anti-HER2 Treatment Research Articles

Outcomes and Prognostic Factors in HER2-Positive Metastatic Breast Cancer Patients Who Had Developed Brain Metastasis in the Treatment Process

Introduction: Patients with HER2-positive metastatic breast cancer are at risk for developing brain metastases. Different anti-HER2 treatments can be used in the management of the disease. In this study, we aimed to evaluate the prognosis and the factors affecting the prognosis in brain metastatic patients with HER2-positive breast cancer. Methods: Clinical and pathological features of HER2-positive metastatic breast cancer patients and magnetic resonance imaging features at the onset of brain metastasis were recorded. Survival analyses were performed using Kaplan-Meier and Cox regression methods. Results: Analyses of the study were performed by including 83 patients. The median age was 49 (25–76). All patients had HER2 receptor-positive tumors. Thirty-five (42.2%) patients had a hormone-positive disease. Thirty-two (38.6%) patients had de novo metastatic disease. Brain metastasis sites were found to be bilateral – 49.4%, right brain – 21.7%, left brain – 12%, and unknown – 16.9%, respectively. The median brain metastasis largest size was 16 mm (range 5–63). The median follow-up time from the post-metastasis period was 36 months. Median overall survival (OS) was found as 34.9 months (95% CI, 24.6–45.2). In multivariate analysis for factors affecting OS, estrogen receptor status (p = 0.025), number of chemotherapy agents used with trastuzumab (p = 0.010), number of HER2-based therapy (p = 0.010), and the largest size of brain metastasis (p = 0.012) were found to be statistically significant. Conclusions: In this study, we demonstrated the prognosis in brain metastatic patients with HER2-positive breast cancer. When the factors affecting the prognosis were evaluated, we determined that the largest size of brain metastasis, estrogen receptor positivity, and the use of TDM-1 and lapatinib plus capecitabine consecutively during the treatment process affected the prognosis of the disease.

Protocol for pyrotinib cardiac safety in patients with HER2-positive early or locally advanced breast cancer-The EARLY-MYO-BC study.

Cardiotoxicity has become the most common cause of non-cancer death among breast cancer patients. Pyrotinib, a tyrosine kinase inhibitor targeting HER2, has been successfully used to treat breast cancer patients but has also resulted in less well-understood cardiotoxicity. This prospective, controlled, open-label, observational trial was designed to characterize pyrotinib's cardiac impacts in the neoadjuvant setting for patients with HER2-positive early or locally advanced breast cancer. The EARLY-MYO-BC study will prospectively enroll HER2-positive breast cancer patients who are scheduled to receive four cycles of neoadjuvant therapy with pyrotinib or pertuzumab added to trastuzumab before radical breast cancer surgery. Patients will undergo comprehensive cardiac assessment before and after neoadjuvant therapy, including laboratory measures, electrocardiography, transthoracic echocardiography, cardiopulmonary exercise testing (CPET), and cardiac magnetic resonance (CMR). To test the non-inferiority of pyrotinib plus trastuzumab therapy to pertuzumab plus trastuzumab therapy in terms of cardiac safety, the primary endpoint will be assessed by the relative change in global longitudinal strain from baseline to completion of neoadjuvant therapy by echocardiography. The secondary endpoints include myocardial diffuse fibrosis (by T1-derived extracellular volume), myocardial edema (by T2 mapping), cardiac volumetric assessment by CMR, diastolic function (by left ventricular volume, left atrial volume, E/A, and E/E') by echocardiography, and exercise capacity by CPET. This study will comprehensively assess the impacts of pyrotinib on myocardial structural, function, and tissue characteristics, and, furthermore, will determine whether pyrotinib plus trastuzumab is a reasonable dual HER2 blockade regimen with regard to cardiac safety. Results may provide information in selecting an appropriate anti-HER2 treatment for HER2-positive breast cancer. https://clinicaltrials.gov/, identifier NCT04510532.

HER2 ‘neu’ promise for mCRC

Following the staggering impact of anti-HER2 treatment in improving the outcomes for breast and gastric cancers, human epidermal growth factor receptor 2 (HER2 neu) has emerged as a promising new oncogenic target for metastatic colorectal carcinoma (mCRC) also. Through this article, we review the role of HER2 in mCRC as a prognostic biormarker as well as a poor predictive factor and mechanism of resistance against anti-EGFR therapy. We discuss the emergence of dual anti-HER2 blockade as effective therapeutic intervention for HER2 amplified mCRC and the advantageous role of ct-DNA in appropriate clinical setting. Furthermore, we explore the encouraging future paradigms for effectively targeting HER2 in mCRC.

HER2-positive invasive lobular carcinoma: a rare breast cancer which may not necessarily require anti-HER2 therapy. A population-based study.

HER2-positive (HER2 +) invasive lobular breast cancer (ILC) is rare and poorly characterised. In particular, patient outcomes compared to those associated with HER2 + invasive ductal cancer (IDC) and HER2-negative (HER2-) ILC, as well as the benefits of anti-HER2 therapy, are not well established. We analysed the data from the Côte d'Or Registry of Breast and Gynaecological Cancers (France) for all patients diagnosed with early-stage HER2 + ILC (62 cases), HER2 + IDC (833 cases) and HER2- ILC (685 cases) between 1998 and 2015 to compare overall and disease-free survival (OS and DFS) between these groups in correlation with anti-HER2 therapy. ILCs were associated with older age, larger tumours, lower histological grades, higher hormonal receptor positivity rates and multifocality, and more common endocrine therapy. OS and DFS between the three groups did not differ. We found that anti-HER2 therapy was associated with a survival benefit in patients with HER2 + IDC. In contrast, the survival of HER2 + ILC patients was not improved by anti-HER2 treatment, remaining close to that of HER2- ILC patients. HER2 + ILC seems not to be associated with better outcomes than HER2 + IDC but may not differ from HER2- ILC in terms of survival.

HER2 and BARD1 Polymorphisms in Early HER2-Positive Breast Cancer Patients: Relationship with Response to Neoadjuvant Anti-HER2 Treatment.

The addition to chemotherapy of anti-HER2 drugs such as trastuzumab or pertuzumab has improved outcomes in HER2-positive breast cancer patients. However, resistance to these drugs in some patients remains a major concern. This study examines the possible association between the response to neoadjuvant anti-HER2 treatment in breast cancer patients and the presence of 28 SNPs in 17 genes involved in different cell processes (PON1, CAT, GSTP1, FCGR3, ATM, PIK3CA, HER3, BARD1, LDB2, BRINP1, chr6 intergenic region, RAB22A, TRPC6, LINC01060, EGFR, ABCB1, and HER2). Tumor samples from 50 women with early breast cancer were genotyped using the iPlex®Gold chemistry and MassARRAY platform, and patients were classified as good responders (Miller-Payne tumor grades 4-5) and poor responders (Miller-Payne tumor grades 1-3), as assessed upon surgery after 6 months of treatment. Proportions of patients with the HER2Ala1170Pro (rs1058808) SNP double mutation were higher in good (58.62%) than poor (20%) responders (p = 0.025). Similarly, proportions of patients carrying the synonymous SNP rs2070096 (BARD1Thr351=) (wv + vv) were higher in patients showing a pathological complete response (46.67%) than in those not showing this response (15.15%) (p = 0.031). The SNPs rs1058808 (HER2Ala1170Pro) and rs2070096 (BARD1Thr351=) were identified here as potential biomarkers of a good response to anti-HER2 treatment.

A clinicopathological study and survival analysis of 99 breast cancers with HER2/CEP17 ratio ≥ 2.0 and an average HER2 copy number < 4.0 per cell in China

BackgroundBreast cancer patients of American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) Group 2 were all HER2-negative according to the 2018 guideline, not HER2-positive as defined in the 2013 guideline.MethodsWe aims to elucidate the unique clinicopathological features of ASCO/CAP Group 2 patients by comparing with classic HER2-nonamplified cancers, and reveal the efficacy of the former to anti-HER2 therapy. The clinicopathological features, treatment and prognosis information of 99 patients between 2014 and 2018 were collected. HER2 status was re-defined using the updated recommendations.ResultsOf the 99 ASCO/CAP Group 2 tumors, 25.5% (25/99) tumors were immunohistochemical (IHC) 0/1+ and 74.7% (74/99) tumors were IHC 2+. According to the updated 2018 guideline, all of them were HER2 negative. When compared to ASCO/CAP Group 5, patients of ASCO/CAP Group 2 displayed higher ratio of histological grade 3 (P = .03), high Ki67 proliferation index (P = .03) and pN3 (more than 9 lymph nodes metastasis, P = .02), and lower estrogen receptor (ER) positivity (P = .04). There was no statistical difference in the survival of patients received anti-HER2 therapy and patients not received anti-HER2 therapy.ConclusionsPatients of ASCO/CAP Group 2 did not received apparent benefit from anti-HER2 treatment. Although according to the updated guidelines and latest reports, HER2 is negative, but when compared with classic HER2-nonamplified cancers, patients of this group seemed to be more aggressive. We suggest that this group still be regarded as an independent category, in order to accumulate more cases in the future to expand the scope of research.

Tumor Microenvironment in Male Breast Carcinoma with Emphasis on Tumor Infiltrating Lymphocytes and PD-L1 Expression.

Male breast cancer (MBC) is rare and usually presents as a locally advanced disease. Stromal tumor-infiltrating lymphocytes (sTILs) are associated with a better response to neoadjuvant chemotherapy and improved prognosis in all molecular subtypes of female breast cancer, but their role in MBC is less clear. We studied sTILs and the expression of programmed cell death ligand 1 (PD-L1) and pan-TRK in MBC. We retrospectively studied 113 cases of MBC surgically treated between 1988 and 2015. The tumors were evaluated for histological type and grade, stage, intrinsic subtype and sTILs. We performed immunohistochemistry for PD-L1 (clone SP142) and pan-TRK (clone EPR17341) on tissue microarrays. Pan-TRK positive cases were further analyzed by next-generation sequencing. The median age was 69 years (range 60-77). Invasive carcinoma of no special type was found in 94.7% of cases, of which 53.1% were grade 2. Estrogen receptor was positive in 92% of the tumors, progesterone receptor in 85.8%, androgen receptor in 70.8%; 4.4% were human epidermal growth factor receptor 2 (HER2)-positive, and 55.8% HER2-low. 40.7% of tumors were luminal A and 51.3% luminal B, 4.4% HER2-enriched and 3.5% triple negative carcinoma. sTILs density was &lt;50% in 96.4% of the tumors, &gt;50% in 3.6% of the tumors. PD-L1 immune cell score &gt;1% was found in 7.1% of the tumors (all of luminal subtype). A weak focal cytoplasmic pan-TRK staining was present in 8.8% but without NTRK fusion. Neither sTILs nor PD-L1 had statistically significant outcomes. Our findings suggest that a subset of MBC patients harbors an immunological environment characterized by increased sTILs with PD-L1 expression. These patients may potentially benefit from immune checkpoint inhibitor therapy. Frequent HER2-low may offer novel anti-HER2 treatment options.

Impact of Anti-HER2 Therapy Alone and With Weekly Paclitaxel on the Ovarian Reserve of Young Women With HER2-Positive Breast Cancer.

The potential gonadotoxicity of anti-HER2 agents remains largely unknown, and limited, conflicting evidence exists for taxanes. Antimüllerian hormone (AMH) is an established biomarker of ovarian reserve that may aid in quantifying anticancer treatment-induced gonadotoxicity. The present biomarker analysis of the randomized phase III neoadjuvant NeoALTTO trial included premenopausal women aged ≤45 years at diagnosis of HER2-positive early breast cancer with available frozen serum samples at baseline (ie, before anticancer treatments), at week 2 (ie, the "biological window" of anti-HER2 therapy alone), and/or at the time of surgery (ie, after completing paclitaxel + anti-HER2 therapy, before starting adjuvant chemotherapy). The present analysis included 130 patients with a median age of 38 years (interquartile ratio [IQR], age 33-42 years). AMH values at the 3 time points differed significantly (P<.001). At baseline, median AMH levels were 1.29 ng/mL (IQR, 0.56-2.62 ng/mL). At week 2, a small but significant reduction in AMH levels was observed (median, 1.10 ng/mL; IQR, 0.45-2.09 ng/mL; P<.001). At surgery, a larger significant decline in AMH levels was observed (median, 0.01 ng/mL; IQR, 0.01-0.03 ng/mL; P<.001). Although the type of anti-HER2 treatment (trastuzumab and/or lapatinib) did not seem to impact the results, age and pretreatment ovarian reserve had a major influence on treatment-induced gonadotoxicity risk. This NeoALTTO biomarker analysis showed that anti-HER2 therapies alone had limited gonadotoxicity but that the addition of weekly paclitaxel resulted in marked AMH decline with possible negative implications for subsequent ovarian function and fertility.

Breakthroughs in the Systemic Treatment of HER2-Positive Advanced/Metastatic Gastric Cancer: From Singlet Chemotherapy to Triple Combination.

Gastric cancer is heterogeneous in morphology, biology, genomics, and treatment response. Alterations in human epidermal growth factor receptor 2 (HER2) overexpression, microsatellite instability (MSI) status, programmed death-ligand 1 (PD-L1) levels, and fibroblast growth factor receptor 2 (FGFR2) can be used as biomarkers. Since the combination of fluoropyrimidine/platinum plus trastuzumab that was investigated in the ToGA trial was approved as a standard of care in HER2-positive patients in 2010, no other agents showed efficacy in the first- (HELOISE, LOGiC, JACOB trials) and second- (TyTAN, GATSBY, T-ACT trials) line treatments. Despite the success in treating breast cancer, various anti-HER2 agents, including a monoclonal antibody (pertuzumab), an antibody-drug conjugate (ADC; trastuzumab emtansine [T-DM1]), and a small molecule (lapatinib) failed to translate into clinical benefits until the KEYNOTE-811 (first-line) and DESTINY-Gastri01 (≥second-line) trials were conducted. The incorporation of HER2-directed treatment with immune checkpoint inhibitors in the form of a monoclonal antibody or ADC is now approved as a standard treatment. Despite the promising results of new agents (engineered monoclonal antibodies, bi-specific antibodies, fusion proteins, and small molecules) in the early phase of development, the management of HER2-positive gastric cancer requires further optimization to achieve precision medicine with a chemotherapeutic backbone. Treatment resistance is a complex process that can be overcome using a combination of chemotherapy, targeted agents, and immune checkpoint inhibitors, including novel agents. HER2 status must be reassessed in patients undergoing anti-HER2 treatment with disease progression after the first-line treatment. As a general guideline, patients who need systemic treatment should receive chemotherapy plus targeted agents, anti-angiogenic agents, immune checkpoint inhibitors, or their combinations.

Contraception in breast cancer survivors from the FEERIC case-control study (performed on behalf of the Seintinelles research network)

ObjectiveTo compare the prevalence of contraception in breast cancer (BC) patients at risk of unintentional pregnancy (i.e. not currently pregnant or trying to get pregnant) and matched controls. Study designThe FEERIC study (Fertility, Pregnancy, Contraception after BC in France) is a prospective, multicenter case-control study, including localized BC patients aged 18–43 years, matched for age and parity to cancer-free volunteer controls in a 1:2 ratio. Data were collected through online questionnaires completed on the Seintinelles research platform. ResultsIn a population of 1278 women at risk of unintentional pregnancy, the prevalence of contraception at study inclusion did not differ significantly between cases (340/431, 78.9%) and controls (666/847, 78.6%, p = 0.97). Contrarily, the contraceptive methods used were significantly different, with a higher proportion of copper IUD use in BC survivors (59.5% versus 25.0% in controls p < 0.001). For patients at risk of unintentional pregnancy, receiving information about chemotherapy-induced ovary damage at BC diagnosis (OR = 2.47 95%CI [ 1.39–4.37] and anti-HER2 treatment (OR = 2.46, 95% CI [ 1.14–6.16]) were significantly associated with the use of a contraception in multivariate analysis. ConclusionIn this large French study, BC survivors had a prevalence of contraception use similar to that for matched controls, though almost one in five women at risk of unintentional pregnancy did not use contraception. Dedicated consultations at cancer care centers could further improve access to information and contraception counseling.

Supporting a patient with learning disabilities through screening and treatment for primary breast cancer

This article presents a case study evaluation of supporting a patient with learning disabilities through the NHS Breast Screening Programme diagnostic pathway and subsequent treatments for breast cancer. The process encompassed best interests meetings and treatment planning, surgeries, chemotherapy and anti-Her2 treatments, radiotherapy and endocrine therapy. Problems that occurred during this period included issues around completing surgery, managing chemotherapy treatment during the COVID-19 pandemic and the feasibility and tolerance of radiotherapy. The role of a breast care nurse in this patient's pathway was to facilitate treatment, support the patient and her family, and to liaise with the wider nursing and medical teams to coordinate care.

Serum LAPTM4B as a Potential Diagnostic and Prognostic Biomarker for Breast Cancer.

Lysosome-associated protein transmembrane-4 beta (LAPTM4B) is an integral membrane protein overexpressed in various cancers and may function as a prognostic tumor marker. The present study is aimed at understanding the clinical significance of serum LAPTM4B in breast cancer (BC). Serum LAPTM4B level was evaluated in 426 BC patients, 40 benign breast disease, and 80 healthy controls by ELISA. We used the receiver operator characteristic (ROC) curve to assess the diagnostic significance. 46 BC patients were recruited to monitor the dynamic change of serum LAPTM4B during adjuvant therapy (AT). In addition, sera from a subset of 330 patients undergoing AT, including anti-HER2 treatment, were collected to evaluate the association between LAPTM4B levels and AT efficacy. Descriptive and explorative statistical analyses were used to assess LAPTM4 B's potential as a diagnostic and prognostic marker in BC. Serum LAPTM4B level was significantly increased in BC patients than benign group and controls. It could well discriminate BC from healthy controls with diagnostic accuracy with an AUC of 0.912, a sensitivity of 85.9%, and a specificity of 83.8%. Compared with pre-AT, serum LAPTM4B concentration remarkably decreased after AT. In addition, patients in the invalid response group (PD + SD) showed higher LAPTM4B levels than the valid response group (PR + CR). Our results proposed that serum LAPTM4B had a high diagnostic and prognostic impact as a circulating biomarker in BC.

HER2 mRNA Levels, Estrogen Receptor Activity and Susceptibility to Trastuzumab in Primary Breast Cancer.

While the results thus far demonstrate the clinical benefit of trastuzumab in breast cancer (BC), some patients do not respond to this drug. HER2 mRNA, alone or combined with other genes/biomarkers, has been proven to be a powerful predictive marker in several studies. Here, we provide evidence of the association between HER2 mRNA levels and the response to anti-HER2 treatment in HER2-positive BC patients treated with adjuvant trastuzumab and show that this association is independent of estrogen receptor (ER) tumor positivity. While HER2 mRNA expression was significantly correlated with HER2 protein levels in ER-negative tumors, no correlation was found in ER-positive tumors, and HER2 protein expression was not associated with relapse risk. Correlation analyses in the ER-positive subset identified ER activity as the pathway inversely associated with HER2 mRNA. Associations between HER2 levels and oncogene addiction, as well as between HER2 activation and trastuzumab sensitivity, were also observed in vitro in HER2-positive BC cell lines. In ER-positive but not ER-negative BC cells, HER2 transcription was increased by reducing ligand-dependent ER activity or inducing ER degradation. Accordingly, HER2 mRNA levels in patients were found to be inversely correlated with blood levels of estradiol, the natural ligand of ER that induces ER activation. Moreover, low estradiol levels were associated with a lower risk of relapse in HER2-positive BC patients treated with adjuvant trastuzumab. Overall, we found that HER2 mRNA levels, but not protein levels, indicate the HER2 dependency of tumor cells and low estrogen-dependent ER activity in HER2-positive tumors.

234 (PB-058) Poster - Neratinib could be effective as monotherapy or in combination with Trastuzumab in HER2 low expressing breast cancer cells and organoid model

The selection of breast cancer patients for anti-HER2 treatment is based on HER2 positivity defined by IHC (Immunohistochemistry) and/or in situ hybridization (ISH). However, there have been some discrepancies and ambiguity on HER2 classification, leading to several cut-off changes over the years and resulting in some of the patients with lower HER2 expressing tumours not offered anti-HER2 treatments. Several studies also suggested that a subset of the HER2 low breast tumours may respond to anti-HER2 treatments. The aim of this study is to understand the mechanisms of action and resistance of HER2 targeting treatments in HER2-low expressing breast cancer cells (BC cells). The HER2 expression of a panel of 8 breast cell lines was assessed by IHC, FISH, western blot and qRT-PCR and their responses to trasztuzumab was assessed based on HER2 expression. We also established a panel of patient-derived organoids (PDOs) from the cancer tissues obtained from breast cancer patients to assess the effects of anti-HER2 agents.

277 (PB-101) Poster - ERBB2 mRNA expression in HER2-low breast cancer

Background: Trastuzumab deruxtecan significantly increased progression-free and overall survival than the physician’s choice of chemotherapy for the HER2-low breast cancer (BC) patients, which opened a new chapter in the treatment of HER2-low BC. However, the ability of traditional immunohistochemistry to distinguish HER2-0 and HER2-low was questioned and some BC patients with suspected low expression of ERBB2 might not benefit from the new anti-HER2 treatment. High mRNA expression of ERBB2 partially explained the response to T-DM1 in HER2 positive breast cancer, which brings up the possibility of precise detection of mRNA expression of ERBB2 to define HER2-low cohort and its guidance on drug administration.

ECG and Echocardiographic Signs of Early Onset of Cardiotoxic Effects in Patients with Breast Cancer after Chemoradiotherapy

<h3>Purpose/Objective(s)</h3> In the broad context of preventive and personalized medicine, in this study we aim to detect early predictive biomarkers of impaired heart function in patients with HER2 positive breast cancer undergoing multi-modal treatments in our institution. <h3>Materials/Methods</h3> Our study group contains 45 positive HER2 patients aged between 30 and 78 years (median age 51 years, mean age 52.2 years) with breast cancer who in the period 2015-2020 underwent multimodal chemotherapy treatments with anthracyclines, treatment surgery, targeted anti-HER2 treatment and radiation therapy (in different modes 2D, 3D and VMAT). During therapy, cardiac function was monitored by echocardiography (ECO) and ECG at regular intervals, which allowed evaluation before, during, and at the end of each stage of treatment. By calculating the risk estimates (odds- and risks ratios) and by building multivariate logistic models we evaluated the associations between the average dose, the maximum dose, V25, V30 corresponding to the whole heart, left ventricle and various arterial routes of coronary circulation, on the one hand and echocardiographic and electrocardiographic semiology in the interval 18-36 months after the start of multimodal treatment. The logistic models allowed us to discriminate both the short-term cardiotoxic effects of the other therapies and the individual effects of radiotherapy, but also to obtain correlative effects of the effects of radiotherapy in relation with the hormonal profile of the tumor, anthracycline dose history, time spacing the onset of other therapies, etc. <h3>Results</h3> Our studied shows that, as a general rule, there is an association between changing ECG semiology (by exacerbating pre-existing pathologies and / or by the appearance of new abnormalities) and the dose delivered both to the heart, the left ventricle in particular and the coronary arteries (except the right coronary arteries, RCA). The effect of the delivered dose on the RCA is associated with changes in echocardiographic semiology. <h3>Conclusion</h3> By estimating the risk relations between dose thresholds and early cardiotoxic effects, this study is the premise of reviewing the current protocols for cardiac monitoring and also for the need to the use high-performance instruments aiming to build predictive tools for the early onset of radiotherapy-related cardiac pathologies.

The impact of standardized structured reporting of pathology reports for breast cancer care

PurposeWith the increasing complexity of modern oncological patient management and the growing amount of information needed from the pathologist, traditional narrative pathology reports (NR) do not suffice. Standardized synoptic reporting (SR) increases both completeness and readability. In the Netherlands SR for breast cancer was introduced in 2009. We explore the impact of synoptic reporting on breast cancer care. MethodsUsing data from the Netherlands Cancer Registry and Dutch Nationwide Pathology Databank, a retrospective population-based cohort study was performed. Data of breast cancer resections from 2007 to 2014 were collected to compare NR and SR for all outcome measures. Kaplan-Meier analyses and log-rank testing were used to estimate overall survival. ResultsOver time there was an increase from 12% to 78.9% in the use of SR. SR resulted in higher completeness of pathology reports, particularly for hormone and HER2/neu receptor status. Although there was no difference in the administration of antihormonal therapy, anti-HER2 treatment was more frequently administered to eligible patients in the SR group. An effect on overall survival could not yet be confirmed on multivariate analysis. ConclusionsWe demonstrate that SR has led to more complete pathology reports, which meets the needs for precision of information in breast cancer care. This is expected to improve communication and discussions between specialists regarding parameters important for adjuvant breast cancer treatment decisions. SR thereby improves breast cancer care and leads to improved allocation of treatment based on pathologic parameters and more personalized treatment regimens.

HELENA: HER2-Low as a prEdictive factor of response to Neoadjuvant chemotherapy in eArly breast cancer

BackgroundHER2 expression has a prognostic and predictive impact in early-stage breast cancer (BC). HER2 positive BC (immunohistochemistry (IHC) score 3 + or 2 + with in situ hybridization (ISH) amplification) are treated with HER2 targeted therapies. The concept of HER2-low BC (IHC score 1 + or 2 + without ISH amplification) is drawing attention as anti-HER2 treatment has recently shown efficacy in this subgroup. We aimed to explore the response to neoadjuvant chemotherapy (NAC) in HER2-low early BC according to the HER2 score (1 + or 2 + without amplification).MethodsWe conducted a retrospective study in two French comprehensive cancer centers. All patients with HER2-low BC treated with NAC from January 2014 to December 2020 were included. The primary objective was to analyze the pathological complete response (pCR) rate to NAC using the Sataloff or RCB system, according to the HER2 score. Secondary objectives were to assess disease free survival (DFS), overall survival (OS) and to explore the immune environment through the Neutrophil-to-Lymphocyte Ratio (NLR), according to HER2 expression. Univariate and multivariate analyses were performed.ResultsWe included 237 tumors for 229 patients. Of these, 160 (67.5%) tumors were HER2 1 + , 77 (32.5%) were HER2 2 + , and 152 (64.1%) were hormone receptor (HR) positive. The median age was 53.9 years. No differences in tumor characteristics were observed between HER2 1 + and HER2 2 + subgroups. pCR was achieved in 38 tumors (17%), without any difference between HER2 1 + and HER2 2 + subgroups (p = 0.77). DFS and OS were significantly different between HER2 1 + and HER2 2 + patients (HR = 0.41,CI95%[0.17;0.97] p = 0.037 and HR = 0.31,CI95%[0.09;1.02] p = 0.042, respectively). HER2 status was still associated with DFS and OS after adjustment for age, HR status and NLR, with better outcomes in favor of HER2 score 2 + (HR = 0.35 [0.15–0.84] and HR = 0.24 [0.07–0.81], respectively). NLR was not associated with worse DFS or OS.ConclusionIn HER2-low early BC, no differences in pCR were observed between HER2 1 + and HER2 2 + tumors, however patients with HER2 2 + tumors had a better DFS and OS than those with HER2 1 + . Further investigations are needed to describe the intrinsic differences in the spectrum of HER2-low BC.

Therapeutic landscape of advanced HER2-positive breast cancer in 2022.

HER2-positive breast cancer is an aggressive subtype of breast cancer with five-year survival rates of 30% for the advanced stage. The development of anti-HER2 treatments has led to a paradigm shift in the management and clinical outcomes of advanced HER2-positive breast cancer patients. The standard first-line treatment consists of taxane-based chemotherapy plus dual anti-HER2 therapies with trastuzumab and pertuzumab. The antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1) has been a second-line therapeutic standard, but the second-line treatment approach is rapidly evolving. Given a substantial advantage of another ADC, Fam-trastuzumab deruxtecan (T-DXd), compared to T-DM1 in a recent randomized trial in the second-line setting, T-DXd is currently the preferred second-line option. Optimal third-line treatment strategies are still not established, and multiple approaches have been used including combinations based on capecitabine, trastuzumab, or both with oral anti-HER2 tyrosine kinase inhibitors. Tucatinib plus capecitabine and trastuzumab, lapatinib plus trastuzumab, neratinib or lapatinib plus capecitabine are some of the FDA approved combinations. Another newer agent approved for third- or later-line therapy in the metastatic setting ismargetuximab, an Fc-engineered anti-HER2 monoclonal antibody, in combination with chemotherapy. Other novel agents currently under clinical trials are the drugs that indirectly target HER2, including immune cell cycle inhibitors, PI3K/mTOR inhibitors, and immunotherapy agents.

Immunosuppressive lncRNA LINC00624 promotes tumor progression and therapy resistance through ADAR1 stabilization

BackgroundDespite the success of HER2-targeted therapy in achieving prolonged survival in approximately 50% of treated individuals, treatment resistance is still an important challenge for HER2+ breast cancer (BC) patients. The...