Metastatic HER2 Research Articles

MOUNTAINEER-02: Phase II/III study of tucatinib, trastuzumab, ramucirumab, and paclitaxel in previously treated HER2+ gastric or gastroesophageal junction adenocarcinoma—Trial in Progress.

TPS252 Background: Tucatinib (TUC), a highly selective HER2-directed TKI recently approved for HER2+ metastatic breast cancer (MBC), is being developed as a novel therapy for patients (pts) with metastatic colorectal cancer (mCRC) and other GI tumors. While trastuzumab (Tras) with chemotherapy is standard in the 1st-line setting for metastatic HER2+ gastric or gastroesophageal junction adenocarcinoma (GEC), no anti-HER2 therapy has demonstrated an OS benefit over chemotherapy in 2nd-line, possibly due to loss of HER2 expression following Tras-based therapy. In GEC xenograft models, dual targeting of HER2 with TUC and Tras showed superior activity to either agent alone. Interim results from the MOUNTAINEER study have shown promising activity for TUC and Tras in HER2+ mCRC. The MOUNTAINEER-02 study is evaluating the efficacy and safety of TUC in combination with Tras, ramucirumab (Ram), and paclitaxel (Pac) in pts with HER2+ GEC. Methods: MOUNTAINEER-02 (NCT04499924) is a phase 2/3 study evaluating TUC and Tras with the 2nd-line standard of care, Ram and Pac. Pts receive TUC 300 mg or placebo PO BID, Tras (6 then 4 mg/kg) or placebo (IV on Days 1 and 15 of each 28-day cycle), Pac (IV on Days 1, 8, 15), and Ram (IV on Days 1 and 15). Eligible pts have locally-advanced unresectable or metastatic HER2+ GEC, have received a HER2-directed antibody, and 1 prior line of therapy for advanced disease. Pts must be ≥18 years of age, with an ECOG ≤1, and have had no prior exposure to Ram, anti-HER2 or anti-EGFR TKI, HER2-directed antibody-drug conjugates, or taxanes ≤12 months before enrollment. Due to the potential impact of TUC on Pac metabolism, the study will include an initial Pac dose finding stage. The open-label phase 2 part will determine the recommended dose of Pac (60 or 80 mg/m²) combined with TUC, Tras, and Ram in 6-12 patients, and evaluate the safety and activity of the regimen in Cohorts 2A and 2B (30 patients each). The randomized, double-blind, phase 3 part will compare the efficacy and safety of TUC and Tras (Arm 3A; ~235 patients) vs. placebo (Arm 3B; ~235 patients), both in combination with Ram and Pac, and also evaluate activity of TUC with Ram and Pac (Arm 3C; ~30 patients). The dual primary phase 3 endpoints are OS and PFS per investigator, with confirmed ORR as a key secondary endpoint. HER2 status is determined at baseline using a blood-based NGS assay, and IHC/ISH of fresh or archival tumor biopsies, if available. Pts must be HER2+ by blood-based NGS in Cohort 2A and phase 3; in Cohort 2B, pts must be HER2+ in a biopsy taken post-progression during/after 1st-line therapy, but HER2-negative by blood-based NGS. Disease assessments per RECISTv1.1 will occur q6 weeks for 36 weeks, then q9 weeks. The pharmacokinetics of TUC, Pac, and their metabolites will be evaluated in a subset of pts, including a cohort with gastrectomies. Enrollment is ongoing in the U.S. Clinical trial information: NCT04499924.

The role of novel poly (ADP-ribose) inhibitors in the treatment of locally advanced and metastatic Her-2/neu negative breast cancer with inherited germline BRCA1/2 mutations. A review of the literature.

The use of the PARP inhibitors (PARPi) in the treatment of breast cancer (BC) with germine mutations has evolved over the years, and further research has been done in order to broaden the horizon of this treatment strategy. Therefore the aim of this paper is to review the efficiency of PARPi in the treatment of BRCA 1/2-mutated locally advanced and metastatic Her-2/net negative BC mentioning their side effects, mechanism of resistance and future directions. Inhibition of PARP transforms single-strand breaks into double-strand breaks (DBS), the accumulation of the latter causing cell death (cell apoptosis). The Olympia AD phase III trial demonstrated a statistically significant progression-free survival rate (PFS) when using the PARPi olaparib in metastatic BC with germline BRCA1/2 mutations without any benefit of the overall survival rate. PARPi therapy is associated with acceptable responsive rates and progression-free survival rates in locally advanced and metastatic BRCA1/2 associated BC through mechanisms that enhance and increase the sensitivity to chemotherapeutic or target agents as they induce a synthetic lethality and cell apoptosis. The side effects are not significant, the most adverse effects being related to the hematological and gastrointestinal systems. Olaparib is currently approved in the first-line treatment of BRCA1/2 mutated Her-2/neu negative metastatic BC at an oral dose of 300 mg twice daily, while Talazoparib represents a category one recommendation in locally advanced and metastatic Her-2/neu negative BC in women with central nervous system metastases.

Targeted therapy in the treatment of HER-2 positive breast cancer with brain metastases

Metastatic damage to the brain is a frequent manifestation in tumors of various localizations, including breast cancer. Until recently, systemic therapy of metastatic brain damage was of limited use; however, with the advent of targeted drugs that are better understood in terms of the specific molecular targets and biological characteristics of metastases, it is now possible to improve treatment results. In an analysis of the results of studies on the problem of metastasis of breast cancer in the brain, a comparison of the use of various targeted drugs in the treatment of metastatic HER2 + breast cancer is presented. The results of a comparison of the degrees of effectiveness of targeted drugs, both in monotherapy and in combination with chemotherapy, were obtained and analyzed.

An evaluation of palbociclib as a breast cancer treatment option: a current update

ABSTRACT Introduction Patients with hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer have benefitted from treatment with palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor capable of selectively targeting mechanisms of cell cycle progression that contribute to tumor cell proliferation. Palbociclib use in this setting demonstrates improved progression-free survival when given in combination with aromatase inhibitors or fulvestrant. Areas covered The authors describe the current state of research surrounding palbociclib use in breast cancer, present evidence supporting a role for palbociclib in additional subtypes of metastatic breast cancer such as HER2-positive (HER2+) and triple-negative, report ongoing clinical trials aimed at expanding the scope of use for palbociclib, and discuss expected clinical results that will better inform decisions on including palbociclib as a part of breast cancer treatment strategies. Expert opinion Preclinical and clinical studies have shown promising evidence for palbociclib use in metastatic HER2+ and androgen receptor-expressing triple-negative breast cancer but mixed results in the adjuvant/neoadjuvant setting, where differences may only be detectable in high-risk disease. Palbociclib combinations may constitute viable replacements for chemotherapy in the neoadjuvant setting as part of de-escalation strategies. Investigation into synergy of palbociclib with immunotherapies is also ongoing based on non-canonical effects of CDK4/6 inhibition on the tumor immune microenvironment.

67TiP HER2CLIMB-02: A randomized, double-blind, phase III study of tucatinib or placebo with T-DM1 for unresectable locally-advanced or metastatic HER2+ breast cancer

67TiP HER2CLIMB-02: A randomized, double-blind, phase III study of tucatinib or placebo with T-DM1 for unresectable locally-advanced or metastatic HER2+ breast cancer

Molecular landscape and efficacy of HER2-targeted therapy in patients with HER2-mutated metastatic breast cancer

Human epidermal growth factor receptor 2 (HER2) protein overexpression or gene amplification is an important predictive biomarker for identifying patients with breast cancer, who may benefit from HER2-targeted therapy. However, little is known about the molecular landscape and efficacy of HER2-targeted therapy in patients with HER2-mutated metastatic breast cancer. We analysed the HER2 mutation features of 1184 patients with invasive breast cancer. In addition, a single-arm, prospective, phase-II study (NCT03412383) of pyrotinib was conducted in patient with metastatic HER2 amplification-negative, mutation-positive breast cancer. Peripheral blood was collected from each patient and circulating tumour DNA (ctDNA) sequencing was performed using a 1021 gene panel. HER2 mutations were detected in 8.9% (105/1184) of patients. The HER2 amplification-positive patients had a higher mutation frequency than the HER2 amplification-negative patients (19.5% vs. 4.8%, P < 0.001). A multivariate Cox regression analysis indicated that patients with HER2 mutations had a shorter progression-free survival (PFS) than HER2 wild-type patients (median PFS 4.7 months vs. 11.0 months, hazard ratio 2.65, 95% confidence interval 1.25–5.65, P = 0.011). Ten HER2 amplification-negative, mutation-positive patients who received pyrotinib monotherapy were ultimately included in the efficacy analysis. The median PFS was 4.9 months. The objective response rate (complete response + partial response) was 40.0% and the clinical benefit rate (complete response + partial response + stable disease over 24 weeks) was 60%. In conclusion, a HER2 gene mutation analysis is potentially useful to identify biomarkers of trastuzumab resistance in HER2 amplification-positive patients. Patients with HER2-mutated, non-amplified metastatic breast cancers may benefit from pyrotinib.

A population-based comparison of treatment, resource utilization, and costs by cancer stage for Ontario patients with HER2-positive breast cancer

PurposeWe sought to expand the currently limited, Canadian, population-based data on the characteristics, treatment pathways, and health care costs according to stage in patients with human epidermal growth factor receptor-2 positive (HER2+) breast cancer (BC).MethodsWe extracted data from the publicly funded health care system in Ontario. Baseline characteristics, treatment patterns, and health care costs were descriptively compared by cancer stage (I–III vs. IV) for adult women diagnosed with invasive HER2+ BC between 2012 and 2016. Resource use was multiplied by unit costs for publicly funded health care services to calculate costs.ResultsOverall, 4535 patients with stage I–III and 354 with stage IV HER2+ BC were identified. Most patients with stage I–III disease were treated with surgery (4372, 96.4%), with the majority having a lumpectomy, and 3521 (77.6%) received radiation. Neoadjuvant (NAT) and adjuvant (AT) systemic treatment rates were 20.1% (n = 920) and 88.8% (n = 3065), respectively. Systemic treatment was received by 311 patients (87.9%) with metastatic HER2+ BC, 264 of whom (84.9%) received trastuzumab. Annual health care costs per patient were nearly 3 times higher for stage IV vs. stage I–III HER2+ BC.ConclusionPer-patient annual costs were substantially higher for women with metastatic HER2+ BC, despite less frequent exposure to surgery and radiation compared to those with early stage disease. Increasing NAT rates in early stage disease represent a critical opportunity to prevent recurrence and reduce the costs associated with treating metastatic HER2+ BC.

Optimizing the management of HER2-negative metastatic breast cancer in the era of PARP inhibitors-proceedings from breast cancer expert group meeting.

The therapeutic landscape of human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) has evolved considerably with the introduction of newer targeted agents such as poly-ADP ribose polymerase inhibitors (PARPi), novel chemotherapeutic agents, immunotherapy, and endocrine therapies. In this scenario, optimizing the appropriate treatment sequence is a daunting task for clinicians. To develop evidence-based answers to key clinical questions on treatment selection and appropriate treatment sequence for the management of patients with HER2- mBC in the era of PARPi, a breast cancer expert group meeting was convened. The expert panel comprised of eight key opinion leaders from Argentina, Brazil, Colombia, Egypt, Mexico, Moscow, South Korea, and the United Arab Emirates, who convened and reviewed the literature, discussed the clinical practices across the participating regions, and formulated answers to key clinical questions for optimizing the management of HER2- mBC. In this review, evidence-based answers have been provided pertaining to (I) the specific mBC population to be considered for BRCA testing, optimal time point of BRCA testing, and genetic counselling in mBC patients; (II) the role of PARPi versus platinum therapy in HER2- mBC patients in the metastatic setting; (III) sequencing treatment in metastatic triple-negative breast cancer (TNBC) and hormone receptor-positive HER2- mBC patients, and defining the place of PARPi in the sequencing algorithms; and (IV) the need for a breast cancer registry for patients with HER2- mBC. This expert review will serve as a comprehensive guide to clinicians for optimizing BRCA testing and managing patients with BRCA mutation (BRCAm) and HER2- mBC. The data collected from the proposed HER2- mBC registry will help understand the treatment practices, identify unmet needs, and develop strategic policies regionally to help improve access to optimized care of HER2- mBC.

274 ASSESSMENT OF THE ANTI-PROLIFERATIVE EFFECTS OF STANDARD CHEMOTHERAPY AND PAN-HER FAMILY TYROSINE KINASE INHIBITORS IN ESOPHAGEAL CANCER CELL LINE MODELS.

Abstract Esophageal cancer is the 9th most common cause of cancer globally with a mortality:incidence ratio of 0.88 and a 5 year mortality rate of 19%. Herceptin, a HER2 targeted monoclonal antibody, is approved for use in metastatic HER2+ gastroesophageal carcinoma. To further examine the benefits of HER family inhibition in esophageal cancer, the effects of pan-HER family TKIs and standard chemotherapy in HER2+ and HER2-low cell line models were examined. Methods Two cell lines, OE19 (HER2+) and FLO-1 (HER2-low) were used to examine the effect of the standard FLOT chemotherapy regimen (5 flurouracil (5FU), oxaliplatin and docetaxel) and pan-HER TKIs neratinib and poziotinib. All compounds were from commercial sources. 2D acid phosphatase-based proliferation assays were utilised to assess the anti-proliferative effects of these agents. Triplicates of each assay were performed and standard deviations were determined. IC50 values were calculated using Calcusyn ® software. Results The OE19 cell line demonstrated a high sensitivity to neratinib and poziotinib with IC50 values of 3.426+/−0.187 nM and 0.307 +/−0.051 nM), respectively. IC50 values for neratinib (0.147+/−0.080 μM) and poziotinib (2.4+/−0.471 μM) were significantly higher (p &amp;lt; 0.05) in the FLO-1 cell line compared to OE19. The IC50 values for oxaliplatin and docetaxel were comparable between the OE19 and FLO-1. However, both cell lines were insensitive to 5FU with IC50 values greater than 10 μM. Conclusion The HER2+ cell line was significantly more sensitive to the pan-HER family TKIs neratinib and poziotinib, compared to the HER2-low cell line. This may indicate a potential use for pan-HER family TKIs in HER2+ esophageal cancer. Further work is being conducted to assess potential synergy between pan-HER family TKIs and chemotherapy in these models.

353TiP HER2CLIMB-02: A randomized, double-blind, phase III study of tucatinib or placebo with T-DM1 for unresectable locally advanced or metastatic HER2+ breast cancer

353TiP HER2CLIMB-02: A randomized, double-blind, phase III study of tucatinib or placebo with T-DM1 for unresectable locally advanced or metastatic HER2+ breast cancer

Triplet Therapy for HER2+ Metastatic Breast Cancer and Brain Metastases

As patients with metastatic HER2+ breast cancer live longer, thanks to improvements in systemic treatment, they have up to a 50% risk for developing

Randomized double-blind clinical trial comparing safety and efficacy of the biosimilar BCD-022 with reference trastuzumab

BackgroundBCD-022 is a trastuzumab biosimilar which was shown to be equivalent to reference trastuzumab in a wide panel of physicochemical studies as well as preclinical studies in vitro and in vivo. International multicenter phase III clinical trial was conducted to comparatively assess efficacy and safety of BCD-022 and reference trastuzumab in combination with paclitaxel used as the therapy of metastatic HER2(+) breast cancer. Pharmacokinetics and immunogenicity were also studied.MethodsPatients with no previous treatment for metastatic HER2(+) breast cancer were randomly assigned 1:1 to BCD-022 or reference trastuzumab and were treated with trastuzumab + paclitaxel. Therapy continued for 6 cycles of therapy (every 3 weeks), until progression of the disease or unbearable toxicity. Primary study endpoint was overall response rate. Study goal was to prove equivalent efficacy of BCD-022 and reference trastuzumab. Equivalence margins for 95% CI for difference in overall response rates were set at [− 20%; 20%].ResultsIn total 225 patients were enrolled into the study, 115 in BCD-022 arm and 110 in reference trastuzumab arm. Overall response rate was 49.6% in BCD-022 arm and 43.6% in reference trastuzumab arm. Limits of 95% CI for difference of overall response rates between arms were [(− 8.05)-19.89%], thus, they lied within predetermined equivalence margins [− 20%; 20%]. Profile of adverse events was similar between groups (any AEs were reported in 93.81% of patients in BCD-022 arm and 94.55% of patients in reference arm). No unexpected adverse reactions were reported throughout the study. No statistically significant differences regarding antibody occurrence rate (either BAb or NAb) was found between BCD-022 (n = 3; 2.65%) and comparator (n = 4; 3.64%). Both drug products are characterized with low occurrence rate and short life of anti-trastuzumab antibodies. Pharmacokinetics assessment after 1st and 6th study drug injection also demonstrated equivalent PK parameters by all outcome measures: AUC0–504, Сmах, Тmax, T1/2. Analysis of Ctrough did not reveal any significant inter-group differences as well.ConclusionsThus, results of this study have demonstrated therapeutic equivalence of trastuzumab biosimilar BCD-022 and referent trastuzumab drug.Trial registrationThe trial was registered with ClinicalTrials.gov (Study Number NCT01764022). The date of registration was January 9, 2013.

Abstract 1913: Soluble TNFα blockade overcomes lapatinib resistance and induces an innate immune response in HER2-positive breast cancer

Abstract Lapatinib (LAP), a dual EGFR/HER2 tyrosine kinase inhibitor, is used as second-line therapy in women with HER2+ breast cancer (BC), but less than 25% of the patients achieve an objective response. An alternative therapeutic approach is needed to overcome LAP resistance in women with metastatic HER2+ BC, particularly in patients with central nervous system (CNS) metastasis where large biological molecules are not effective. Previously, we reported that women with HER2+ tumors that express transmembrane glycoprotein mucin 4 (MUC4) have worse survival, and that HER2+/MUC4+ cell lines resistant to trastuzumab (T) express higher levels of tumor necrosis factor α (TNF) than T-sensitive cell lines. In addition, we proved that inhibition of soluble TNF (sTNF) decreases the expression of MUC4 and reverses T resistance. The aim of this work is to evaluate the participation of sTNF and transmembrane TNF (tmTNF) in LAP resistance in vivo and in the anti-tumor innate immune response. We used the LAP-resistant human BC cell line JIMT-1 and compared etanercept (E), a fusion protein that non-selectively blocks both sTNF and tmTNF, with the dominant negative-TNF protein INB03 (DN), that neutralizes sTNF without affecting tmTNF. Nude mice bearing JIMT-1 tumors (~50 mm3), received LAP (100 mg/kg) daily by oral gavage and IgG (5 mg/kg), E (5 mg/kg), DN (10 mg/kg), LAP+E or LAP+DN, twice a week i.p. Tumor volume was monitored routinely. At the end of the experiment, tumor-infiltrating immune cells were evaluated by immunofluorescence and analyzed by flow cytometry. DN or E treatments did not exhibit any anti-tumor effect alone, but in combination with LAP (LAP+DN and LAP+E) tumor growth decreased in a 54% and 34% vs. IgG, respectively (p&amp;lt;0.0001). LAP+DN combination was significantly more effective in decreasing JIMT-1 tumor growth than LAP+E (p&amp;lt;0.05). Analysis of tumor-infiltrating immune cells showed that tumor growth inhibition was accompanied by an increase in NK cell activation and degranulation, and a decrease in monocytic-myeloid-derived suppressor cells in the tumor bed of LAP+E and LAP+DN treated groups (p&amp;lt;0.01, vs. IgG). This is the first report to show that TNF blockade is able to overcome LAP resistance. In addition, TNF neutralization together with LAP treatment unleashes an anti-tumor innate immune response. These data, combined with previous results, suggest that MUC4 expression in patients with HER2+ BC could act not only as a biomarker of T resistance but also of LAP resistance. Women with HER2+/MUC4+ tumors undergoing treatment with LAP would benefit from the combined administration of LAP with the selective sTNF inhibitor DN to help overcome resistance; a hypothesis to be tested in a clinical trial. This therapeutic strategy may be particularly useful in patients with CNS metastasis because LAP and DN cross the blood-brain-barrier. Citation Format: Sofia Bruni, Florencia L. Mauro, Mara De Martino, Agustina Roldán Deamicis, María F. Mercogliano, Patricia V. Elizalde, Roxana Schillaci. Soluble TNFα blockade overcomes lapatinib resistance and induces an innate immune response in HER2-positive breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1913.

Abstract 1501: Exceptional response to anti HER-2 targeted therapy in patient with HER2/neu negative breast cancer with HER2/neu positive CTCs

Abstract Background: Treatment resistance is a major challenge in the management of metastatic breast cancer due to several clinical and molecular factors. Tumor heterogeneity is a very important factor responsible for treatment resistance and failures in solid tumors, including breast cancer. In this disease, several studies demonstrated biomarkers conversions when comparing primary disease and distant recurrence supporting a mandatory repeated tissue biopsy before treatment in advanced setting. Liquid biopsy including circulating tumor cells and circulating tumor DNA has further augmented the chances of capturing tumor heterogeneity and clonal evolution giving invaluable information that can guide treatment selection. We will describe a unique and interesting case, in which molecular evaluation and treatment decision demonstrated the importance of integrating both, tissue-based and liquid biopsy information. Case Presentation: 65 y.o. post-menopausal Caucasian female with history of R breast DCIS s/p bilateral mastectomy in 2013. She was initially diagnosed in 2006, with had left breast atypical ductal hyperplasia. Afterwards, she was serially monitored with imaging. In 2013, routine mammogram discovered a region of calcifications on her R breast behind the nipple (no imaging report available for review). She had subsequent lumpectomy which revealed DCIS ER+, PR-, HER2-. Mammogram 5 weeks revealed a new lesion in the upper R quadrant. Core needle biopsy revealed DCIS. Had bilateral skin sparing mastectomies with reconstruction, R axillary LN dissection with 0/5 lymph nodes. No evidence of invasive disease on the path report. While being evaluated for new reconstruction repeat scans revealed pulmonary nodules and abnormalities in the R axilla and breast. PET scan demonstrated hypermetabolic R axillary and subpectoral lymph nodes, hypermetabolic focal areas within subcutaneous tissues anterior to the right breast implant extending to the skin surface. R axillary node biopsy revealed breast cancer cells ER+, PR-, HER2-. Received chemotherapy, FEC followed by weekly paclitaxel, and subsequently underwent implant removal and skin and remaining breast tissues removal. Completed RT of the chest wall and axilla and started palbociclib plus letrozole which continued for 15 months with no evidence of disease on serial repeat imaging.PET scan 6 months ago demonstrated liver metastases. Liver bx confirmed metastatic HER2 neg disease. Blood samples were evaluated for CTCs detection as part of ongoing IRB approved study. More than 60 cells were identified with 40 % of those being HER2 positive.Patient started treatment with docetaxel, trastuzumab, pertuzumab. PET scan after 3 months demonstrated complete resolution of the liver metastases. Repeat CTCs collection demonstrated a total number of CTCs 4 and no HER2 positive cells were detected. Patient continued the same treatment with recent scans without evidence of disease. Conclusion: This case represents an example of successful treatment selection based on evidence collected from CTCs enumeration and biomarker analysis demonstrating discordance with tissue biopsy. Liquid biopsy, including CTCs and ctDNA provides complementary information to understand complex and heterogeneous tumor biology in advanced breast cancer and allow real-time implementation of precision oncology. Citation Format: Elena Vagia, Andrew Davis, Lorenzo Gerratana, Qiang Zhang, Youbin Zhang, Marian Tenler, Pedro Hermida de Viveiros, William Gradishar, Massimo Cristofanilli. Exceptional response to anti HER-2 targeted therapy in patient with HER2/neu negative breast cancer with HER2/neu positive CTCs [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1501.

PARP inhibitors in the treatment of metastatic breast cancer patients with germline BRCA1/2 mutations. Experience of treatment with talazoparib in clinical practice

Germline BRCA1/2 mutations account for about 10% of all breast cancer. BRCA1/2 proteins are involved in homologous recombination - DNA double-strand break repair mechanism. Poly-(ADP ribose) polymerases (PARP) are required to repair DNA single-strand breaks through base excision repair. PARP inhibitors represent a modern option of treatment of metastatic HER2 negative breast cancer with germline BRCA1/2 mutations. Mechanism of action of PARP inhibitors is based on the concept of synthetic lethality under conditions of BRCA dysfunction, when both DNA repair mechanisms, homologous recombination and base excision repair, are impaired. This leads to the apoptosis of cancer cells. Currently two PARP inhibitors are registered in Russia for the treatment of BRCA-associated metastatic HER2 negative breast cancer – olaparib and talazoparib. Efficacy of PARP inhibitors olaparib and talazoparib versus standard chemotherapy has been studied in very similarly designed phase III trials OlympiAD и EMBRACA. Benefit in the progression free survival, acceptable toxicity profile and positive impact on quality of life support inclusion of PARP inhibitors in treatment schemes of metastatic BRCAassociated breast cancer. Very important is the role of PARP inhibitors in treatment of very aggressive triple negative breast cancer with limited number of effective therapy options. We represent here a clinical case of treatment of metastatic triple negative breast cancer with talazoparib in 4th line of therapy.

Working together for the family: determination of HER oncogene co-amplifications in breast cancer.

HER2 is a well-studied tyrosine kinase (TK) membrane receptor which functions as a therapeutic target in invasive ductal breast carcinomas (IDC). The standard of care for the treatment of HER2-positive breast is the antibody trastuzumab. Despite specific treatment unfortunately, 20% of primary and 70% of metastatic HER2 tumors develop resistance. HER2 belongs to a gene family, with four members (HER1-4) and these members could be involved in resistance to anti-HER2 therapies. In this study we designed a probemix to detect the amplification of the four HER oncogenes in a single reaction. In addition, we developed a protocol based on the combination of MLPA with ddPCR to detect the tumor proportion of co-amplified HERs. On 111 IDC, the HER2 MLPA results were validated by FISH (Adjusted r2 = 0,91, p < 0,0001), CISH (Adjusted r2 = 0,938, p < 0,0001) and IHC (Adjusted r2 = 0,31, p < 0,0001). HER1-4 MLPA results were validated by RT-qPCR assays (Spearman Rank test p < 0,05). Of the 111 samples, 26% presented at least one HER amplified, of which 23% showed co-amplifications with other HERs. The percentage of cells with HER2 co-amplified varied among the tumors (from 2–72,6%). Independent in-silico findings show that the outcome of HER2+ patients is conditioned by the status of HER3 and HER4. Our results encourage further studies to investigate the relationship with patient’s response to single or combined treatment. The approach could serve as proof of principle for other tumors in which the HER oncogenes are involved.

Sterile, abscess-like cerebral lesion during trastuzumab therapy after HER2 status switch in a triple negative breast cancer patient: a case report and literature review

BackgroundBreast cancer is a global health problem – it is the most common malignancy among women. Triple negative breast cancers (TNBC) account for 10–20% of female breast cancer. Most TNBC cases confer poor prognosis. Brain metastasis appears in more than 15% in the triple negative breast cancer population, which causes serious decrease in survival. Changes of immunophenotype are not uncommon in breast cancer, offering new therapeutic options in cases where targetable proteins or pathways are being identified.Case presentationAfter five lines of chemotherapy and 82 months following the first diagnosis, our patient with brain metastatic triple negative breast cancer had human epidermal growth factor receptor 2 (HER2) genetic heterogeneity in the metastatic tissue sample interpreted as HER2 status conversion. After the removal of the metastasis, we started first line therapy for metastatic HER2 positive cancer with trastuzumab and paclitaxel. After the first cycle of trastuzumab, on day 8, she had a seizure, and neurosurgical examination showed an abscess-like lesion. The punctate proved to be sterile by microbiological and pathological examination, so we continued cytostatic therapy without the anti-HER2 antibody. 3 months later, we could not identify the previous abscess-like lesion in the control computer tomography (CT) scan, and our patient had no neurological deficits.ConclusionWe emphasize the importance of regular tissue confirmation of predictive markers in progressive tumorous disease even if our presented case is not unequivocally a “conversion case”. Tumor subtype is determined according to algorithms and definitions published in guidelines, nevertheless, use of different guidelines may lead to controversial interpretation in cases where HER2 genetic heterogeneity is present. Furthermore, we suggest that seronegative, aseptic intracranial fluid effusion after the removal of a brain metastasis may possibly be a side effect of trastuzumab.

Second line trastuzumab emtansine following horizontal dual blockade in a real-life setting.

Despite relevant medical advancements, metastatic breast cancer remains an uncurable disease. HER2 signaling conditions tumor behavior and treatment strategies of HER2 expressing breast cancer. Cancer treatment guidelines uniformly identify dual blockade with pertuzumab and trastuzumab plus a taxane as best first line and trastuzumab emtansine as preferred second line choice. However, there is no prospectively designed available study focusing on the sequence and outcomes of patients treated with T-DM1 following the triplet. In the following report, data concerning a wide series of patients treated in a real-life setting are presented. Results obtained in terms of response and median progression free survival suggests a significant role for T-DM1 in disease control of metastatic HER2 expressing breast cancer.

HER2-LAMP vaccines effectively traffic to endolysosomal compartments and generate enhanced polyfunctional T cell responses that induce complete tumor regression

BackgroundThe advent of immune checkpoint blockade antibodies has demonstrated that effective mobilization of T cell responses can cause tumor regression of metastatic cancers, although these responses are heterogeneous and restricted...

The efficacy of the combination of eribulin and trastuzumab in advanced HER2-positive breast cancer: the results of Russian observational study

The article presents the experience of 19 Russian medical institutions on the use of eribulin in combination with trastuzumab in various treatment lines of metastatic HER2+ breast cancer in routine clinical practice.&#x0D; Aim. The main objective of this retrospective observational study was to evaluate the efficacy and tolerability of eribulin and trastuzumab combo in HER2+ breast cancer patients pretreated with anthracyclines and taxanes. The analysis included 60 patients who received at least 2 cycles of eribulin in combination with trastuzumab. 2 patients (3.3%) received treatment as the 1st line, as the 2nd 14 (23.3%), as the 3rd 16 (26.7%), and as the 4th and more 28 (46.7%).&#x0D; Materials and methods. Complete response was achieved in 2 (3.3%) patients, partial response in 9 (15%), stable disease in 33 (55%), stabilization for more than 6 months in 11 (18.3%), disease progression was detected in 16 (26.7%) patients. The objective response rate was 18.3% in the whole group, the clinical benefit rate 36.7%.&#x0D; Results. The objective response rate in the group of the luminal subtype (ER/PR+HER2+) was 26.9%, in HER2-overexpressed subtype (ER-PR-HER2+) 8.8% and 64.7%, respectively, disease progression was recorded 2.3 times more often 35.3% versus 15.5% in the luminal subtype group. The median progression-free survival in patients with HER2+ breast cancer was 4.95 months (95% confidence interval CI 3.048.29 months), in luminal subtype 6.38 months (95% CI 3.338.54 months), in non-luminal 4.44 months (95% CI 2.47.96 months); p=0.306. The treatment was well tolerated, the spectrum of adverse events corresponded to the eribulin toxicity profile.&#x0D; Conclusions. The uniqueness of this study lies in the fact that on a large clinical material from the standpoint of real clinical practice, a very promising treatment regimen that is not used routinely in a number of countries has been studied, its effectiveness and satisfactory tolerance have been confirmed.