Telangiectasias induced by combination tucatinib and ado-trastuzumab emtansine in a patient with metastatic breast cancer.

BACKGROUND: Tucatinib is a tyrosine kinase inhibitor currently used in salvage therapy for human epidermal growth factor receptor 2 (HER2)-positive breast and colorectal cancer. The use of tucatinib alone or in combination with ado-trastuzumab emtansine (T-DM1) in the treatment of advanced HER2-positive cancers is rapidly expanding. OBJECTIVE/METHODS: We report the case of a 66-year-old female who presented to the dermatology clinic with a one-year history of widespread telangiectasias that began after initiation of combination chemotherapy with tucatinib and T-DM1 for metastatic HER2-positive invasive ductal carcinoma. RESULTS: The patient's lesions regressed upon cessation of combination therapy and reappeared in the setting of tucatinib re-initiation, with gradual improvement over the following four months following electrocautery to the affected regions. CONCLUSIONS: We postulate that telangiectasias may be a previously unreported dermatologic side effect of combination treatment with tucatinib and T-DM1. Electrocautery is a safe and effective procedure to reduce the appearance of telangiectasias and improve patient satisfaction during chemotherapy.

NSABP FB-10: a phase Ib/II trial evaluating ado-trastuzumab emtansine (T-DM1) with neratinib in women with metastatic HER2-positive breast cancer.

BACKGROUND: We previously reported our phase Ib trial, testing the safety, tolerability, and efficacy of T-DM1 + neratinib in HER2-positive metastatic breast cancer patients. Patients with ERBB2 amplification in ctDNA had deeper and more durable responses. This study extends these observations with in-depth analysis of molecular markers and mechanisms of resistance in additional patients. METHODS: Forty-nine HER2-positive patients (determined locally) who progressed on-treatment with trastuzumab + pertuzumab were enrolled in this phase Ib/II study. Mutations and HER2 amplifications were assessed in ctDNA before (C1D1) and on-treatment (C2D1) with the Guardant360 assay. Archived tissue (TP0) and study entry biopsies (TP1) were assayed for whole transcriptome, HER2 copy number, and mutations, with Ampli-Seq, and centrally for HER2 with CLIA assays. Patient responses were assessed with RECIST v1.1, and Molecular Response with the Guardant360 Response algorithm. RESULTS: The ORR in phase II was 7/22 (32%), which included all patients who had at least one dose of study therapy. In phase I, the ORR was 12/19 (63%), which included only patients who were considered evaluable, having received their first scan at 6 weeks. Central confirmation of HER2-positivity was found in 83% (30/36) of the TP0 samples. HER2-amplified ctDNA was found at C1D1 in 48% (20/42) of samples. Patients with ctHER2-amp versus non-amplified HER2 ctDNA determined in C1D1 ctDNA had a longer median progression-free survival (PFS): 480 days versus 60 days (P = 0.015). Molecular Response scores were significantly associated with both PFS (HR 0.28, 0.09-0.90, P = 0.033) and best response (P = 0.037). All five of the patients with ctHER2-amp at C1D1 who had undetectable ctDNA after study therapy had an objective response. Patients whose ctHER2-amp decreased on-treatment had better outcomes than patients whose ctHER2-amp remained unchanged. HER2 RNA levels show a correlation to HER2 CLIA IHC status and were significantly higher in patients with clinically documented responses compared to patients with progressive disease (P = 0.03). CONCLUSIONS: The following biomarkers were associated with better outcomes for patients treated with T-DM1 + neratinib: (1) ctHER2-amp (C1D1) or in TP1; (2) Molecular Response scores; (3) loss of detectable ctDNA; (4) RNA levels of HER2; and (5) on-treatment loss of detectable ctHER2-amp. HER2 transcriptional and IHC/FISH status identify HER2-low cases (IHC 1+ or IHC 2+ and FISH negative) in these heavily anti-HER2 treated patients. Due to the small number of patients and samples in this study, the associations we have shown are for hypothesis generation only and remain to be validated in future studies. Clinical Trials registration NCT02236000.

Effects of trastuzumab emtansine on canine urothelial carcinoma cells in vitro and in vivo.

Urothelial carcinoma (UC) is the most common malignancy of the urinary tract in dogs and has aggressive behaviour. Although human epidermal growth factor receptor 2 (HER2) is a known therapeutic target with evidence in canine UC, the efficacy of anti-HER2 antibody drugs remains unknown. This study aimed to investigate the effects of anti-HER2 antibody drugs including trastuzumab and trastuzumab emtansine (T-DM1) on canine UC cell lines in vitro and in vivo. Four canine UC cell lines (Nene, TCCUB, Love, and Sora) were used. In western blotting, HER2 protein expression was observed in all the cell lines. Although both trastuzumab and T-DM1 showed dose-dependent growth inhibitory activity in the cell lines, T-DM1 showed much stronger activity than that of trastuzumab. In flow cytometry analyses with the canine UC cell line (Sora), T-DM1 but not trastuzumab significantly increased the percentages of early and late apoptotic cells in annexin V apoptotic assays and the sub-G1 phase fraction in cell cycle analyses. For the in vivo experiment, the canine UC cells (Sora) were subcutaneously injected into nude mice. Four days after inoculation, trastuzumab, T-DM1, or vehicle was administered intraperitoneally once a week for three times. Tumour volumes were significantly smaller in the T-DM1 group compared to the trastuzumab and vehicle control groups. These findings indicate that T-DM1 exerts a stronger antitumour effect than that of trastuzumab on canine UC cells in vitro and in vivo, possibly by inducing apoptosis due to DM1.

HER2 heterogeneity and treatment response-associated profiles in HER2-positive breast cancer in the NCT02326974 clinical trial.

BACKGROUNDHER2-targeting therapies have great efficacy in HER2-positive breast cancer, but resistance, in part due to HER2 heterogeneity (HET), is a significant clinical challenge. We previously described that in a phase II neoadjuvant trastuzumab emtansine (T-DM1) and pertuzumab (P) clinical trial in early-stage HER2-positive breast cancer, none of the patients with HER2-HET tumors had pathologic complete response (pCR).METHODSTo investigate cellular and molecular differences among tumors according to HER2 heterogeneity and pCR, we performed RNA sequencing and ERBB2 FISH of 285 pretreatment and posttreatment tumors from 129 patients in this T-DM1+P neoadjuvant trial. A subset of cases was also subject to NanoString spatial digital profiling.RESULTSPretreatment tumors from patients with pCR had the highest level of ERBB2 mRNA and ERBB signaling. HER2 heterogeneity was associated with no pCR, basal-like features, and low ERBB2 expression yet high ERBB signaling sustained by activation of downstream pathway components. Residual tumors showed decreased HER2 protein levels and ERBB2 copy number heterogeneity and increased PI3K pathway enrichment and luminal features. HET tumors showed minimal treatment-induced transcriptomic changes compared with non-HET tumors. Immune infiltration correlated with pCR and HER2-HET status.CONCLUSIONResistance mechanisms in HET and non-HET tumors are distinct. HER2-targeting antibodies have limited efficacy in HET tumors. Our results support the stratification of patients based on HET status and the use of agents that target downstream components of the ERBB signaling pathway in patients with HET tumors.TRIAL REGISTRATIONClinicalTrials.gov NCT02326974.FUNDINGThis study was funded by Roche and the National Cancer Institute.

Comparison of trastuzumab emtansine, trastuzumab deruxtecan, and disitamab vedotin in a multiresistant HER2-positive breast cancer lung metastasis model.

Human epidermal growth factor 2 (HER2)-positive breast cancer with lung metastases resistant to targeted agents is a common therapeutic challenge. Absence of preclinical lung metastasis models that are resistant to multiple anti-HER2 targeted drugs hampers the development of novel therapies. We established a novel HER2-positive breast cancer cell line (L-JIMT-1) with a high propensity to form lung metastases from the parenteral JIMT-1 cell line by injecting JIMT-1 cells into immunodeficient SCID mice. Lung metastases developed in all mice injected with L-JIMT-1 cells, and more rapidly and in greater numbers compared with the parental JIMT-1 cells. L-JIMT-1 cells expressed more epidermal growth factor receptor and HER2 than JIMT-1 cells. L-JIMT-1 cells were resistant to all five tyrosine kinase inhibitors tested in vitro (afatinib, erlotinib, lapatinib, sapitinib, and tucatinib). When we compared JIMT-1 and L-JIMT-1 sensitivity to three HER2-targeting antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and disitamab vedotin (DV) in vitro, JIMT-1 cells were resistant T-DXd, partially sensitive to T-DM1, and sensitive to DV, while L-JIMT-1 cells were resistant to both T-DM1 and T-DXd, but moderately sensitive to DV. In a mouse model, all three ADCs inhibited the growth of L-JIMT-1 lung metastases compared to a vehicle, but DV and T-DXd more strongly than T-DM1, and DV treatment led to the smallest tumor burden. The L-JIMT breast cancer lung metastasis model developed may be useful in the evaluation of anti-cancer agents for multiresistant HER2-positive advanced breast cancer.

Addressing Residual Disease in HER2-Positive and Triple-Negative Breast Cancer: What Is Next?

PURPOSE OF REVIEW: To summarize the treatment strategies for patients with human epidermal growth factor receptor 2 (HER2)-positive disease and triple-negative breast cancer (TNBC) who have residual disease after preoperative systemic therapy. RECENT FINDINGS: There has been a shift towards neoadjuvant systemic therapy for selected patients with HER2-positive and TNBC. Assessing the tumor's response to therapy provides prognostic information and allows individualization of the postoperative treatment for these patients based on the tumor response to neoadjuvant therapy. Patients with TNBC with residual disease after neoadjuvant therapy can be treated with pembrolizumab, capecitabine, or olaparib. Those with HER2-positive disease are treated with adjuvant trastuzumab emtansine. The treatment of early breast cancer has evolved significantly, and patient outcomes continue to improve. As better treatments are developed, we will need biomarkers to determine which patients may benefit from certain therapies to continue to improve outcomes by right-sizing treatments and limiting toxicities.

Targeting TACC3 Induces Immunogenic Cell Death and Enhances T-DM1 Response in HER2-Positive Breast Cancer.

Trastuzumab emtansine (T-DM1) was the first and one of the most successful antibody-drug conjugates (ADC) approved for treating refractory HER2-positive breast cancer. Despite its initial clinical efficacy, resistance is unfortunately common, necessitating approaches to improve response. Here, we found that in sensitive cells, T-DM1 induced spindle assembly checkpoint (SAC)-dependent immunogenic cell death (ICD), an immune-priming form of cell death. The payload of T-DM1 mediated ICD by inducing eIF2α phosphorylation, surface exposure of calreticulin, ATP and HMGB1 release, and secretion of ICD-related cytokines, all of which were lost in resistance. Accordingly, ICD-related gene signatures in pretreatment samples correlated with clinical response to T-DM1-containing therapy, and increased infiltration of antitumor CD8+ T cells in posttreatment samples was correlated with better T-DM1 response. Transforming acidic coiled-coil containing 3 (TACC3) was overexpressed in T-DM1-resistant cells, and T-DM1 responsive patients had reduced TACC3 protein expression whereas nonresponders exhibited increased TACC3 expression during T-DM1 treatment. Notably, genetic or pharmacologic inhibition of TACC3 restored T-DM1-induced SAC activation and induction of ICD markers in vitro. Finally, TACC3 inhibition in vivo elicited ICD in a vaccination assay and potentiated the antitumor efficacy of T-DM1 by inducing dendritic cell maturation and enhancing intratumoral infiltration of cytotoxic T cells. Together, these results illustrate that ICD is a key mechanism of action of T-DM1 that is lost in resistance and that targeting TACC3 can restore T-DM1-mediated ICD and overcome resistance. SIGNIFICANCE: Loss of induction of immunogenic cell death in response to T-DM1 leads to resistance that can be overcome by targeting TACC3, providing an attractive strategy to improve the efficacy of T-DM1.

Pharmacokinetics and pharmacodynamics of antibody-drug conjugates for the treatment of patients with breast cancer.

INTRODUCTION: Currently three antibody-drug-conjugates (ADC) are approved by the European Medicines Agency (EMA) for treatment of breast cancer (BC) patient: trastuzumab-emtansine, trastuzumab-deruxtecan and sacituzumab-govitecan. ADC are composed of a monoclonal antibody (mAb) targeting a specific antigen, a cytotoxic payload and a linker. Pharmacokinetics (PK) and pharmacodynamics (PD) distinguish ADC from conventional chemotherapy and must be understood by clinicians. AREAS COVERED: Our review delineates the PK/PD profiles of ADC approved for the treatment of BC with insight for future development. This is an expert opinion literature review based on the EMA's Assessment Reports, enriched by a comprehensive literature search performed on Medline in August 2023. EXPERT OPINION: All three ADC distributions are described by a two-compartment structure: tissue and serum. Payload concentration peak is immediate but remains at low concentration. The distribution varied for all ADC only with body weight. mAb will be metabolised firstly by the saturable complex formation of ADC/Tumour-Receptor and secondly by binding of FcgRs in immune cells. They are all excreted in the bile and faeces with minimal urine elimination. Dose adjustments, apart from weight, are not recommended. Novel ADC are composed of cleavable linkers with various targets/payloads with the same PK/PD properties, but novel structures of ADC are in development.

Axillary Nodal Response to Neoadjuvant T-DM1 Combined with Pertuzumab in a Prospective Phase II Multi-Institution Clinical Trial.

BACKGROUND: Patients with ERBB2 (HER2)-positive breast cancer experience high pathologic complete response (pCR) rates after standard neoadjuvant anti-HER2 systemic therapy. We examined axillary pathologic nodal response to neoadjuvant dual HER2-targeted therapy alone, based on breast pathologic response, in a multi-institution clinical trial. STUDY DESIGN: Patients with HER2-positive breast cancer were enrolled to a phase II single-arm trial, which administered 6 cycles of neoadjuvant trastuzumab emtansine (T-DM1) plus pertuzumab. Rates of pathologic nodal disease (ypN) in patients who were clinically node-negative (cN0) and node-positive (cN1) were analyzed, by residual breast disease (pCR and residual cancer burden [RCB] I to III). RESULTS: One hundred fifty-eight patients completed preoperative treatment and proceeded to surgery. Of 92 patients who were cN0, 48 (52.2%) and 10 (10.9%) experienced breast pCR and RCB I, respectively. Of these, 100% were ypN0. Of 34 with RCB II to III, 26 (76.5%) were ypN0. Of 30 patients who were cN1 with breast pCR, 100% were ypN0; of the 12 patients who were cN1 with RCB I, 66.7% were ypN0; and of the 24 patients who were cN1 with RCB II to III, 25% were ypN0. ypN0 rates were significantly different between patients who did and did not experience a pCR, in both cN0 (p = 0.002) and cN1 (p < 0.001) subgroups. CONCLUSIONS: Patients with HER2-positive breast cancer treated with dual HER2-targeted therapy who experienced a breast pCR or RCB I response were frequently ypN0. These findings support future trials considering omission of axillary surgical staging for patients with HER2-positive breast cancer in neoadjuvant trials of active HER2-targeted regimens, particularly if they experience breast pCR or RCB I.

Cost-Effectiveness Analysis of Trastuzumab Deruxtecan Versus Trastuzumab Emtansine for Patients With Human Epidermal Growth Factor Receptor 2 Positive Metastatic Breast Cancer in the United States.

OBJECTIVES: To assess the cost-effectiveness of trastuzumab deruxtecan compared with trastuzumab emtansine as second-line therapy for patients with human epidermal growth factor receptor 2 positive metastatic breast cancer from a US healthcare sector perspective. METHODS: A 3-state partitioned survival model was developed to estimate the cost-effectiveness of trastuzumab deruxtecan compared with trastuzumab emtansine. For both treatments, modeled patients were administered treatment intravenously every 3 weeks indefinitely or until disease progression. Transition parameters were principally derived from the updated DESTINY-Breast03 phase III randomized clinical trial. Costs include drug costs extracted from Centers for Medicare and Medicaid Services average sales price and administrative, adverse event, and third-line therapy costs derived from published literature, measured in 2022 US dollars. Health utilities for health states and disutilities for adverse events were sourced from published literature. Effects were measured in quality-adjusted life years (QALYs). We conducted both probabilistic sensitivity analysis and comprehensive scenario analysis to test model assumptions and robustness, while utilizing a lifetime horizon. RESULTS: In our base-case analysis, total costs for trastuzumab deruxtecan were $1 266 945, compared with $820 082 for trastuzumab emtansine. Total QALYs for trastuzumab deruxtecan were 5.09, compared with 3.15 for trastuzumab emtansine. The base-case incremental cost-effectiveness ratio was $230 285/QALY. Probabilistic sensitivity analysis indicated that trastuzumab deruxtecan had an 11.1% probability of being cost-effective at a $100 000 per QALY willingness-to-pay threshold. CONCLUSIONS: Despite the higher efficacy of trastuzumab deruxtecan in patients with human epidermal growth factor receptor 2 positive metastatic breast cancer, our findings raise concern regarding its value at current prices.

Prevalence and Therapeutic Targeting of High-Level ERBB2 Amplification in NSCLC.

INTRODUCTION: ERBB2 amplification in lung cancer remains poorly characterized. HER2 (encoded by ERBB2) is a transmembrane tyrosine kinase capable of ligand-independent dimerization and signaling when overexpressed, and a common cause of HER2 overexpression is ERBB2 amplification. Here, we evaluated the clinicopathologic and genomic characteristics of ERBB2-amplified NSCLC and explored a HER2 antibody-drug conjugate (ADC) therapeutic strategy. METHODS: Our institutional next-generation DNA sequencing data (OncoPanel) from 5769 NSCLC samples (5075 patients) were queried for cases having high-level ERBB2 amplification (≥6 copies). Clinical and demographic characteristics were extracted from the electronic medical records. Efficacy of the pan-ERBB inhibitor afatinib or HER2 ADCs (trastuzumab deruxtecan and trastuzumab emtansine) was evaluated in NSCLC preclinical models and patients with ERBB2 amplification. RESULTS: High-level ERBB2 amplification was identified in 0.9% of lung adenocarcinomas and reliably predicted overexpression of HER2. ERBB2 amplification events are detected in two distinct clinicopathologic and genomic subsets of NSCLC: as the sole mitogenic driver in tumors arising in patients with a smoking history or as a concomitant alteration with other mitogenic drivers in patients with a light or never smoking history. We further reveal that trastuzumab deruxtecan is effective therapy in in vitro and in vivo preclinical models of NSCLC harboring ERBB2 amplification and report two cases of clinical activity of an anti-HER2 ADC in patients who acquired ERBB2 amplification after previous targeted therapy. CONCLUSIONS: High-level ERBB2 amplification reliably predicts HER2 overexpression in patients with NSCLC, and HER2 ADC is effective therapy in this population.

Adjuvant Trastuzumab Emtansine Versus Paclitaxel and Trastuzumab in Stage I HER2-Positive Breast Cancer: The ATEMPT Trial.

This ASO perspective reviews the findings of a randomized, phase II clinical trial evaluating adjuvant trastuzumab emtansine (T-DM1) compared with paclitaxel and trastuzumab (TH) in stage I human epidermal growth factor receptor 2-positive breast cancer, as reported recently by the ATEMPT trial investigators. Patients treated with T-DM1 had better disease-free survival but did not have fewer treatment toxicities. The T-DM1-treated group had higher rates of treatment discontinuations, therefore long-term follow-up will be required to evaluate survival differences between T-DM1 and TH.

Third-line treatment patterns in HER2-positive metastatic breast cancer: a retrospective analysis of real-world data in Canada.

There is an increasing demand for real-world data pertaining to the usage of cancer treatments, especially in settings where no standard treatment is specifically recommended. This study presents the first real-world analysis of third-line treatment patterns in HER2-positive metastatic breast cancer (mBC) patients in Canada. The purpose was to assess evolution of clinical practice and identify unmet needs in post-second-line therapy. Retrospective data from medical records of 66 patients who received third-line treatment before 31st October 2018, and data from 56 patients who received third-line treatment after this date, extracted from the Personalize My Treatment (PMT) cancer patient registry, were analyzed. In the first cohort, the study revealed heterogeneity in the third-line setting, with trastuzumab, lapatinib, and T-DM1 being the main treatment options. Even though data were collected before the wide availability of tucatinib, neratinib and trastuzumab deruxtecan in Canada, the PMT cohort revealed the emergence of new therapeutic combinations and a shift from lapatinib usage to T-DM1 choice was observed. These findings underscore the evolving nature of third-line treatment strategies in Canada, a facet that is intrinsically tied to the availability of new drugs. The absence of a consensus on post-second-line treatment highlights the pressing need for more efficient therapeutic alternatives beyond the currently available options. This study not only offers valuable insights into the present landscape of third-line treatment in Canada but validates the significance and effectiveness of the PMT registry as a tool for generating pan-Canadian real-world evidence in oncology and its capacity to provide information on evolution of therapeutic practices.

Real world data on the demographic and clinicopathological profile and management of patients with early-stage HER2-positive breast cancer and residual disease treated with adjuvant trastuzumab emtansine (KARMA study).

INTRODUCTION: Trastuzumab emtansine (T-DM1) significantly improves invasive disease-free survival and reduces the risk of recurrence in patients with HER2-positive early breast cancer (EBC) with residual disease (RD). The KARMA study aimed to describe the characteristics and management of these patients in clinical practice in Spain. MATERIAL AND METHODS: We conducted a multicentre retrospective study in patients with HER2-positive EBC with RD following neoadjuvant treatment (NeoT) and who had received ≥1 dose of T-DM1 as adjuvant treatment. The primary endpoint was the evaluation of sociodemographic and clinicopathological characteristics of these patients. RESULTS: A total of 114 patients were included (March-July 2020). At diagnosis, most tumours were infiltrating ductal carcinoma (IDC) (93.9 %), grade 2 (56.1 %), and hormone receptor (HR)-positive (79.8 %). Over 75 % of patients had disease in operable clinical stages (T1-3 N0-1). In the neoadjuvant setting, 86.8 % of patients received trastuzumab plus pertuzumab, and 23.6 % achieved radiological complete response. Breast-conserving surgery was performed in 55.8 % of patients. Surgical specimens showed that 89.5 % of patients had IDC, 49.1 % grade 2, 84.1 % HR-positive, and 8.3 % HER2-negative disease. Most patients had RD classified as RCB-II and Miller/Payne grade 3/4. Grade 3 treatment-related adverse events (trAEs) occurred in 5.3 % of patients. No grade 4/5 AEs occurred. Over 95 % of patients were free of invasive-disease during T-DM1 adjuvant treatment. CONCLUSION: The KARMA study describes the characteristics of patients with HER2-positive EBC with RD after NeoT and the real-life management of a T-DM1 adjuvant regimen, which showed a manageable safety profile in line with the KATHERINE trial data.

Cost-utility analysis of trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer in Chinese setting.

PURPOSE: Trastuzumab deruxtecan (T-DXd) expressed substantial improvement in the progression-free survival and overall survival contrasted with trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer (mBC), becoming the second-line standard of care, promisingly. We aim to estimate the cost-utility of T-DXd versus T-DM1 in HER2-positive mBC from the Chinese healthcare perspective. METHODS: A partitioned survival model was applied to examine the cost-utility of T-DXd versus T-DM1. Clinical patients and outcome data were sourced from the DESTINY-Breast 03 trial. Costs and utilities were sourced in Chinese setting. Total costs, quality-adjusted life months (QALMs), and an incremental cost-utility ratios (ICUR) were calculated for cost-utility analysis. The willingness-to-pay threshold was set at $3188/QALM. Univariate, scenario, and probabilistic sensitivity analyses were performed. RESULTS: T-DXd group gained ∆QALM of 7.09 months and ∆Cost of $304,503 compared with T-DM1 therapy, which caused an ICUR of $42,936/QALM. The results of sensitivity analyses confirmed the base-case findings. Furthermore, T-DXd must reduce the price to enter the Chinese mainland market. At least when the cycle cost of T-DXd is reduced to $2975, T-DXd has an 83.3% chance of becoming a better choice. CONCLUSIONS: T-DXd appears to be not cost effective compared with T-DM1 for HER2-positive mBC patients previously treated with trastuzumab and a taxane.

Anti-HER2 Drugs for the Treatment of Advanced HER2 Positive Breast Cancer.

OPINION STATEMENT: Approximately 15-20% of breast cancers (BC) demonstrate HER2 overexpression/gene amplification. Historically, before the era of HER2-directed therapies, this subtype was associated with poor prognosis. Anti-HER2 agents dramatically changed the natural course of disease and significantly prolonged patients' survival. In recent years, a number of new anti-HER2 therapies have been developed, and their approvals offer new therapeutic options for patients with advanced HER2-positive breast cancer. At present, HER2 pathway blocking drugs used in the treatment of metastatic breast cancer worldwide include trastuzumab and pertuzumab in the first-line treatment; trastuzumab deruxtecan and trastuzumab emtansine in the second line; and tucatinib, neratinib, lapatinib, and margetuximab in further lines of treatment of advanced HER2 positive breast cancer. Additionally, there are many clinical trials underway evaluating drugs blocking the HER2 pathway in advanced disease setting. This article presents new treatment options, discussing the most important findings from clinical trials and real-world reports, clinical benefits and risks of treatment, as well as efficacy of re-treatment with trastuzumab in metastatic breast cancer. New data challenge the current standards, and a number of questions arise regarding the optimal sequence of anti-HER2 targeted therapies, the optimal combination, including endocrine agents in luminal HER2 positive tumors and treatment of special patient population such as patients with brain metastases (BM).

Three-year remission of metastatic breast cancer with treatment with ado-trastuzumab emtansine.

Globally, breast cancer is the most frequently diagnosed malignancy and the leading cause of oncological death in women. Metastatic disease at diagnosis (de novo stage IV breast cancer) will be identified in about 5% of patients. Treatment options vary based on several factors, namely whether the tumour is hormone receptor positive and whether human epidermal growth factor receptor 2 (HER2) is overexpressed. Here, we report a case of HER2 positive metastatic breast cancer on a woman in her late 30s, with remission for over 3 years under second-line treatment with ado-trastuzumab emtansine, with no significant toxicity and good tolerability. The timing to stop treatment under these circumstances presents a challenge and more data are needed to substantiate the decision to stop or maintain treatment in this small population.

Predicting Response to Antibody Drug Conjugates: A Focus on Antigens' Targetability.

Antibody-drug conjugates (ADCs) represent a cornerstone in the treatment of many cancers nowadays. ADCs fulfill their function by binding a target on tumor cell membrane to deliver a cytotoxic payload; in addition, those moieties capable of crossing cancer cell membranes can achieve near-by cells that do not express the target antigen, exerting the so-called "bystander" cytotoxic effect. The presence of a specific target antigen expressed on cancer cells has been for long considered crucial for ADCs and commonly required for the inclusion of patients in clinical trials with ADCs. To date, only ado-trastuzumab-emtansine, fam-trastuzumab deruxtecan-nxki, and mirvetuximab soravtansine-gynx are approved according to the expression of a target antigen in solid tumors, while the clinical use of other ADCs (eg, sacituzumab govitecan) is not conditioned by the presence of a specific biomarker. Given the ever-growing number of approved ADCs and those under investigation, it is essential to find new biomarkers to guide their use, especially in those settings for which different ADCs are approved to establish the best therapeutic sequence based on robust biomarkers. Hence, this work addresses the role of target antigens in predicting response to ADCs, focusing on examples of antigens' targetability according to their expression on cancer cells' surface or to the presence of specific target aberrations (eg, mutation or over-expression). New methods for the assessment and quantification of targets' expression, like molecular imaging and in vitro assays, might be key tools to improve biomarker analysis and eventually deliver better outcomes by refined patient selection.

HER2 Genetic Intratumor Heterogeneity Is Associated With Resistance to Trastuzumab and Trastuzumab Emtansine Therapy in Recurrent High-Grade Endometrial Cancer.

Anti-HER2 targeted therapies have recently demonstrated clinical activity in the treatment of high-grade endometrial carcinomas (ECs), particularly serous carcinomas with HER2 amplification and/or overexpression. Intratumor heterogeneity of HER2 amplification or HER2 genetic intratumor heterogeneity (G-ITH) has been associated with resistance to anti-HER2 therapies in breast and gastroesophageal cancers; however, its clinical relevance in EC is unknown. To characterize HER2 G-ITH in EC, archival specimens from a clinically annotated cohort of 57 ECs treated with trastuzumab or trasutuzmab emtansine in the recurrent (n = 38) or adjuvant (n = 19) setting were subjected to central pathology review, HER2 assessment by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), and next-generation sequencing. HER2 G-ITH, defined as HER2 amplification in 5% to 50% of tumor cells examined by FISH, was identified in 36% (19/53) of ECs and was associated with lower HER2 copy number and levels of protein expression. HER2 IHC revealed spatially distinct areas of strong expression juxtaposed with areas of low/absent expression in tumors with the "cluster" pattern of G-ITH, whereas the "mosaic" pattern was typically associated with a diffuse admixture of cells with variable levels of HER2 expression. HER2 G-ITH was frequently observed in cases with IHC/FISH or FISH/next-generation sequencing discrepancies and/or with an equivocal/negative FISH result (9/13, 69%). Although the objective response rate to anti-HER2 therapy in recurrent ECs was 52% (13/25) for tumors lacking HER2 G-ITH, none (0%, 0/10) of the patients with HER2 G-ITH achieved a complete or partial response (P = .005). HER2 G-ITH was significantly associated with worse progression-free survival (hazard ratio, 2.88; 95% CI, 1.33-6.27; P = .005) but not overall survival. HER2 IHC score, HER2/CEP17 ratio, HER2 copy number, histologic subtype, and other genetic alterations, including PIK3CA hotspot mutations, were not significantly associated with therapeutic response or survival outcomes. Treatment responses were not restricted to serous carcinomas, supporting consideration of anti-HER2 therapy in patients with HER2-positive high-grade ECs of non-serous histology. Our results demonstrate that HER2 G-ITH is an important determinant of response to trastuzumab and trastuzumab emtansine in EC, providing a rationale for the development of novel therapeutic strategies to target HER2-nonamplified resistant tumor subpopulations, such as HER2 antibody-drug conjugates with bystander effects.