstrated the pooled relative risk of any grade peripheral neuropathy and peripheral sensory neuropathy was significantly lower with the T-DM1 containing regimens compared to the taxane-based regimens for HER2-positive cancers. This could be an area of consideration when choosing therapy for the patients who are at higher risk of developing or have pre-existing peripheral neuropathy. Table 1TrialAuthorYearDiseaseT-DM1ControlTotal No. of PatientsT-DM1ControlMARIANNEPerez et al.2016Advanced BCT-DM1; andT-DM1+ PTaxane + trastuzumab727353GATSBYThuss-Patience et al.2017Advanced gastric cancerT-DM1Taxane224111KRISTINEHurvitz et al.2018Stage II-III BCT-DM1+ PDocetaxel+carboplatin+trastuzumab+ P223219P: PertuzumabBC: Breast Cancer Citation Format: Nusrat Jahan, Lukman Tijani, Francis Mogollon-Duffo MD, Rafiullah Khan, Somedeb Ball, Shabnam Rehman, Catherine Jones. Relative risk of peripheral neuropathy with trastuzumab emtansine compared to taxane-based regimens in HER2-positive cancers: A systematic review and meta-analysis of published phase 3 randomized controlled trials [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-24.

Abstract P5-14-15: Risk of peripheral neuropathy with trastuzumab emtansine: A systematic review and meta-analysis of published phase 3 randomized controlled trials

Abstract Background: Trastuzumab Emtansine (T-DM1) is a HER2-targeted antibody-drug conjugate consisting of anti-HER2 IgG1 antibody trastuzumab and maytansine derivative DM-1. Trastuzumab component of T-DM1 inhibits HER2 receptor signaling and mediates antibody-dependent cell-mediated cytotoxicity. It also ensures selective intracellular delivery of DM-1 into the HER2 overexpressing cells. DM-1 is a microtubule inhibitor causing cell cycle arrest and apoptosis. Currently T-DM1 is approved for HER2-positive breast cancer at both the metastatic and the adjuvant settings. In different studies, peripheral neuropathy has been reported as a significant adverse effect of T-DM1. We conducted a systematic review and meta-analysis of phase 3 randomized controlled trials (RCTs) to determine the relative risk of peripheral neuropathy associated with T-DM1 compare to other regimens in HER2-positive cancers. Methods: We conducted a systematic search at PUBMED, MEDLINE, EMBASE databases and professional societies meeting abstracts as per PRISMA guidelines from inception until March 31st, 2019. Published phase 3 RCTs comparing T-DM1 with other therapies in patients with HER2-positive cancers and reporting the number of events of peripheral neuropathy in both intervention and control arms were included in the final analysis. The primary meta-analytic approach was a random effects model using the Mantel-Haenszel (MH) method, and it was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was tested with I2 value and Cochran’s Q-test. Results: Five RCTs (EMILIA, GATSBY, KRISTINE, MARIANNE, and TH3RESA) randomizing 3,422 participants (2067 in the T-DM1 arms and 1355 in the control arms) were included in the final analysis. Four studies (EMILIA, KRISTINE, MARIANNE, and TH3RESA) were conducted in breast cancer patients, and one (GATSBY) was done in gastric/gastro-esophageal junction adenocarcinoma patients. GATSBY was a phase 2/3 RCT and rest were phase 3 RCTs. Patients in the control arms received variable systemic therapies across trials: a taxane based regimen was used in GATSBY, KRISTINE, and MARIANNE trials; a capecitabine and lapatinib combination was used in EMILIA trial; and a treatment of physician’s choice was used in TH3RESA trial. Dose of T-DM1 was usually 3.6 mg/kg every 3 weeks, except for GATSBY study where it was used as 2.4 mg/kg weekly dose. The pooled RR of any grade peripheral neuropathy was not significantly different in the T-DM1 group compared to the control group (pooled RR:0.83, 95%CI: 0.45-1.55, P= 0.57, I2=87%). No publication bias was appreciated across all the studies included in the final analysis. Conclusion: Our meta-analysis demonstrated the relative risk of any grade peripheral neuropathy was not significantly higher in the T-DM1 containing regimens compared to other therapies in patients with HER2-positive cancers. Citation Format: Nusrat Jahan, Fred Hardwicke. Risk of peripheral neuropathy with trastuzumab emtansine: A systematic review and meta-analysis of published phase 3 randomized controlled trials [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-15.

Abstract P5-14-10: Relative risk of grade 3 and higher hematological toxicities with trastuzumab emtansine: A systematic review and meta-analysis of published phase 3 randomized controlled trials

Abstract Background: Trastuzumab Emtansine (T-DM1) is a HER2 targeted antibody-drug conjugate consisting of anti-HER2 IgG1 antibody trastuzumab and maytansine derivative DM-1. Trastuzumab inhibits HER2 receptor signaling and mediates antibody-dependent cell-mediated cytotoxicity; and DM-1 is a microtubule inhibitor causing cell cycle arrest and apoptosis. In addition, the former ensures selective intracellular delivery of the latter into the HER2 overexpressing cells. Currently, T-DM1 is approved for HER2-positive breast cancer both in the metastatic and in the adjuvant settings. We conducted a systematic review and meta-analysis of phase 3 randomized controlled trials (RCTs) using T-DM1 to determine the relative risk of grade 3 and higher hematological toxicities associated with T-DM1. Methods: We conducted a systematic search at PUBMED, MEDLINE, EMBASE and meeting abstracts as per PRISMA guidelines from inception until March 31st, 2019. Published phase 3 RCTs comparing T-DM1 with other therapies in patients with HER2-positive cancers and reporting the number of events of grade 3 and higher hematological toxicities in both intervention and control arms were included in the final analysis. The primary meta-analytic approach was a random effects model using the Mantel-Haenszel (MH) method, and it was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was tested with I2 value and Cochran’s Q-test. Results: Six RCTs (EMILIA, GATSBY, KRISTINE, KATHERINE, MARIANNE, and TH3RESA) randomizing 4882 participants (2807 in the T-DM1 arms and 2075 in the control arms) were included in the final analysis for grade 3 and higher anemia and thrombocytopenia. KATHERINE trial did not report the number of grade 3 and higher neutropenia. Five RCTs (EMILIA, GATSBY, KRISTINE, MARIANNE and TH3RESA) including 3422 (2067 in the T-DM1 arms and 1355 in the control arms) were included in the final analysis for grade 3 and higher neutropenia. Five studies (EMILIA, KATHERINE, KRISTINE, MARIANNE, and TH3RESA) were conducted in breast cancer patients, and one (GATSBY) was done in gastric/gastro-esophageal junction adenocarcinoma patients. GATSBY was a phase 2/3 study and rest were phase 3 RCTs. Patients in the control arms received variable systemic therapies across trials: taxane based regimens were used in GATSBY, KRISTINE, and MARIANNE trials; capecitabine and lapatinib combination was used in EMILIA trial; treatments of physician’s choice were used in TH3RESA trial; and trastuzumab alone was used in KATHERINE trial. The pooled RR of grade 3 and higher thrombocytopenia was significantly higher in the T-DM1 group compared to the control group (pooled RR: 8.59, 95% CI: 1.54-48.00, P= 0.01, I2= 82%). The pooled RR of grade 3 and higher anemia was not significantly different in the T-DM1 group compared to the control group (pooled RR: 1.23, 95% CI: 0.63-2.41, P= 0.54, I2= 72%). The pooled RR of grade 3 and higher neutropenia was significantly lower in the T-DM1 group compared to the control group (pooled RR: 0.16, 95% CI: 0.09 -0.32, P&amp;lt; 0.00001, I2= 76%). Conclusion: T-DM1 was associated with increased risk of grade 3 and higher thrombocytopenia, but reduced risk of grade 3 and higher neutropenia compared to control regimens. The exact mechanism of these findings is not clear, yet they may have some implications in adopting appropriate therapeutic strategies for the patients. The patients who are on T-DM1, a careful monitoring of the platelet will be helpful for the early identification of thrombocytopenia and initiation of appropriate interventions. On the other hand, T-DM1 may be a relatively safer option for the patients who are at risk of developing neutropenia and infectious complications. Citation Format: Nusrat Jahan, Rafiullah Khan, Shabnam Rehman, Fred Hardwicke, Francis Mogollon-Duffo, Lukman Tijani. Relative risk of grade 3 and higher hematological toxicities with trastuzumab emtansine: A systematic review and meta-analysis of published phase 3 randomized controlled trials [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-10.

Abstract P1-18-29: Neopersur: Neoadjuvant pertuzumab in a real world data population in the south of Spain

Abstract Background: Pertuzumab (P) has been aproved in neoadjuvant setting for HER2 positive early breasta cancer patients in association with Trastuzumab (T) and chemotherapy. Diverse studies support this combination as NeoSphere, Tryphaena, GeparSepto or Berenice trial. Some of these studies combine P - T with taxanes and sequencing anthracyclines, and other use antraciclines-free regimen as Carboplatine-Docetaxel-P-T. The patologic complete response (pCR) showed achieve percentages from 45.8 % to 66.6% depending on chemotherapy combination. In Spain, the approval of new drugs is a national issue, but sometimes regional regulatory agencies could modify some indications. We have carry out this study in routine patients as our daily clinical practice. Aims: This is a retrospective and multicentric study that has investigated the clinical characteristics, treatment patterns, safety and clinical outcomes for patient with HER-2 positive early breast cancer patients. Methods: We have collected all HER2 positive early breast cancer patients treated with P in neoadjuvant setting in our hospitals. The effect of adding Pertuzumab on pCR was analyzed, as well as other predictive factors of response using logistic regression analyses. Results: A total of 298 patients met the selection criteria. The median age was 50 years (range 24-88 years), 54,2% were premenopausic. 4 patients were stage I, 194 patients stage II, 95 patients were stage III and one patient was stage IV. 76,3% of the patient had a ki67 &amp;gt;20%. The majority of the patient received anthracyclines and taxanes with P and T regimen (80,7%), 13,2% received carboplatin-docetaxel-P-T combination and only 6,1% received taxane-P-T. 292 patients were analysed for response. pCR was seen in 61,7 % of the patients, dividing by hormonal receptor (HR) status, pCR was 53,29% in HR-positive and 72,14% in HR-negative. 63,4% of the patients received breast conservative surgery. Grade 3-4 chemo-related toxicity was presented in 14,2% of patients, 3 patients presented cardiac toxicity. Different treatments patterns were seen between hospitals: only 15 patients (5,1%) complete adjuvant Pertuzumab, 4 patients (1,4%) received adjuvant Neratinib and 2 patients (0,7%) received adjuvant TDM1. Only 12 patients (4,1%) has presented a distant recurrence, 6 of them (50%) had achieved a previous pCR. Conclusion: In our knowledge, this is the biggest real-world-data presented until this year, for Pertuzumab in the neoadjuvant setting of HER2 positive breast cancer patients. Our results are consistent with those published in previous clinical trial. pCR by subtypepCR NOpCR YESTotalLuminal B HER2+7181152HER2+39101140Total110182292 Citation Format: Alejandro Falcón González, Rocío Álvarez Ambite, Elisenda Llabrés Valenti, Rocío Urbano Cubero, Maria del Carmen Álamo de la Gala, Antonia Martínez Guisado, Carlos José Rodríguez González, Marta Amérigo Góngora, Encarnación González Flores, Salvador Gámez Casado, María Valero Arbizu, Alicia Quilez Cutillas, Josefina Cruz Jurado, Pedro Sánchez Rovira, Fernando Henao Carrasco, Javier Salvador Bofill, Manuel Ruiz Borrego. Neopersur: Neoadjuvant pertuzumab in a real world data population in the south of Spain [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-29.

Abstract P2-16-22: Can we improve pCR prediction in early breast cancers treated with neoadjuvant chemotherapy using a simple machine learning algorithm based on 18-FDG and clinico-pathological parameters?

Abstract Purpose To test the hypothesis that a simple machine learning algorithm could improve pathological complete response (pCR) prediction in breast cancer patients treated with neoadjuvant chemotherapy (NAC) using an integrative approach based on clinico-pathological and metabolic factors. Methods A total of 311 patients with non-metastatic breast cancer were included. Baseline clinico-pathologic features were evaluated before NAC and tumor uptake of FDG was evaluated before and after one course of NAC. The predictive value of clinico-pathologic and metabolic parameters on pCR was calculated by means of logistic regression analysis and a simple machine learning algorithm generating a hierarchical predictive model using a classification and regression tree (CART). Results: The CART model performed better than all the clinico-pathological and metabolic parameters that were predictive of pCR after univariate analysis. The CART model identified five different groups (G): G1 (luminal cancer with Ki67≤30%), G2 (luminal cancer with Ki67&amp;gt;30% and baseline SUVmax≤10.1), G3 (luminal cancer with Ki67&amp;lt;30% and baseline SUVmax&amp;gt; 10.1), G4 (Her2 positive or triple negative cancer with ΔSUVmax ≤50%) and G5 (Her2 positive or triple negative cancer with ΔSUVmax &amp;gt;50%). The pCR rates predicted by the model for each of the identified groups were G1: 7.2%, G2: 16.7%, G3: 54.6%, G4: 35% and G5: 85% Conclusion This study showed that CART, a simple machine learning algorithm, integrating clinico-pathological and metabolic parameters easily obtainable in routine clinical practice, can improve pCR prediction in early breast cancer and identify subgroups that will not benefit from NAC Baseline patient characteristics of the entire cohort and according to the tumor subtypeCharacteristicsGlobalLumALumBHER2THN311321198476Age (median)4950.249.351.143.3Histological type NST/Other290/2127/5107/1281/375/1Grade 14%22%4%1%0%Grade 237%56%46%32%19%Grade 357%22%47%62%80%Grade missing2%0%3%5%1%ER+58%100%89%45%0%PgR+48%88%75%37%0%ER and PgR neg36%0%0%43%0%HER2 positif27%0%0%100%0%Nodal status negative32%13%32%35%33%Nodal status positive64%50%63%63%61%Nodal status missing data4%37%5%2%6%Stage 11%0%0%0%1%Stage 2A25%28%24%11%28%Stage 2B26%34%24%31%17%Stage 3A16%9%17%13%18%Stage 3B21%22%23%25%17%Stage 3C7%3%7%5%11%Missing stage5%3%5%4%8%mean SUV max (PET-FDG)8.94.859.28.411.7 Univariate and multivariate analyses for pCR predictionVariablepCR (%)OR (95% CI)Univariate analysisp valueOR (95% CI)Multivariate analysisp valueMolecular subtypeLum A1 (3.1)0.15 (0.01-0.076)&amp;lt;0.0010.44 (0.02-2.71)0.029Lum B22 (17.7)11HER241 (48.8)4.42 (2.38-8.41)3.64 (1.40-9.65)TN31 (43.7)3.59 (1.87-7.01)1.65 (0.56-5.02)Histiological grade1/224 (18;8)1&amp;lt;0.001368 (38.6)2.73 (1.61-4.74)Baseline Ki67&amp;lt;=30%26 (19)1&amp;lt;0.001&amp;gt;30%60 (41.4)3.01 (1.77-5.23)AJCC TNM Stage0.36nodal statusN033 (33)0.53N+58 (29)Body surface area&amp;lt;=1.73160 (52.8)2.11 (1.28-3.51)0.003&amp;gt;1.73143 (47.2)1Baseline SUV max&amp;lt;=10.127 (22)1&amp;lt;0.00110.04&amp;gt;10.139 (47.6)3.22 (1.77-5.98)2.24 (1.04-4.67)Delta SUV max&amp;lt;50%17 (22.7)1&amp;lt;0.001&amp;gt;=50%22 (66.7)6.82 (2.83-17.41) Citation Format: Marc-Antoine Benderra, Martine Antoine, Sonia Zilberman, Sandrine Richard, Fatima Kebir, Sofiane Bendifallah, Jean-Pierre Lotz, Emile Darai, Joseph Gligorov, Khaldoun Kerrou. Can we improve pCR prediction in early breast cancers treated with neoadjuvant chemotherapy using a simple machine learning algorithm based on 18-FDG and clinico-pathological parameters? [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-22.

Abstract P1-18-35: MT-5111, a novel HER2 targeting engineered toxin body, under clinical development to overcome mechanisms of resistance to existing HER2 targeted therapies

Abstract Engineered toxin bodies (ETBs) are differentiated, targeted therapeutics comprised of a proprietarily engineered form of Shiga-like Toxin A subunit (SLTA) genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action and are capable of forcing internalization, self-routing through intracellular compartments to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation of ribosomes. MT-5111 is a de-immunized ETB targeting HER2 for solid tumors. MT-5111 works through a novel mechanism of direct cell-kill, via enzymatic ribosome inactivation, and may not be subject to resistance mechanisms that exist for TKI, ADC, or antibody modalities. MT-5111 is a 55 kilodalton protein and may have improved tumor penetration features in the solid tumor settings. MT-5111 has been designed to bind a HER2 domain distinct from the trastuzumab and pertuzumab binding sites and retains binding to HER2 and cell-kill activity even in the presence of these monoclonal antibodies. As such, MT-5111 may have the potential to be combined with other HER2 targeted therapies. MT-5111 specifically binds and kills HER2 expressing cells in a manner consistent with SLTA-mediated cellular cytotoxicity. MT-5111 effectively killed eight of nine cell lines with moderate to high HER2 surface expression, five of which were breast cancer cell lines. No cytotoxicity was observed on multiple HER2-negative cell lines at MT-5111 levels &amp;gt;500 fold higher than IC50 levels in HER2-positive cells. The cytotoxic activity of MT-5111 (picomolar range) is dependent on the presence of the HER2 receptor, and efficient killing is observed prior to receptor saturation. As a large molecule protein, MT-5111 is not a substrate of drug efflux transporters such as MDR1 which has been demonstrated to be one of the primary mechanisms of resistance to the antibody drug conjugate T-DM1. Specifically, T-DM1 resistant cell lines with moderate HER2 expression (JIMT-1 breast cancer and SNU-216 gastric cancer lines) were sensitive to MT-5111 but were not effectively killed by T-DM1, highlighting the benefit of a novel MOA to treat resistant disease. Further, MT-5111 has demonstrated effective cell-killing in vitro against trastuzumab resistant cell lines (HCC1954 breast cancer). MT-5111 binds both human and cynomolgus monkey HER2 protein similarly. From repeat dose studies in non-human primates, the serum exposure of MT-5111 was used to model the pharmacokinetics of MT-5111 dosing in human. This modelling suggests that MT-5111 can be administered at doses in humans above the IC50 required for HER2-specific cellular cytotoxicity in vitro. MT-5111 was designed to achieve a short half-life to allow for efficient tumor cell targeting but minimal serum exposure time to avoid systemic effects over time. This short half-life was confirmed in primates (t1/2 of ~2 to 5 hours). A Phase 1, first in human, open-label dose escalation, and expansion study of MT-5111 (NCT04029922) in subjects with HER2-positive solid tumors whose disease has progressed after treatment with other approved therapies is open for enrollment. In conclusion, MT-5111 represents a novel HER2 targeted therapy which could provide benefit in subjects with HER2-positive cancers and potentially overcome mechanisms of tumor resistance to existing HER2 targeted therapies. Citation Format: Jack P Higgins, Asis Sarkar, Eric T Williams, Aimee Iberg, Roger Waltzman, Erin K Willert. MT-5111, a novel HER2 targeting engineered toxin body, under clinical development to overcome mechanisms of resistance to existing HER2 targeted therapies [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-35.

Abstract GS5-04: Accuracy of post-neoadjuvant chemotherapy image-guided breast biopsy to predict the presence of residual cancer: A multi-institutional pooled analysis

Abstract Background: Image-guided biopsy of the residual imaging abnormality / tumor bed at the end of neoadjuvant chemotherapy (NAC) is increasingly used to assess residual disease in the breast, facilitate risk-adaptive surgery and potentially identify exceptional responders who may not require surgical intervention. The aim of this pooled analysis was to further assess the accuracy of post-NAC, image-guided biopsy to predict residual disease in the breast. The findings could help define an optimal post-NAC biopsy protocol to support trials omitting surgery in selected groups of patients. Methods: Multi-institutional, individual patient data on post-NAC image-guided biopsy was collected and pooled following Institutional Review Board (IRB) approval from each centre (Royal Marsden Hospital, Seoul National University Hospital, MD Anderson Cancer Center). Biopsy sampling accuracy was defined as representative if pathology features suggestive of tumor bed or residual cancer were identified. Pathologic complete response (pCR) was defined as no residual disease in the breast (ypT0). Biopsy predictive accuracy was calculated using final surgical pathology as the reference standard. Simple descriptive statistics and non-parametric analyses were performed. Results: Data were analyzed from 166 women who underwent post-NAC image-guided biopsy. Median age was 49 years (range: 25-76). The majority (n=160) had invasive ductal carcinoma (IDC) with phenotype distribution of 31 (18.7%), 47 (28.3%), 29 (17.5%) and 59 (35.5%) respectively for hormone receptor (HR) positive / Human Epidermal Growth Factor Receptor (HER)-2 negative, HR and HER2 positive, HR negative / HER2 positive and triple negative (TN). Median tumor size on pre-treatment imaging was 33.5 mm (range: 12-100). The overall pCR rate was 51.2% [16.1% for HR positive / HER2 negative, 44.7% for HR positive / HER2 positive, 69% for HR negative / HER2 positive and 66.1% for TN]. The majority (n=143) underwent vacuum assisted biopsy (VAB) and 23 had core cut (CC) biopsy. Median size of the biopsy needle was 10 gauge (range: 7-14) and median number of samples was 6 (range: 2-18). The biopsy was performed under ultrasound (n=129) or stereo guidance (n=37) and in 159 cases was representative of the tumor bed. When the image-guided biopsy (VAB and CC) was representative, the false negative rate (FNR) across the whole cohort was 18.7% (95% CI 9.8-26.8). Exploratory analysis of accuracy of VAB in cases with a residual imaging abnormality &amp;lt; 2 cm to allow adequate sampling and at least 6 representative biopsies taken (n=76) showed a FNR of 3.2% (95% CI 0-8.8), a negative predictive value (NPV) of 97.4% (95% CI 84.6-99.6) and an overall accuracy of 89.5% (95% CI: 80.3-95.3). Subgroup analysis in patients with HER2 positive or TN cancer (n=66) who are the most likely to be exceptional responders and achieve pCR showed similar accuracy of the technique with a FNR of 4.2% (95% CI 0-10.7), a negative predictive value (NPV) of 97.2% (95% CI 83.6-99.6) and an overall accuracy of 87.9% (95% CI: 77.5-94.6). Conclusions: This large pooled multicenter data suggests that a standardized protocol using image-guided VAB of a tumor bed measuring up to 2 cm with at least 6 samples allows reliable prediction of residual disease and pCR. These results should inform the design of de-escalation trials in NAC exceptional responders testing the safety of eliminating surgery. Citation Format: Marios Konstantinos Tasoulis, Han-Byoel Lee, Wei Yang, Romney Pope, Savitri Krishnamurthy, Soo-Yeon Kim, Nariya Cho, Victoria Teoh, Gaiane M Rauch, Benjamin D Smith, Vicente Valero, Wonshik Han, Royal Marsden Hospital MDT, Fiona MacNeill, Henry M Kuerer. Accuracy of post-neoadjuvant chemotherapy image-guided breast biopsy to predict the presence of residual cancer: A multi-institutional pooled analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS5-04.

Abstract P5-04-18: Unfavourable tumour stromal immune cell infiltrates but not circulating immune cell profiles in Aboriginal women with breast cancer

Abstract Breast cancer (BrCa) in Aboriginal Australian women carries more than double the risk of death relative to non-Aboriginal Patients. This higher death is partially explained by factors such as higher stage at diagnosis, younger age, increased co-morbidities, remoteness, socioeconomic disadvantage, and access to culturally sensitive health services. Aboriginal women in a Western Australian cohort also more frequently had tumours with adverse biological features including high grade and luminal B or HER2-enriched phenotype. However, an unexplained detriment remained relative to non-Aboriginal women after accounting for these factors. The immune environment of a tumour as well as of the patient in general can impact on native tumour behaviour as well as response to treatment. Studies in many tumour types including meta-analyses in breast cancer correlate higher circulating neutrophil: lymphocyte ratios (NLR) and neutrophil:platelet ratios (NPR) with poorer outcome. Further to this, tumour infiltrating lymphocyte (TIL) levels also have prognostic significance, associating with improved outcome in triple negative and HER2 positive cancers receiving chemotherapy but with adverse outcomes in estrogen receptor positive (ER+) cancers, potentially through to links to anti-estrogen resistance. To further explore drivers of poor outcome in Aboriginal women we studied circulating NLRs and NPRs in a cohort of Indigenous women matched by remoteness of residence and age to non-Indigenous women in Western Australia. Considering the impact of incidental inflammatory conditions over time only levels from counts taken within 90 days either side of diagnosis were considered. Tissue sections where available were assessed for TILs by standard published methods. NLR was available on 214 patients. The median ratio for Indigenous patients (2.46) was not different to non-Indigenous patients (2.13). Considering patients with NLR &amp;gt; 3.0, a cut-off noted to have poorer prognosis in meta-analysis (ref), there was a stronger trend to higher relapse in non-Indigenous (HR 2.14, p=0.07) than Indigenous patients (HR =1.38, p=0.43) for higher NLR. High NLR was not more common in Indigenous relative to non-Indigenous patients (32% v 25%, p=0.37). Considering very high NLR, significantly more Indigenous women had NLRs &amp;gt;5.0 (4.8 v 6.3%, p=0.04). PLR was available on 225 patients. The median for Indigenous patients (126) was not different to non-Indigenous patients (130). Considering patients with PLR &amp;gt; 185, a cut-off noted to have poorer prognosis in meta-analysis (ref), there were non-significant trends to higher relapse in both Indigenous (HR 1.94, p=0.1) and non-Indigenous patients (HR =1.67, p=0.26) for higher PLR. However, high PLR was not more common in Indigenous relative to non-Indigenous patients (15.4 v 21.6%, p=0.24). Stromal TILs were available on 86 patients. Mean % TIL count was significantly higher in Indigenous women (10.7 v 6.6%, p=0.003). This difference was significant for ER+ (9.6 v 3.5%, p=0.004) but not ER- tumours (20.0 v 21.6%, p=0.79). Significantly more Aboriginal patients with ER positive tumours had &amp;gt;=10% TIL infiltrates (41.7 v 9.8%, p=0.0025) but not those with ER- cancers (70 v 40%, p=0.18). In summary, measured circulating immune or inflammatory profiles did not substantially differ between Aboriginal and non-Aboriginal breast cancer patients. In contrast, although numbers are small, ER+ tumours in Aboriginal women had a higher incidence of significant TIL infiltrates which may both contribute to poorer prognosis and predict for higher utility from immunotherapy. An expansion of the cohort is underway along with immune cell sub-typing and immune checkpoint molecule assessments. Citation Format: Andrew David Redfern, Jacinta J Fong, Lisa J Spalding, Sherene Loi, Benjamin Dessauvagie, Jennet Harvey, Katie Meehan. Unfavourable tumour stromal immune cell infiltrates but not circulating immune cell profiles in Aboriginal women with breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-04-18.

Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance.

Trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), has improved survival in patients with HER2-positive advanced gastric or gastroesophageal junction cancer (AGC). The inevitable development of resistance to trastuzumab remains a problem, however, with several treatment strategies that have proven effective in breast cancer having failed to show clinical benefit in AGC. In this review, we summarize the mechanisms underlying resistance to HER2-targeted therapy and outline past and current challenges in the treatment of HER2-positive AGC refractory to trastuzumab. We further describe novel agents such as HER2 antibody–drug conjugates that are under development and have shown promising antitumor activity in early studies.

Analysis of the Cost-Effectiveness of Liquid Biopsy to Determine Treatment Change in Patients with Her2-Positive Advanced Breast Cancer in Colombia.

BackgroundBreast cancer is highly prevalent worldwide and leads to high health-care costs. HER2-positive subtype represents 30% of all breast cancers and is associated with a poor prognosis. Patients treated with anti-HER2 therapies frequently develop resistance and require pharmacological treatment change. Liquid biopsy is a minimally invasive and an easily accessible technique, with high sensitivity and specificity, to detect molecular treatment resistance even before the onset of clinical manifestations and can thus be used to reduce unnecessary anti-HER2 treatment costs.ObjectiveTo evaluate the cost-effectiveness of using liquid biopsy (ctDNA detection) to determine treatment change in women with HER2-positive advanced breast cancer in Colombia.MethodologyWe performed an economic evaluation using decision tree modeling and deterministic analyses based on literature search for first and second lines of treatment (trastuzumab, pertuzumab, docetaxel, and TDM1); resistance; outcomes; and sensitivity and specificity of tests detecting molecular resistance. The effectiveness was measured using quality-adjusted life year (QALY) score, and costs were obtained from databases with national validity, suppliers, the Colombian Drug Price Information System (SISMED), and local studies.ResultsThe use of liquid biopsy (ctDNA detection) with conventional treatment was more expensive and less effective than conventional treatment without liquid biopsy (US $177,985.35 and 0.533889206 QALY, respectively). The incremental cost with liquid biopsy was US $7,333.17 and the incremental effectiveness was 0.00042256 QALY relative to the conventional method.ConclusionIncluding liquid biopsy in the treatment of HER2-positive advanced breast cancer was considered currently inapplicable in Colombia because it was not cost effective. Our results open a window of opportunity to improve the development and implementation of ctDNA testing in Colombia, potentially reducing current costs. More evidence is required on the utility of this test, depending on the financial capacity of Colombia and other countries.