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Human epidermal growth factor receptor 2 (HER2) overexpression emerges as an attractive therapeutic target in gynecological malignancies. Recently, Trastuzumab-Deruxtecan (T-DXd) has shown substantial efficacy in HER2 overexpressing carcinomas, most prominently in ovarian, endometrial and cervical patients. We have examined the efficacy of T-DXd in patients with metastatic endometrial, ovarian and cervical malignancies that were treated in the Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens. Methods Patients with gynecological malignancies with HER2 expression 2 + /3 + as assessed by immunohistochemistry (IHC) that were treated with T-DXd were retrospectively identified. Patients received T-DXd intravenously at a dose of 5.4 mg/kg every 3 weeks until disease progression or unacceptable toxicity. Results In total, 10 patients treated with T-DXd for recurrent/metastatic disease were identified. Regarding histology, there were 5 patients with uterine neoplasms (serous carcinoma (n = 3), uterine carcinosarcoma (n = 1), uterine leiomyosarcoma (n = 1)), 1 patient with squamous cervical carcinoma and 4 patients with ovarian cancer (ovarian carcinosarcoma (n = 2), high-grade serous carcinoma (n = 1) and mucinous ovarian carcinoma (n = 1)). Median age was 65.4 years (25th-75th percentile, 58.1–75.2 years). 5 patients had HER2 expression 3 + by IHC and 5 patients had HER2 expression 2 +. Median number of previous lines of therapy was 4 (range 2–6), 2 patients with uterine serous carcinoma were pretreated with trastuzumab and 4 patients had already received immunotherapy. In the entire cohort median progression-free survival (PFS) was 5.4 months (95%CI 0.8–9.8 months). Regarding responses, 5 patients had partial response (including 2 patients that were pretreated with trastuzumab), 1 patient had stable disease at 12 weeks and 4 patients had disease progression at initial assessment. All patients but one that derived clinical benefit had HER2 3 + expression. Discussion In the real-world setting, T-DXd showed activity in a cohort of heavily pre-treated patients with HER2-expressing gynecological malignancies. [ABSTRACT FROM AUTHOR]

Abstract Background Colorectal cancer (CRC) is a leading cause of cancer-related mortality, highlighting the necessity for multifaceted treatment strategies, including preoperative treatment (PT), which can enhance surgical outcomes and provide prognostic insights. This study aims to clarify the impact of PT-induced changes in mismatch repair (MMR) and human epidermal growth factor receptor 2 (HER2) expression, potentially informing tailored treatment strategies and improving clinical outcomes for CRC patients. Methods This retrospective study analyzed 120 paired samples from CRC patients who underwent preoperative treatment, comparing pre- and post-treatment specimens. A control group of 60 untreated surgical specimens was also included. Immunohistochemistry assessed MMR proteins (MSH6, MSH2, MLH1, PMS2) and HER2 expression. MSI status was determined in samples with low MMR expression. Results Compared to pre-treatment samples, post-treatment samples exhibited lower levels of MSH6, MSH2, and total MMR expression, along with higher levels of HER2 expression. However, when compared to the untreated control group, there were no significant differences in the expression of MSH6, total MMR, and HER2. All samples that exhibited weak MMR expression and those that shifted to deficient mismatch repair (dMMR) status following treatment had stable microsatellite status. No clear clinicopathological characteristics or prognostic factors were found to be associated with changes in MMR and HER2 expression, except for the use of fluorouracil or capecitabine, which was related to changes in total MMR scores. ypTNM stage and TRG scores were identified as independent factors affecting disease progression in our study. Conclusions PT is associated with a reduction in MMR expression, notably for the MSH2 protein, while it does not appear to influence HER2 expression.

Abstract There is limited research on the clinicopathological characteristics of combined hepatocellular-cholangiocarcinoma (cHCC-CCA) currently. The aim of this study is to summerize the clinicopathological factors and prognosis of cHCC-CCA, which could help us understand this disease. 72 cases of cHCC-CCA from West China Hospital of Sichuan University were collected. Tissue components were reviewed by pathologists. Immunohistochemistry was used to detect the status of mismatch repair (MMR) and human epidermal growth factor receptor 2 (HER2) in cHCC-CCA, as well as the quantity and distribution of CD3+ T cells and CD8+ T cells. Fluorescence in situ hybridization was used to detect fibroblast growth factor receptor 2 (FGFR2) gene alteration. COX univariate and multivariate analyses were used to evaluate risk factors, and survival curves were plotted. 49 cases were classified as classic type cHCC-CCA and 23 cases as intermediate cell carcinoma. The cut-off value for diagnosing classic type was determined to be ≥ 30% for the cholangiocarcinoma component based on prognostic calculations. All tumors were MMR proficient. The rate of strong HER2 protein expression (3+) was 8.3%, and the frequency of FGFR2 gene alteration was 26.4%. CD3+ T cells and CD8+ T cells were mainly distributed at the tumor margin, and were protective factors for patients with cHCC-CCA. The overall survival of the 72 patients was 18.9 months, with a median survival of 12 months. Tumor size, TNM stage, and serum AFP level were prognostic factors for cHCC-CCA. The proportion of cholangiocarcinoma component reaching the threshold of 30%, may provide a reference for future pathology diagnosis. FGFR2 gene alteration was 26.4%, providing a clue for anti-FGFR2 therapy. However, more data is needed for further verification.

Abstract Background With the development of novel anti-HER2 targeted drugs, such as ADCs, it has become increasingly important to accurately interpret HER2 expression in breast cancer. Previous studies have demonstrated high intra-observer and inter-observer variabilities in evaluating HER2 staining by human eyes. There exists a strong requirement to develop artificial intelligence (AI) systems to achieve high-precision HER2 expression scoring for better clinical therapy. Methods In the present study, we collected breast cancer tissue samples and stained consecutive sections with anti-Calponin and anti-HER2 antibodies. High-quality digital images were selected from immunohistochemical slides and interpreted as HER2 3+, 2+, 1+, and 0. AI models were trained and assessed using annotated training and testing sets. The AI model was trained to automatically identify ductal carcinoma in situ (DCIS) by Calponin staining and myoepithelial annotation and filter out DCIS components in HER2-stained slides using image-overlapping techniques. Furthermore, we organized two-phase validation studies. In phase one, pathologists interpreted 112 HER2 whole-slide images (WSIs) without AI assistance, whereas in phase two, pathologists read the same slides using the AI system after a washing period of 2 weeks. Results Our AI model greatly improved the accuracy of reading (0.902 vs. 0.710). The number of HER2 1 + patients misdiagnosed as HER2 0 was significantly reduced (32/279 vs. 65/279), and they benefitted from ADC drugs. In addition, the AI algorithm improved the intra-group consistency of HER2 readings by pathologists with different years of experience (intra-class correlation coefficient [ICC]: 0.872–0.926 vs. 0.818–0.908), with the improvement most pronounced among junior pathologists (0.885 vs. 0.818). Conclusions We proposed a high-precision AI system to identify and filter out DCIS components and automatically evaluate HER2 expression in invasive breast cancer.

Background: Colorectal cancer (CRC) is a leading cause of cancer-related mortality, highlighting the necessity for multifaceted treatment strategies, including preoperative treatment (PT), which can enhance surgical outcomes and provide prognostic insights. This study aims to clarify the impact of PT-induced changes in mismatch repair (MMR) and human epidermal growth factor receptor 2 (HER2) expression, potentially informing tailored treatment strategies and improving clinical outcomes for CRC patients. Methods: This retrospective study analyzed 120 paired samples from CRC patients who underwent preoperative treatment, comparing pre- and post-treatment specimens. A control group of 60 untreated surgical specimens was also included. Immunohistochemistry assessed MMR proteins (MSH6, MSH2, MLH1, PMS2) and HER2 expression. MSI status was determined in samples with low MMR expression. Results: Compared to pre-treatment samples, post-treatment samples exhibited lower levels of MSH6, MSH2, and total MMR expression, along with higher levels of HER2 expression. However, when compared to the untreated control group, there were no significant differences in the expression of MSH6, total MMR, and HER2. All samples that exhibited weak MMR expression and those that shifted to deficient mismatch repair (dMMR) status following treatment had stable microsatellite status. No clear clinicopathological characteristics or prognostic factors were found to be associated with changes in MMR and HER2 expression, except for the use of fluorouracil or capecitabine, which was related to changes in total MMR scores. ypTNM stage and TRG scores were identified as independent factors affecting disease progression in our study. Conclusions: PT is associated with a reduction in MMR expression, notably for the MSH2 protein, while it does not appear to influence HER2 expression. [ABSTRACT FROM AUTHOR]

There is limited research on the clinicopathological characteristics of combined hepatocellular-cholangiocarcinoma (cHCC-CCA) currently. The aim of this study is to summerize the clinicopathological factors and prognosis of cHCC-CCA, which could help us understand this disease. 72 cases of cHCC-CCA from West China Hospital of Sichuan University were collected. Tissue components were reviewed by pathologists. Immunohistochemistry was used to detect the status of mismatch repair (MMR) and human epidermal growth factor receptor 2 (HER2) in cHCC-CCA, as well as the quantity and distribution of CD3+ T cells and CD8+ T cells. Fluorescence in situ hybridization was used to detect fibroblast growth factor receptor 2 (FGFR2) gene alteration. COX univariate and multivariate analyses were used to evaluate risk factors, and survival curves were plotted. 49 cases were classified as classic type cHCC-CCA and 23 cases as intermediate cell carcinoma. The cut-off value for diagnosing classic type was determined to be ≥ 30% for the cholangiocarcinoma component based on prognostic calculations. All tumors were MMR proficient. The rate of strong HER2 protein expression (3+) was 8.3%, and the frequency of FGFR2 gene alteration was 26.4%. CD3+ T cells and CD8+ T cells were mainly distributed at the tumor margin, and were protective factors for patients with cHCC-CCA. The overall survival of the 72 patients was 18.9 months, with a median survival of 12 months. Tumor size, TNM stage, and serum AFP level were prognostic factors for cHCC-CCA. The proportion of cholangiocarcinoma component reaching the threshold of 30%, may provide a reference for future pathology diagnosis. FGFR2 gene alteration was 26.4%, providing a clue for anti-FGFR2 therapy. However, more data is needed for further verification. [ABSTRACT FROM AUTHOR]

Abstract Background Evaluation of human epidermal growth factor receptor 2 (HER2) overexpression caused by erb-b2 receptor tyrosine kinase 2 (ERBB2) amplification (AMP) by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) is essential for treating unresectable metastatic gastric cancer (GC). A targeted tumour sequencing test enables comprehensive assessment of alterations in cancer-related genes, including ERBB2. This study aimed to evaluate the concordance between the targeted tumour sequencing test and IHC/FISH for detecting HER2-positive GC and to clarify the significance of ERBB2 AMP and concomitant genetic alterations in HER2 downstream pathways (DPs) in anti-HER2 therapy for unresectable metastatic GC patients. Methods ERBB2 copy number alteration (CNA) was examined via a targeted tumour sequencing test in 152 formalin-fixed paraffin-embedded (FFPE) GC tissues. ERBB2 CNA was compared to HER2 status evaluated by IHC/FISH in FFPE block sections, which were identical to those subjected to the targeted tumour sequencing test. Treatment outcomes of anti-HER2 therapy in 11 patients with unresectable metastatic GC was evaluated. Results ERBB2 AMP (≥ 2.5-fold change) was detected by the targeted tumour sequencing test in 15 patients (9.9%), and HER2 positivity (IHC 3 + or IHC 2+/FISH positive) was detected in 21 patients (13.8%). The overall percent agreement, positive percent agreement, negative percent agreement and Cohen’s kappa between ERBB2 CNA and HER2 status were 94.7%, 66.7%, 99.2% and 0.75, respectively. Progression-free survival for trastuzumab therapy in patients with ERBB2 AMP was significantly longer than that in patients with no ERBB2 AMP detected by the targeted tumour sequencing test (median 14 months vs. 4 months, P = 0.007). Treatment response to trastuzumab therapy was reduced in patients with ERBB2 AMP and concomitant CNAs of genes in HER2 DPs. One patient with ERBB2 AMP and concomitant CNAs of genes in HER2 DPs achieved a durable response to trastuzumab deruxtecan as fourth-line therapy. Conclusions A targeted tumour sequencing test is a reliable modality for identifying HER2-positive GC. ERBB2 AMP and concomitant genetic alterations detected through the targeted tumour sequencing test are potential indicators of treatment response to trastuzumab therapy. The targeted tumour sequencing test has emerged as a plausible candidate for companion diagnostics to determine indications for anti-HER2 therapy in the era of precision medicine for GC.

Abstract Background Novel ADC drugs provide a new therapeutic strategy for gastric cancer.The present study aimed to analyze the clinical efficacy and drug toxicities of disitamab vedotin (RC48) plus immune checkpoint inhibitors(ICIs) and RC48 as third-line therapies and beyond for advanced and metastatic gastric cancer patients. Methods This was an observational multicenter real-world study.From August 2021 to January 2022,patients with HER2-positive or HER2-low advanced and metastatic gastric cancer and failed from two or more lines of prior therapy were enrolled and treated with RC48 plus ICIs or RC48. In this study, progression free survival(PFS) was the primary end point. Other evaluation indicators were objective response rate(ORR),disease control rate(DCR),overall survival(OS) and drug toxicities. Results 45 patients were enrolled,of which 25 patients received RC48 plus ICIs,20 patients received RC48.Patients who received RC48 plus ICIs obtained better ORR (36.0% vs. 10.0%, P = 0.044) and DCR (80.0% vs. 50.0%, P = 0.034) compared with RC48,and simultaneously,the median PFS in RC48 plus ICIs group were superior to RC48 group(6.2 m vs. 3.9 m).The median OS was not reached.No statistically differences were found between HER2-positive and HER2-low group with respect to ORR (27.3% vs. 16.7%, P = 0.464),DCR (66.7% vs. 66.7%, P = 1.000),median PFS(5.7 m vs. 4.3 m, P = 0.299).The most common adverse events (AEs) were decreased white blood count,decreased neutrophil count,fatigue,hypoaesthesia and alopecia.Grade 3–4 AEs occurred in 7(35.0%) patients of RC48 group and 10(40.0%) patients of RC48 plus ICIs group,respectively. Conclusion Compared with RC48 monotherapy, ICIs plus RC48 demonstrated superior third-line and beyond therapeutic efficacy for HER2-positive or HER2-low advanced and metastatic gastric cancer patients with manageable safety.

Abstract Background RC48-antibody-drug conjugates (ADC) link humanized anti-HER2 immunoglobulin with monomethyl auristatin E (MMAE). Clinical trials suggest promising antitumor activity in HER2-expressing solid tumors. This study probes RC48-ADC’s efficacy and safety in patients with HER2-expressing advanced or metastatic solid tumors. Method Data was collected from 23 advanced cancer patients treated with RC48-ADC at our oncology center between July 2021 and December 2022. These patients exhibited at least 1 + expression of HER2 immunohistochemistry, had previously experienced at least one failed systemic chemotherapy, and were treated with RC48-ADC until the occurrence of intolerable adverse reactions or disease progression. The primary endpoint was the disease control rate (DCR), and secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Results 23 of 25 screened patients received RC48 treatment. The ORR was 43.5% (95% CI, 23.2-63.7%) with a median PFS of 6.0 months (95% CI, 4.8–7.4). In the low-to-medium HER2 expression subgroup, ORR was 37.5%, median PFS 5.75 months. In the high HER2 expression subgroup, ORR was 57.1%, median PFS 7 months. For the cohort combining RC48 with PD-1 inhibitors, ORR was 53.8%, median PFS 8 months. In the concurrent local radiation therapy subgroup, ORR was 40.0%, median PFS 6.0 months. Treatment-related adverse events (TRAEs) were anemia (60.8%), leukopenia (56.2%), raised transaminases (52.17%), and neutropenia (43.5%). Five patients (21.7%) experienced Grade 3 symptoms, including anemia (21.7%) and neutropenia (14.0%). No Grade 4 adverse reactions or deaths were reported. Conclusion RC48-ADC shows promising efficacy and manageable safety in HER2-expressing advanced or metastatic solid tumor patients.

Background: Novel ADC drugs provide a new therapeutic strategy for gastric cancer.The present study aimed to analyze the clinical efficacy and drug toxicities of disitamab vedotin (RC48) plus immune checkpoint inhibitors(ICIs) and RC48 as third-line therapies and beyond for advanced and metastatic gastric cancer patients. Methods: This was an observational multicenter real-world study.From August 2021 to January 2022,patients with HER2-positive or HER2-low advanced and metastatic gastric cancer and failed from two or more lines of prior therapy were enrolled and treated with RC48 plus ICIs or RC48. In this study, progression free survival(PFS) was the primary end point. Other evaluation indicators were objective response rate(ORR),disease control rate(DCR),overall survival(OS) and drug toxicities. Results: 45 patients were enrolled,of which 25 patients received RC48 plus ICIs,20 patients received RC48.Patients who received RC48 plus ICIs obtained better ORR (36.0% vs. 10.0%, P = 0.044) and DCR (80.0% vs. 50.0%, P = 0.034) compared with RC48,and simultaneously,the median PFS in RC48 plus ICIs group were superior to RC48 group(6.2 m vs. 3.9 m).The median OS was not reached.No statistically differences were found between HER2-positive and HER2-low group with respect to ORR (27.3% vs. 16.7%, P = 0.464),DCR (66.7% vs. 66.7%, P = 1.000),median PFS(5.7 m vs. 4.3 m, P = 0.299).The most common adverse events (AEs) were decreased white blood count,decreased neutrophil count,fatigue,hypoaesthesia and alopecia.Grade 3–4 AEs occurred in 7(35.0%) patients of RC48 group and 10(40.0%) patients of RC48 plus ICIs group,respectively. Conclusion: Compared with RC48 monotherapy, ICIs plus RC48 demonstrated superior third-line and beyond therapeutic efficacy for HER2-positive or HER2-low advanced and metastatic gastric cancer patients with manageable safety. [ABSTRACT FROM AUTHOR]

Abstract Purpose The human EGFR2 (HER2) signaling pathway is one of the most actively studied targets in cancer transformation research. Ttriplex-forming oligonucleotides (TFOs) activate DNA damage and induce apoptosis. We aim to encapsulate TFO-HER2 with nano-particle ZW-128 to suppress breast cell growth in vitro and in vivo. Experimental design We designed a set of TFO fragments targeting HER2 and verified their effectiveness. We encapsulated TFO-HER2 in ZW-128 to form nano-drug TFO@ZW-128. Cell counting kit 8, flow cytometry, and western blotting were used to evaluate the effect of TFO@ZW-128 on cell proliferation and the expressions of related proteins. The ant-itumor effect of TFO@ZW-128 was evaluated in vivo using nude mice breast cancer model. Results TFO@ZW-128 had efficient cellular uptake in amplified HER2 breast cancer cells. TFO@ZW-128 showed an 80-fold increase in TFO utilization compared with TFO-HER2 in the nude mouse breast cancer model. Meanwhile, TFO@ZW-128 dramatically inhibited the growth of HER2-overexpressing tumors compared with TFO-HER2 (P

Background: RC48-antibody-drug conjugates (ADC) link humanized anti-HER2 immunoglobulin with monomethyl auristatin E (MMAE). Clinical trials suggest promising antitumor activity in HER2-expressing solid tumors. This study probes RC48-ADC's efficacy and safety in patients with HER2-expressing advanced or metastatic solid tumors. Method: Data was collected from 23 advanced cancer patients treated with RC48-ADC at our oncology center between July 2021 and December 2022. These patients exhibited at least 1 + expression of HER2 immunohistochemistry, had previously experienced at least one failed systemic chemotherapy, and were treated with RC48-ADC until the occurrence of intolerable adverse reactions or disease progression. The primary endpoint was the disease control rate (DCR), and secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Results: 23 of 25 screened patients received RC48 treatment. The ORR was 43.5% (95% CI, 23.2-63.7%) with a median PFS of 6.0 months (95% CI, 4.8–7.4). In the low-to-medium HER2 expression subgroup, ORR was 37.5%, median PFS 5.75 months. In the high HER2 expression subgroup, ORR was 57.1%, median PFS 7 months. For the cohort combining RC48 with PD-1 inhibitors, ORR was 53.8%, median PFS 8 months. In the concurrent local radiation therapy subgroup, ORR was 40.0%, median PFS 6.0 months. Treatment-related adverse events (TRAEs) were anemia (60.8%), leukopenia (56.2%), raised transaminases (52.17%), and neutropenia (43.5%). Five patients (21.7%) experienced Grade 3 symptoms, including anemia (21.7%) and neutropenia (14.0%). No Grade 4 adverse reactions or deaths were reported. Conclusion: RC48-ADC shows promising efficacy and manageable safety in HER2-expressing advanced or metastatic solid tumor patients. [ABSTRACT FROM AUTHOR]

Abstract Background Dishevelled paralogs (DVL1, 2, 3) are key mediators of Wnt pathway playing a role in constitutive oncogenic signaling influencing the tumor microenvironment. While previous studies showed correlation of β-catenin with T cell gene expression, little is known about the role of DVL2 in modulating tumor immunity. This study aimed to uncover the novel interaction between DVL2 and HER2-positive (HER2+) breast cancer (BC) in regulating tumor immunity and disease progression. Methods DVL2 loss of function studies were performed with or without a clinically approved HER2 inhibitor, Neratinib in two different HER2+ BC cell lines. We analyzed RNA (RT-qPCR) and protein (western blot) expression of classic Wnt markers and performed cell proliferation and cell cycle analyses by live cell imaging and flow cytometry, respectively. A pilot study in 24 HER2+ BC patients was performed to dissect the role of DVL2 in tumor immunity. Retrospective chart review on patient records and banked tissue histology were performed. Data were analyzed in SPSS (version 25) and GraphPad Prism (version 7) at a significance p

Abstract Background Precision medicine with gene panel testing based on next-generation sequencing for patients with cancer is being used increasingly in clinical practice. HER2, which encodes the human epidermal growth factor receptor 2 (HER2), is a potentially important driver gene. However, therapeutic strategies aimed at mutations in the HER2 extracellular domain have not been clarified. We therefore investigated the effect of EGFR co-targeted therapy with HER2 on patient-derived cancer models with the HER2 extracellular domain mutation E401G, based on our previous findings that this mutation has an epidermal growth factor receptor (EGFR)-mediated activation mechanism. Methods We generated a xenograft (PDX) and a cancer tissue-originated spheroid (CTOS) from a patient’s cancer containing an amplified HER2 E401G mutation. With these platforms, we compared the efficacy of afatinib, a tyrosine kinase inhibitor having anti-HER2 and anti-EGFR activity, with two other therapeutic options: lapatinib, which has similar properties but weaker EGFR inhibition, and trastuzumab plus pertuzumab, for which evidence exists of treatment efficacy against cancers with wild-type HER2 amplification. Similar experiments were also performed with H2170, a cell line with wild-type HER2 amplification, to contrast the characteristics of these drug’s efficacies against HER2 E401G. Results We confirmed that PDX and CTOS retained morphological and immunohistochemical characteristics and HER2 gene profiles of the original tumor. In both PDX and CTOS, afatinib reduced tumor size more than lapatinib or trastuzumab plus pertuzumab. In addition, afatinib treatment resulted in a statistically significant reduction in HER2 copy number at the end of treatment. On the other hand, in H2170 xenografts with wild-type HER2 amplification, trastuzumab plus pertuzumab was most effective. Conclusions Afatinib, a dual inhibitor of HER2 and EGFR, showed a promising effect on cancers with amplified HER2 E401G, which have an EGFR-mediated activation mechanism. Analysis of the activation mechanisms of mutations and development of therapeutic strategies based on those mechanisms are critical in precision medicine for cancer patients.

Abstract Background This retrospective study explored the relationship between hormone receptor (HR), human epidermal growth factor receptor 2 (HER2) status, and bone involvement in the first distant metastases (DM) of Chinese breast cancer (BC) patients who lacked the HER2 targeted therapy. Such therapy was rarely received due to its lag approval or high cost in China compared with the developed countries. Methods All eligible women with primary unilateral stage I – III BC and first DM diagnosed in 2008—2018 at one cancer center were identified for enrollment. Based on chart records, a full or no/partial compliance status of endocrine therapy (ET) was assigned for HR-positive patients. Multivariate logistic regression was used to estimate the adjusted odd ratio (aOR), its 95%CI and p value. Results Four hundred eighteen patients had an average age of 50.7 years and median disease-free survival of 27.1 months at DM. Bone, lung, liver and brain metastasis rates in patients were 55.7%, 34.7%, 33.0% and 8.1%, respectively. Compared to HR-negative patients, HR-positive patients with the full and non/partial compliance of ET were significantly associated with higher risk of bone involvement with an aOR of 2.329 (1.316 – 1.741, p = 0.004) and 2.317 (1.330 – 4.036, p = 0.003), respectively. No difference of such risk was found between the two groups of ET compliance (p = 0.984) nor between HER2-negative and HER2-positive patients (aOR 0.827, p = 0.431). Stratified analyses further indicated that HR-positive was associated with bone involvement only in HER2-negative BC patients (p = 0.006—0.015). Conclusions HR-positive tumors are significantly associated with bone involvement in HER2-negative metastatic BC patients. ET does not appear to impact this association. HER2 status per se is not associated with such risk.

Abstract Background Breast 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. Methods We 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. Results Of 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. Conclusions Patients 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.

Abstract Background The TROIKA trial established that HD201 and trastuzumab were equivalent in terms of primary endpoints (total pathological complete response) following neoadjuvant treatment. The objective of the present analysis was to compare survival outcomes and final safety. Methods In the TROIKA trial, patients with ERBB2-positive early breast cancer were randomized and treated with either HD201 or the referent trastuzumab. Eligible patients received 8 cycles of either HD201 or referent trastuzumab (loading dose, 8 mg/kg; maintenance dose, 6 mg/kg) every 3 weeks in combination with 8 cycles of chemotherapy (4 cycles of docetaxel, 75 mg/m2, followed by 4 cycles of epirubicin, 75 mg/m2, and cyclophosphamide, 500 mg/m2) in the neoadjuvant setting. The patients then underwent surgery followed by 10 cycles of adjuvant HD201 or referent trastuzumab according to their initial randomization to complete one year of trastuzumab-directed therapy. Event-free and overall survival rates were calculated using Kaplan–Meier analysis. The hazard ratio for event-free survival was estimated by Cox proportional hazards regression. Results The final analysis was performed after all patients completed the study at a median follow-up of 37.7 months (Q1-Q3, 37.3–38.1 months). A total of 502 randomized patients received either HD201 or the referent trastuzumab, and 474 (94.2%) were eligible for inclusion in the per-protocol set. In this population, the 3-year event-free survival rates were 85.6% (95% CI: 80.28–89.52) and 84.9% (95% CI: 79.54–88.88) in the HD201 and referent trastuzumab groups, respectively (log rank p = 0.938) (HR 1.02, 95% CI: 0.63–1.63; p = 0.945). The 3-year overall survival rates were comparable between the HD201 (95.6%; 95% CI: 91.90–97.59) and referent trastuzumab treatment groups (96.0%, 95% CI: 92.45–97.90) (log rank p = 0.606). During the posttreatment follow-up period, adverse events were reported for 64 (27.4%) and 72 (29.8%) patients in the HD201 and the reference trastuzumab groups, respectively. Serious adverse events were rare and none of which were related to the study treatment. Conclusions This final analysis of the TROIKA trial further confirms the comparable efficacy and safety of HD201 and trastuzumab. Trial registration ClinicalTrials.gov identifier: NCT03013504.

Purpose: The human EGFR2 (HER2) signaling pathway is one of the most actively studied targets in cancer transformation research. Ttriplex-forming oligonucleotides (TFOs) activate DNA damage and induce apoptosis. We aim to encapsulate TFO-HER2 with nano-particle ZW-128 to suppress breast cell growth in vitro and in vivo. Experimental design: We designed a set of TFO fragments targeting HER2 and verified their effectiveness. We encapsulated TFO-HER2 in ZW-128 to form nano-drug TFO@ZW-128. Cell counting kit 8, flow cytometry, and western blotting were used to evaluate the effect of TFO@ZW-128 on cell proliferation and the expressions of related proteins. The ant-itumor effect of TFO@ZW-128 was evaluated in vivo using nude mice breast cancer model. Results: TFO@ZW-128 had efficient cellular uptake in amplified HER2 breast cancer cells. TFO@ZW-128 showed an 80-fold increase in TFO utilization compared with TFO-HER2 in the nude mouse breast cancer model. Meanwhile, TFO@ZW-128 dramatically inhibited the growth of HER2-overexpressing tumors compared with TFO-HER2 (P < 0.05). Furthermore, TFO@ZW-128-induced cell apoptosis was in a p53-independent manner. Conclusions: In this study, we designed nano-drug TFO@ZW-128, which has proven effective and non-toxic in targeted therapy for ectopic HER2-expressing tumors. [ABSTRACT FROM AUTHOR]

Background: Breast malignancies are now the most common and deadliest type of neoplasms among women worldwide. Novel therapeutic approaches are needed to combat advanced stages of breast cancer. In this study, we aimed to investigate the expression and co-expression status of three immune checkpoints (PD-1, PD-L1, and LAG-3), as well as tumor-infiltrating lymphocytes (TIL) scores, and to further establish their potential correlations with clinicopathologic features. Methods: We performed a retrospective study on 361 pathologic samples of breast cancer. Immunohistochemistry was performed to assess the status of the immune checkpoint markers, and H&E staining was used to score TILs. The correlations of the immune checkpoint markers of tumor cells and tumor-associated immune cells and TIL scores with clinicopathological characteristics were analyzed. Results: Out of 361 assessed samples, LAG-3 was positive in 51%, while IC PD-L1 and TC PD-L1 were detectable in 36% and 8.9%, respectively. Moreover, both IC PD-L1 and LAG-3 stained positively in 24.4% of samples. IC PD-L1 expression was significantly higher in tumors with higher nuclear, mitotic, and overall grades and tubule formation. In addition, TC PD-L1 and LAG-3 exhibited a similar trend for higher overall grading. Tumors with positive estrogen- and progesterone-receptor (ER and PR) expression had significantly lower IC PD-L1 and TC PD-L1 staining, while LAG-3 positivity was more prevalent in HER2 positive samples. Tumors that were positive for these biomarkers had significantly higher Ki-67 scores. LAG-3 expression showed significant correlations with PD-1 and IC PD-L1 expression. Besides, the co-expression of LAG-3 and IC PD-L1 was significantly more encountered in luminal B and triple-negative subtypes, compared to the luminal A subtype. Regarding TILs, their scoring was significantly higher in ER and PR negative and HER2 positive samples. Intriguingly, samples with positive staining for LAG-3, IC PD-L1, and TC PD-L1 had significantly higher TIL scorings. Conclusions: Immune checkpoints show differentially different levels of expression in certain molecular subtypes of breast cancer. Moreover, they reveal a meaningful correlation with each other, proliferation indices, and histologic grades. Finally, a sizable proportion of breast cancers co-express PD-L1 and LAG-3, which will make them appropriate targets for future combined ICIs. [ABSTRACT FROM AUTHOR]

Abstract Background and objectives Trastuzumab is an important targeted drug for HER2-positive gastric cancer. The treatment efficacy of a more cost-effective and accessible trastuzumab biosimilar, HLX02, was not well investigated, especially when combined with antiangiogenic treatment. In addition, the tumour microenvironment detected by functional MRI was still unclear during treatment. This study attempts to evaluate the therapeutic effect of antiangiogenic agents combined with HLX02 in a HER2-positive gastric cancer xenograft model and to detect microenvironmental changes using intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI). Materials and methods We subcutaneously injected MKN-45 human gastric cancer cells into BALB/C nude mice to establish a tumour model. Twenty-eight mice were divided into four groups and treated with saline (Group 1), Endostar (Group 2), trastuzumab biosimilar HLX02 (Group 3), or the combination of Endostar and HLX02 (Group 4). We then performed IVIM-DWI before and at different time points after treatment. HE, HER2, TUNEL, E-cadherin staining, and α-SMA and CD31 double-staining were used to confirm the pathological changes. Results Group 4 demonstrated the smallest tumour volume at the end of treatment. The D value in Group 4 increased more dramatically, with the highest value on Day 20, compared with the other groups. Perfusion-related parameters (D* and f values) in Groups 2 and 4 increased initially and reversed after Day 10. Group 4 showed the lowest CD31 and HER2 and the highest TUNEL- and E-cadherin-positive staining rates. The D value was positively correlated with TUNEL but negatively correlated with HER2 staining. The D* and f values had positive correlations with CD31 and E-cadherin expression and the vessel maturity index. Conclusions The trastuzumab biosimilar drug HLX02 exhibited good treatment efficacy in HER2-positive gastric cancer, especially when combined with Endostar. IVIM-DWI can noninvasively monitor the process of vascular normalization and reflect the treatment effect early at the molecular level.

Abstract Background The determination of HER2 expression status contributes significantly to HER2-targeted therapy in breast carcinoma. However, an economical, efficient, and non-invasive assessment of HER2 is lacking. We aimed to develop a clinicoradiomic nomogram based on radiomics scores extracted from multiparametric MRI (mpMRI, including ADC-map, T2W1, DCE-T1WI) and clinical risk factors to assess HER2 status. Methods We retrospectively collected 214 patients with pathologically confirmed invasive ductal carcinoma between January 2018 to March 2021 from Fudan University Shanghai Cancer Center, and randomly divided this cohort into training set (n = 128, 42 HER2-positive and 86 HER2-negative cases) and validation set (n = 86, 28 HER2-positive and 58 HER2-negative cases) at a ratio of 6:4. The original and transformed pretherapy mpMRI images were treated by semi-automated segmentation and manual modification on the DeepWise scientific research platform v1.6 ( http://keyan.deepwise.com/ ), then radiomics feature extraction was implemented with PyRadiomics library. Recursive feature elimination (RFE) based on logistic regression (LR) and LASSO regression were adpoted to identify optimal features before modeling. LR, Linear Discriminant Analysis (LDA), support vector machine (SVM), random forest (RF), naive Bayesian (NB) and XGBoost (XGB) algorithms were used to construct the radiomics signatures. Independent clinical predictors were identified through univariate logistic analysis (age, tumor location, ki-67 index, histological grade, and lymph node metastasis). Then, the radiomics signature with the best diagnostic performance (Rad score) was further combined with significant clinical risk factors to develop a clinicoradiomic model (nomogram) using multivariate logistic regression. The discriminative power of the constructed models were evaluated by AUC, DeLong test, calibration curve, and decision curve analysis (DCA). Results 70 (32.71%) of the enrolled 214 cases were HER2-positive, while 144 (67.29%) were HER2-negative. Eleven best radiomics features were retained to develop 6 radiomcis classifiers in which RF classifier showed the highest AUC of 0.887 (95%CI: 0.827–0.947) in the training set and acheived the AUC of 0.840 (95%CI: 0.758–0.922) in the validation set. A nomogram that incorporated the Rad score with two selected clinical factors (Ki-67 index and histological grade) was constructed and yielded better discrimination compared with Rad score (p = 0.374, Delong test), with an AUC of 0.945 (95%CI: 0.904–0.987) in the training set and 0.868 (95%CI: 0.789–0.948; p = 0.123) in the validation set. Moreover, calibration with the p-value of 0.732 using Hosmer–Lemeshow test demonstrated good agreement, and the DCA verified the benefits of the nomogram. Conclusion Post largescale validation, the clinicoradiomic nomogram may have the potential to be used as a non-invasive tool for determination of HER2 expression status in clinical HER2-targeted therapy prediction.

Abstract Cancer-therapy related cardiotoxicity (CTRCT) is a significant and frequent complication of monoclonal antibody directed therapy, especially Trastuzumab, for human epidermal growth factor receptor 2 (HER2) overexpressing breast cancers. Reliable, clinically available molecular predictive markers of CTRCT have not yet been developed. Identifying specific genetic variants and their molecular markers, which make the host susceptible to this complication is key to personalised risk stratification. A systematic review was conducted until April 2021, using the Medline, Embase databases and Google Scholar, to identify studies genetic and RNA-related markers associated with CTRCT in HER2 positive breast cancer patients. So far, researchers have mainly focused on HER2 related polymorphisms, revealing codons 655 and 1170 variants as the most likely SNPs associated with cardiotoxicity, despite some contradictory results. More recently, new potential genetic markers unrelated to the HER2 gene, and linked to known cardiomyopathy genes or to genes regulating cardiomyocytes apoptosis and metabolism, have been detected. Moreover, microRNAs are gaining increasing recognition as additional potential molecular markers in the cardio-oncology field, supported by encouraging preliminary data about their relationship with cardiotoxicity in breast cancers. In this review, we sought to synthesize evidence for genetic variants and RNA-related molecular markers associated with cardiotoxicity in HER2-positive breast cancer.

Abstract Background Human epidermal growth factor receptor 2 (HER2)-positive tumors are defined by protein overexpression (3+) or gene amplification using immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), respectively. HER2-positive tumors have historically included both IHC(3+) and IHC(2+, equivocal)/FISH(+) tumors and received the same treatment. Differences in biology between these two tumor types, however, are poorly understood. Considering anti-HER2 drugs bind directly to HER2 protein on the cell surface, we hypothesized anti-HER2 therapies would be less effective in IHC(2+)/FISH(+) tumors than in IHC(3+) tumors, leading to differences in patient outcomes. Methods A total of 447 patients with HER2-positive invasive carcinoma who underwent curative surgery were retrospectively investigated. HER2 status was assessed in surgical specimens, except in patients who received neo-adjuvant chemotherapy, where biopsy specimens were employed. Results Age, tumor size, lymph node status and ER status were independent factors relating to disease-free-survival, but no difference was observed between IHC(3+) and IHC(2+)/FISH(+) tumors. Kaplan-Meier analysis found patient outcomes did not differ, even after stratifying into those that did (n = 314), or did not (n = 129), receive chemotherapy with anti-HER2 drugs. In 134 patients who received NAC, pathological complete response rates in IHC(3+) and IHC(2+)/FISH(+) tumors were 45% and 21%, respectively. Survival after developing metastasis was significantly shorter in the IHC(2+)/FISH(+) group. Conclusions The prognosis of patients with IHC(2+)/FISH(+) tumors did not differ from IHC(3+) tumors. However, the significance of HER2 protein overexpression in relation to treatment response remains unclear and warrants further investigations.

Background: Dishevelled paralogs (DVL1, 2, 3) are key mediators of Wnt pathway playing a role in constitutive oncogenic signaling influencing the tumor microenvironment. While previous studies showed correlation of β-catenin with T cell gene expression, little is known about the role of DVL2 in modulating tumor immunity. This study aimed to uncover the novel interaction between DVL2 and HER2-positive (HER2+) breast cancer (BC) in regulating tumor immunity and disease progression. Methods: DVL2 loss of function studies were performed with or without a clinically approved HER2 inhibitor, Neratinib in two different HER2+ BC cell lines. We analyzed RNA (RT-qPCR) and protein (western blot) expression of classic Wnt markers and performed cell proliferation and cell cycle analyses by live cell imaging and flow cytometry, respectively. A pilot study in 24 HER2+ BC patients was performed to dissect the role of DVL2 in tumor immunity. Retrospective chart review on patient records and banked tissue histology were performed. Data were analyzed in SPSS (version 25) and GraphPad Prism (version 7) at a significance p < 0.05. Results: DVL2 regulates the transcription of immune modulatory genes involved in antigen presentation and T cell maintenance. DVL2 loss of function down regulated mRNA expression of Wnt target genes involved in cell proliferation, migration, invasion in HER2+ BC cell lines (±Neratinib). Similarly, live cell proliferation and cell cycle analyses reveal that DVL2 knockdown (±Neratinib) resulted in reduced proliferation, higher growth arrest (G1), limited mitosis (G2/M) compared to non-targeted control in one of the two cell lines used. Analyses on patient tissues who received neoadjuvant chemotherapy (n = 14) further demonstrate that higher DVL2 expression at baseline biopsy pose a significant negative correlation with % CD8α levels (r = − 0.67, p < 0.05) while have a positive correlation with NLR (r = 0.58, p < 0.05), where high NLR denotes worse cancer prognosis. These results from our pilot study reveal interesting roles of DVL2 proteins in regulating tumor immune microenvironment and clinical predictors of survival in HER2+ BC. Conclusion: Our study demonstrates potential immune regulatory role of DVL2 proteins in HER2+ BC. More in-depth mechanistic studies of DVL paralogs and their influence on anti-tumor immunity may provide insight into DVLs as potential therapeutic targets benefiting BC patients. [ABSTRACT FROM AUTHOR]

Background: The TROIKA trial established that HD201 and trastuzumab were equivalent in terms of primary endpoints (total pathological complete response) following neoadjuvant treatment. The objective of the present analysis was to compare survival outcomes and final safety. Methods: In the TROIKA trial, patients with ERBB2-positive early breast cancer were randomized and treated with either HD201 or the referent trastuzumab. Eligible patients received 8 cycles of either HD201 or referent trastuzumab (loading dose, 8 mg/kg; maintenance dose, 6 mg/kg) every 3 weeks in combination with 8 cycles of chemotherapy (4 cycles of docetaxel, 75 mg/m2, followed by 4 cycles of epirubicin, 75 mg/m2, and cyclophosphamide, 500 mg/m2) in the neoadjuvant setting. The patients then underwent surgery followed by 10 cycles of adjuvant HD201 or referent trastuzumab according to their initial randomization to complete one year of trastuzumab-directed therapy. Event-free and overall survival rates were calculated using Kaplan–Meier analysis. The hazard ratio for event-free survival was estimated by Cox proportional hazards regression. Results: The final analysis was performed after all patients completed the study at a median follow-up of 37.7 months (Q1-Q3, 37.3–38.1 months). A total of 502 randomized patients received either HD201 or the referent trastuzumab, and 474 (94.2%) were eligible for inclusion in the per-protocol set. In this population, the 3-year event-free survival rates were 85.6% (95% CI: 80.28–89.52) and 84.9% (95% CI: 79.54–88.88) in the HD201 and referent trastuzumab groups, respectively (log rank p = 0.938) (HR 1.02, 95% CI: 0.63–1.63; p = 0.945). The 3-year overall survival rates were comparable between the HD201 (95.6%; 95% CI: 91.90–97.59) and referent trastuzumab treatment groups (96.0%, 95% CI: 92.45–97.90) (log rank p = 0.606). During the posttreatment follow-up period, adverse events were reported for 64 (27.4%) and 72 (29.8%) patients in the HD201 and the reference trastuzumab groups, respectively. Serious adverse events were rare and none of which were related to the study treatment. Conclusions: This final analysis of the TROIKA trial further confirms the comparable efficacy and safety of HD201 and trastuzumab. Trial registration: ClinicalTrials.gov identifier: NCT03013504. [ABSTRACT FROM AUTHOR]

Background: This retrospective study explored the relationship between hormone receptor (HR), human epidermal growth factor receptor 2 (HER2) status, and bone involvement in the first distant metastases (DM) of Chinese breast cancer (BC) patients who lacked the HER2 targeted therapy. Such therapy was rarely received due to its lag approval or high cost in China compared with the developed countries. Methods: All eligible women with primary unilateral stage I – III BC and first DM diagnosed in 2008—2018 at one cancer center were identified for enrollment. Based on chart records, a full or no/partial compliance status of endocrine therapy (ET) was assigned for HR-positive patients. Multivariate logistic regression was used to estimate the adjusted odd ratio (aOR), its 95%CI and p value. Results: Four hundred eighteen patients had an average age of 50.7 years and median disease-free survival of 27.1 months at DM. Bone, lung, liver and brain metastasis rates in patients were 55.7%, 34.7%, 33.0% and 8.1%, respectively. Compared to HR-negative patients, HR-positive patients with the full and non/partial compliance of ET were significantly associated with higher risk of bone involvement with an aOR of 2.329 (1.316 – 1.741, p = 0.004) and 2.317 (1.330 – 4.036, p = 0.003), respectively. No difference of such risk was found between the two groups of ET compliance (p = 0.984) nor between HER2-negative and HER2-positive patients (aOR 0.827, p = 0.431). Stratified analyses further indicated that HR-positive was associated with bone involvement only in HER2-negative BC patients (p = 0.006—0.015). Conclusions: HR-positive tumors are significantly associated with bone involvement in HER2-negative metastatic BC patients. ET does not appear to impact this association. HER2 status per se is not associated with such risk. [ABSTRACT FROM AUTHOR]

Background: Breast 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. Methods: We 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. Results: Of 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. Conclusions: Patients 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. [ABSTRACT FROM AUTHOR]

Background: Precision medicine with gene panel testing based on next-generation sequencing for patients with cancer is being used increasingly in clinical practice. HER2, which encodes the human epidermal growth factor receptor 2 (HER2), is a potentially important driver gene. However, therapeutic strategies aimed at mutations in the HER2 extracellular domain have not been clarified. We therefore investigated the effect of EGFR co-targeted therapy with HER2 on patient-derived cancer models with the HER2 extracellular domain mutation E401G, based on our previous findings that this mutation has an epidermal growth factor receptor (EGFR)-mediated activation mechanism. Methods: We generated a xenograft (PDX) and a cancer tissue-originated spheroid (CTOS) from a patient's cancer containing an amplified HER2 E401G mutation. With these platforms, we compared the efficacy of afatinib, a tyrosine kinase inhibitor having anti-HER2 and anti-EGFR activity, with two other therapeutic options: lapatinib, which has similar properties but weaker EGFR inhibition, and trastuzumab plus pertuzumab, for which evidence exists of treatment efficacy against cancers with wild-type HER2 amplification. Similar experiments were also performed with H2170, a cell line with wild-type HER2 amplification, to contrast the characteristics of these drug's efficacies against HER2 E401G. Results: We confirmed that PDX and CTOS retained morphological and immunohistochemical characteristics and HER2 gene profiles of the original tumor. In both PDX and CTOS, afatinib reduced tumor size more than lapatinib or trastuzumab plus pertuzumab. In addition, afatinib treatment resulted in a statistically significant reduction in HER2 copy number at the end of treatment. On the other hand, in H2170 xenografts with wild-type HER2 amplification, trastuzumab plus pertuzumab was most effective. Conclusions: Afatinib, a dual inhibitor of HER2 and EGFR, showed a promising effect on cancers with amplified HER2 E401G, which have an EGFR-mediated activation mechanism. Analysis of the activation mechanisms of mutations and development of therapeutic strategies based on those mechanisms are critical in precision medicine for cancer patients. [ABSTRACT FROM AUTHOR]

Background and Objectives: Trastuzumab is an important targeted drug for HER2-positive gastric cancer. The treatment efficacy of a more cost-effective and accessible trastuzumab biosimilar, HLX02, was not well investigated, especially when combined with antiangiogenic treatment. In addition, the tumour microenvironment detected by functional MRI was still unclear during treatment. This study attempts to evaluate the therapeutic effect of antiangiogenic agents combined with HLX02 in a HER2-positive gastric cancer xenograft model and to detect microenvironmental changes using intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI).Materials and Methods: We subcutaneously injected MKN-45 human gastric cancer cells into BALB/C nude mice to establish a tumour model. Twenty-eight mice were divided into four groups and treated with saline (Group 1), Endostar (Group 2), trastuzumab biosimilar HLX02 (Group 3), or the combination of Endostar and HLX02 (Group 4). We then performed IVIM-DWI before and at different time points after treatment. HE, HER2, TUNEL, E-cadherin staining, and α-SMA and CD31 double-staining were used to confirm the pathological changes.Results: Group 4 demonstrated the smallest tumour volume at the end of treatment. The D value in Group 4 increased more dramatically, with the highest value on Day 20, compared with the other groups. Perfusion-related parameters (D* and f values) in Groups 2 and 4 increased initially and reversed after Day 10. Group 4 showed the lowest CD31 and HER2 and the highest TUNEL- and E-cadherin-positive staining rates. The D value was positively correlated with TUNEL but negatively correlated with HER2 staining. The D* and f values had positive correlations with CD31 and E-cadherin expression and the vessel maturity index.Conclusions: The trastuzumab biosimilar drug HLX02 exhibited good treatment efficacy in HER2-positive gastric cancer, especially when combined with Endostar. IVIM-DWI can noninvasively monitor the process of vascular normalization and reflect the treatment effect early at the molecular level. [ABSTRACT FROM AUTHOR]

Abstract Background Phosphatase and tensin homolog (PTEN) loss is associated with tumorigenesis, tumor progression, and therapy resistance in breast cancer. However, the clinical value of PTEN as a biomarker in these patients is controversial. We sought to determine whether the benefit of traditional biomarkers testing is improved by the analysis of PTEN status for the identification of high-risk breast cancer. Methods A cohort of 608 patients with breast cancer was included in this study. Based on the expression on the neoplastic cells compared to the normal internal controls by immunohistochemistry (IHC), cases were classified as PTEN-low (PTEN-L) or PTEN-retained (PTEN-WT). The former constituted the study group, while the latter the control group. Analysis of gene expression was performed on publicly available genomic data and included 4265 patients from the METABRIC and MSK cohorts retrieved from cBioPortal. The Shapiro-Wilk test was used to analyze the normal distributions of continuous variables. Relationships between PTEN status and the clinicopathologic and molecular features of the patient population were assessed using Fisher’s exact test or Chi-squared/Wilcoxon rank-sum test. Survival curves were built according to the Kaplan-Meier method. Results Alteration in PTEN status was significantly different at protein and gene levels, where the reduced protein expression was observed in 280/608 cases (46.1%) from our group, while genetic aberrations in only 315/4265 (7.4%) cases of the METABRIC and MSK cohorts. PTEN-L tumors were significantly enriched for hormone receptors (HR) and HER2 negativity (n = 48, 17.1%) compared to PTEN-WT tumors (n = 22, 6.7%; p = 0.0008). Lack of HR with or without HER2 overexpression/amplification was significantly associated with worse overall survival (OS) in PTEN-L but not in PTEN-WT breast cancers (p

Abstract Background Docetaxel in combination with two HER2-directed therapies, trastuzumab and pertuzumab, is the current standard frontline therapy for patients with metastatic HER2-positive breast cancer. Ado-trastuzumab (T-DM1), an antibody-drug conjugate of trastuzumab and a cytotoxic microtubule-inhibitory agent, emtansine, is approved in patients that have progressed with prior trastuzumab-based therapy. However, the benefit of T-DM1 in patients previously treated with pertuzumab therapy for metastatic breast cancer remains unclear. Methods We identified thirty-three adults with metastatic HER2-positive breast cancer treated between March 2013 and July 2018 with T-DM1 either as subsequent therapy after progression on a pertuzumab-based regimen (i.e., “pertuzumab-pretreated”) or without prior exposure to pertuzumab (i.e., “pertuzumab-naïve”). Collected data included patient demographics, treatment history, adverse events, and clinical outcomes. For both cohorts receiving T-DM1, the primary endpoint was PFS and secondary endpoints were overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and T-DM1-related toxicity rate. Results Pertuzumab-pretreated patients (n = 23, with 21 evaluable for T-DM1 efficacy) had a median PFS of 9.5 months (95% CI: 2.9–NA), 1-year OS rate of 67.4% (95% CI: 50.0–90.9%) with an unreached median, ORR of 14.3% (95% CI: 3.0–36.3%), and CBR of 52.4% (95% CI: 29.8–74.3%), with none of these measures being statistically different than those estimated for the pertuzumab-naïve group (n = 10). Treatment with T-DM1 after prior pertuzumab exposure (median T-DM1 duration 2.9 months) resulted in no grade ≥ 3 adverse events. Conclusions In our cohort, prior exposure to pertuzumab did not significantly impact T-DM1’s clinical efficacy or safety profile as second- or later-line therapy in patients with metastatic HER2-positive breast cancer.

Abstract Background The V-Akt murine thymoma viral oncogene (AKT) 1 (E17K) is a subfamily of serine/threonine protein kinases that affects the survival, proliferation, and invasion of cancer cells. The clinicopathological features and frequencies in Asian populations with AKT1 mutations in breast and endometrial cancers are unclear. Hence, we aimed to determine the frequencies and relationships between clinicopathological features and AKT1 mutations in Asian women with cancer. Methods We extracted DNA from 311 and 143 samples derived from patients with breast and endometrial cancers to detect the AKT1 point mutation (hotspot), E17K. We examined correlations between clinicopathological features and AKT1 mutation status. Results The frequency of AKT1 mutations in breast cancer was 7.4%, and they were found more frequently in human epidermal growth factor receptor 2 (HER2)-negative breast cancer subtypes, although this was not statistically significant (P = 0.08). The frequency of AKT1 mutations in endometrial cancer was 4.1%, and the mutations were histologically detected only in endometrioid types. However, AKT1 mutations did not correlate with relapse-free or overall survival of patients with breast or endometrial cancer. Conclusions AKT1 mutations are associated with HER2-negative subtype in breast cancer and in endometrial cancer with endometrioid histology. The frequencies of AKT1 mutations in breast and endometrial cancers were similar between Asian and other regional women. The frequency of mutations is too low in both tumor types to talk about predictive significance.

BackgroundHuman epidermal growth factor receptor 3 (HER3) is important in maintaining epidermal growth factor receptor-driven cancers and mediating resistance to targeted therapy. A phase I study of anti-HER3 monoclonal antibody LJM716 was conducted with the primary objective to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), and dosing schedule. Secondary objectives were to characterize safety/tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity.MethodsThis open-label, dose-finding study comprised dose escalation, followed by expansion in patients with squamous cell carcinoma of the head and neck or esophagus, and HER2-overexpressing metastatic breast cancer or gastric cancer. During dose escalation, patients received LJM716 intravenous once weekly (QW) or every two weeks (Q2W), in 28-day cycles. An adaptive Bayesian logistic regression model was used to guide dose escalation and establish the RDE. Exploratory pharmacodynamic tumor studies evaluated modulation of HER3 signaling.ResultsPatients received LJM716 3-40 mg/kg QW and 20 mg/kg Q2W (54 patients; 36 patients at 40 mg/kg QW). No dose-limiting toxicities (DLTs) were reported during dose-escalation. One patient experienced two DLTs (diarrhea, hypokalemia [both grade 3]) in the expansion phase. The RDE was 40 mg/kg QW, providing drug levels above the preclinical minimum effective concentration. One patient with gastric cancer had an unconfirmed partial response; 17/54 patients had stable disease, two lasting >30 weeks. Down-modulation of phospho-HER3 was observed in paired tumor samples.ConclusionsLJM716 was well tolerated; the MTD was not reached, and the RDE was 40 mg/kg QW. Further development of LJM716 is ongoing.Trial registrationClinicaltrials.gov registry number NCT01598077 (registered on 4 May, 2012).

Abstract Background Trastuzumab has changed the prognosis of HER2+ breast cancer. We aimed to investigate the prognosis of ER+/HER2+ patients treated with trastuzumab, thus to guide escalation endocrine treatment in ER+ breast cancer. Methods ER-positive early breast cancer patients operated at Ruijin Hospital between Jan. 2009 and Dec. 2017 were retrospectively included. Eligible patients were grouped as HER2-negative (HER2-neg) or HER2-positive with trastuzumab treatment (HER2-pos-T). Kaplan-Meier analysis and Cox proportional hazards model were used to compare the disease-free survival (DFS) and overall survival (OS) between these two groups. Results A total of 3761 patients were enrolled: 3313 in the HER2-neg group and 448 in the HER2-pos-T group. Patients in the HER2-pos-T group were associated with pre/peri-menopause, higher histological grade, LVI, higher Ki-67 level, lower ER and PR levels (all P

Background: The determination of HER2 expression status contributes significantly to HER2-targeted therapy in breast carcinoma. However, an economical, efficient, and non-invasive assessment of HER2 is lacking. We aimed to develop a clinicoradiomic nomogram based on radiomics scores extracted from multiparametric MRI (mpMRI, including ADC-map, T2W1, DCE-T1WI) and clinical risk factors to assess HER2 status.Methods: We retrospectively collected 214 patients with pathologically confirmed invasive ductal carcinoma between January 2018 to March 2021 from Fudan University Shanghai Cancer Center, and randomly divided this cohort into training set (n = 128, 42 HER2-positive and 86 HER2-negative cases) and validation set (n = 86, 28 HER2-positive and 58 HER2-negative cases) at a ratio of 6:4. The original and transformed pretherapy mpMRI images were treated by semi-automated segmentation and manual modification on the DeepWise scientific research platform v1.6 ( http://keyan.deepwise.com/ ), then radiomics feature extraction was implemented with PyRadiomics library. Recursive feature elimination (RFE) based on logistic regression (LR) and LASSO regression were adpoted to identify optimal features before modeling. LR, Linear Discriminant Analysis (LDA), support vector machine (SVM), random forest (RF), naive Bayesian (NB) and XGBoost (XGB) algorithms were used to construct the radiomics signatures. Independent clinical predictors were identified through univariate logistic analysis (age, tumor location, ki-67 index, histological grade, and lymph node metastasis). Then, the radiomics signature with the best diagnostic performance (Rad score) was further combined with significant clinical risk factors to develop a clinicoradiomic model (nomogram) using multivariate logistic regression. The discriminative power of the constructed models were evaluated by AUC, DeLong test, calibration curve, and decision curve analysis (DCA).Results: 70 (32.71%) of the enrolled 214 cases were HER2-positive, while 144 (67.29%) were HER2-negative. Eleven best radiomics features were retained to develop 6 radiomcis classifiers in which RF classifier showed the highest AUC of 0.887 (95%CI: 0.827-0.947) in the training set and acheived the AUC of 0.840 (95%CI: 0.758-0.922) in the validation set. A nomogram that incorporated the Rad score with two selected clinical factors (Ki-67 index and histological grade) was constructed and yielded better discrimination compared with Rad score (p = 0.374, Delong test), with an AUC of 0.945 (95%CI: 0.904-0.987) in the training set and 0.868 (95%CI: 0.789-0.948; p = 0.123) in the validation set. Moreover, calibration with the p-value of 0.732 using Hosmer-Lemeshow test demonstrated good agreement, and the DCA verified the benefits of the nomogram.Conclusion: Post largescale validation, the clinicoradiomic nomogram may have the potential to be used as a non-invasive tool for determination of HER2 expression status in clinical HER2-targeted therapy prediction. [ABSTRACT FROM AUTHOR]

Abstract Background Over than one third (28–58%) of pregnancy-associated breast cancer (PABC) cases are characterized by positive epidermal growth factor receptor 2-positive (HER2) expression. Trastuzumab anti-HER2 monoclonal antibody is still the benchmark treatment of HER2-positive breast tumors. However, FDA has categorized Trastuzumab as a category D drug for pregnant patients with breast cancer. This systemic review aims to synthesize all currently available data of trastuzumab administration during pregnancy and provide an updated view of the effect of trastuzumab on fetal and maternal outcome. Methods Eligible articles were identified by a search of MEDLINE bibliographic database and ClinicalTrials.gov for the period up to 01/09/2020; The algorithm consisted of a predefined combination of the words “breast”, “cancer”, “trastuzumab” and “pregnancy”. This study was performed in accordance with the PRISMA guidelines. Results A total of 28 eligible studies were identified (30 patients, 32 fetuses). In more than half of cases, trastuzumab was administered in the metastatic setting. The mean duration of trastuzumab administration during gestation was 15.7 weeks (SD: 10.8; median: 17.5; range: 1–32). Oligohydramnios or anhydramnios was the most common (58.1%) adverse event reported in all cases. There was a statistically significant decrease in oligohydramnios/anhydramnios incidence in patients receiving trastuzumab only during the first trimester (P = 0.026, Fisher’s exact test). In 43.3% of cases a completely healthy neonate was born. 41.7% of fetuses exposed to trastuzumab during the second and/or third trimester were born completely healthy versus 75.0% of fetuses exposed exclusively in the first trimester. All mothers were alive at a median follow-up of 47.0 months (ranging between 9 and 100 months). Of note, there were three cases (10%) of cardiotoxicity and decreased ejection fraction during pregnancy. Conclusions Overall, treatment with trastuzumab should be postponed until after delivery, otherwise pregnancy should be closely monitored.

Background: Human epidermal growth factor receptor 2 (HER2)-positive tumors are defined by protein overexpression (3+) or gene amplification using immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), respectively. HER2-positive tumors have historically included both IHC(3+) and IHC(2+, equivocal)/FISH(+) tumors and received the same treatment. Differences in biology between these two tumor types, however, are poorly understood. Considering anti-HER2 drugs bind directly to HER2 protein on the cell surface, we hypothesized anti-HER2 therapies would be less effective in IHC(2+)/FISH(+) tumors than in IHC(3+) tumors, leading to differences in patient outcomes.Methods: A total of 447 patients with HER2-positive invasive carcinoma who underwent curative surgery were retrospectively investigated. HER2 status was assessed in surgical specimens, except in patients who received neo-adjuvant chemotherapy, where biopsy specimens were employed.Results: Age, tumor size, lymph node status and ER status were independent factors relating to disease-free-survival, but no difference was observed between IHC(3+) and IHC(2+)/FISH(+) tumors. Kaplan-Meier analysis found patient outcomes did not differ, even after stratifying into those that did (n = 314), or did not (n = 129), receive chemotherapy with anti-HER2 drugs. In 134 patients who received NAC, pathological complete response rates in IHC(3+) and IHC(2+)/FISH(+) tumors were 45% and 21%, respectively. Survival after developing metastasis was significantly shorter in the IHC(2+)/FISH(+) group.Conclusions: The prognosis of patients with IHC(2+)/FISH(+) tumors did not differ from IHC(3+) tumors. However, the significance of HER2 protein overexpression in relation to treatment response remains unclear and warrants further investigations. [ABSTRACT FROM AUTHOR]

Abstract Background Esophagogastric adenocarcinoma (EGA) currently represents a main cause of cancer related death. Despite an intensified treatment for locally advanced or metastatic EGA with a doublet chemotherapy consisting of a platinum compound and a fluoropyrimidine in combination with trastuzumab for HER2-positive disease or in selected cases with docetaxel, survival remains poor. Recently, immune-oncology based strategies relevantly improved the treatment of different solid tumors and showed some promise in late or later stage trials in EGA. Notably, the combination of immunotherapy with trastuzumab to enhance anti-tumor immunity through activation of innate and adaptive immunity was beneficial in preclinical studies or clinical studies in breast cancer. Methods The INTEGA study is an open-label, randomized, multicenter, exploratory phase II trial designed to assess clinical performance, safety and tolerability of ipilimumab or 5-FU/folinic acid and oxaliplatin (FOLFOX) in combination with nivolumab and trastuzumab in patients with previously untreated HER2-positive, locally advanced or metastatic EGA. The primary objective is to determine the clinical performance of ipilimumab or FOLFOX in combination with nivolumab and trastuzumab in terms of overall survival. Secondary objectives are safety and tolerability, efficacy in terms of progression-free survival and objective response rate and blood-based signatures (e.g. immune response or suppression of anti-HER2 resistance) that may correlate with treatment response. Discussion Recent evidence from the phase II NCT02954536 study (oxaliplatin, capecitabine, trastuzumab and pembrolizumab) suggests the clinical feasibility of combining chemotherapy, trastuzumab and checkpoint inhibition in EGA. However, evidence for a chemotherapy-free regimen is also mounting in HER2-positive disease (NCT02689284) i.e. margetuximab and Pembrolizumab. Both studies excelled with high overall response rates and manageable toxicities. The INTEGA study aims to comparatively assess these results and select a promising new 1st line regimen which then needs to be confirmed in a randomized phase III trial. Further, the translational part of the study might help to better stratify patients and tailor treatment of either arm. Trial registration NCT03409848 24.01.2018.

Background: Docetaxel in combination with two HER2-directed therapies, trastuzumab and pertuzumab, is the current standard frontline therapy for patients with metastatic HER2-positive breast cancer. Ado-trastuzumab (T-DM1), an antibody-drug conjugate of trastuzumab and a cytotoxic microtubule-inhibitory agent, emtansine, is approved in patients that have progressed with prior trastuzumab-based therapy. However, the benefit of T-DM1 in patients previously treated with pertuzumab therapy for metastatic breast cancer remains unclear.Methods: We identified thirty-three adults with metastatic HER2-positive breast cancer treated between March 2013 and July 2018 with T-DM1 either as subsequent therapy after progression on a pertuzumab-based regimen (i.e., "pertuzumab-pretreated") or without prior exposure to pertuzumab (i.e., "pertuzumab-naïve"). Collected data included patient demographics, treatment history, adverse events, and clinical outcomes. For both cohorts receiving T-DM1, the primary endpoint was PFS and secondary endpoints were overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and T-DM1-related toxicity rate.Results: Pertuzumab-pretreated patients (n = 23, with 21 evaluable for T-DM1 efficacy) had a median PFS of 9.5 months (95% CI: 2.9-NA), 1-year OS rate of 67.4% (95% CI: 50.0-90.9%) with an unreached median, ORR of 14.3% (95% CI: 3.0-36.3%), and CBR of 52.4% (95% CI: 29.8-74.3%), with none of these measures being statistically different than those estimated for the pertuzumab-naïve group (n = 10). Treatment with T-DM1 after prior pertuzumab exposure (median T-DM1 duration 2.9 months) resulted in no grade ≥ 3 adverse events.Conclusions: In our cohort, prior exposure to pertuzumab did not significantly impact T-DM1's clinical efficacy or safety profile as second- or later-line therapy in patients with metastatic HER2-positive breast cancer. [ABSTRACT FROM AUTHOR]

Background: Phosphatase and tensin homolog (PTEN) loss is associated with tumorigenesis, tumor progression, and therapy resistance in breast cancer. However, the clinical value of PTEN as a biomarker in these patients is controversial. We sought to determine whether the benefit of traditional biomarkers testing is improved by the analysis of PTEN status for the identification of high-risk breast cancer.Methods: A cohort of 608 patients with breast cancer was included in this study. Based on the expression on the neoplastic cells compared to the normal internal controls by immunohistochemistry (IHC), cases were classified as PTEN-low (PTEN-L) or PTEN-retained (PTEN-WT). The former constituted the study group, while the latter the control group. Analysis of gene expression was performed on publicly available genomic data and included 4265 patients from the METABRIC and MSK cohorts retrieved from cBioPortal. The Shapiro-Wilk test was used to analyze the normal distributions of continuous variables. Relationships between PTEN status and the clinicopathologic and molecular features of the patient population were assessed using Fisher's exact test or Chi-squared/Wilcoxon rank-sum test. Survival curves were built according to the Kaplan-Meier method.Results: Alteration in PTEN status was significantly different at protein and gene levels, where the reduced protein expression was observed in 280/608 cases (46.1%) from our group, while genetic aberrations in only 315/4265 (7.4%) cases of the METABRIC and MSK cohorts. PTEN-L tumors were significantly enriched for hormone receptors (HR) and HER2 negativity (n = 48, 17.1%) compared to PTEN-WT tumors (n = 22, 6.7%; p = 0.0008). Lack of HR with or without HER2 overexpression/amplification was significantly associated with worse overall survival (OS) in PTEN-L but not in PTEN-WT breast cancers (p < .0001). Moreover, PTEN-L protein expression but not gene alterations was related to the outcome, in terms of both OS and disease-free survival (p = 0.002).Conclusions: The combined analysis of PTEN, HER2, and HR status offers relevant information for a more precise risk assessment of patients with breast cancer. [ABSTRACT FROM AUTHOR]

Background: The V-Akt murine thymoma viral oncogene (AKT) 1 (E17K) is a subfamily of serine/threonine protein kinases that affects the survival, proliferation, and invasion of cancer cells. The clinicopathological features and frequencies in Asian populations with AKT1 mutations in breast and endometrial cancers are unclear. Hence, we aimed to determine the frequencies and relationships between clinicopathological features and AKT1 mutations in Asian women with cancer.Methods: We extracted DNA from 311 and 143 samples derived from patients with breast and endometrial cancers to detect the AKT1 point mutation (hotspot), E17K. We examined correlations between clinicopathological features and AKT1 mutation status.Results: The frequency of AKT1 mutations in breast cancer was 7.4%, and they were found more frequently in human epidermal growth factor receptor 2 (HER2)-negative breast cancer subtypes, although this was not statistically significant (P = 0.08). The frequency of AKT1 mutations in endometrial cancer was 4.1%, and the mutations were histologically detected only in endometrioid types. However, AKT1 mutations did not correlate with relapse-free or overall survival of patients with breast or endometrial cancer.Conclusions: AKT1 mutations are associated with HER2-negative subtype in breast cancer and in endometrial cancer with endometrioid histology. The frequencies of AKT1 mutations in breast and endometrial cancers were similar between Asian and other regional women. The frequency of mutations is too low in both tumor types to talk about predictive significance. [ABSTRACT FROM AUTHOR]

BackgroundAmplification of the human epidermal growth factor receptor 2 (HER2) gene occurs in approximately 20% of invasive breast cancer cases and is associated with a more aggressive disease course than HER2-negative breast cancer. HER2-targeted therapies have altered the natural history of HER2-positive breast cancer, a trend that will likely further improve with the recent approval of new agents. A prospective, observational cohort study was designed and initiated to provide real-world insights into current treatment patterns, long-term survival, and patients' experiences with initial and subsequent treatments for HER2-positive metastatic breast cancer (MBC).Methods/designThe Systematic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs) is a US-based prospective observational cohort study enrolling patients ≥18 years of age with recently diagnosed HER2-positive MBC not previously treated with systemic therapy in the metastatic setting. The primary objective of the study is to identify treatment patterns and clinical outcomes in recently diagnosed patients in a variety of practice settings. Secondary objectives include comparative efficacy, safety, and patient-reported outcomes (PROs). Healthcare resource utilization is an exploratory end point. Tumor tissue and blood sample collection is optional.The SystHERs registry will enroll approximately 1000 patients over a 3-year period, after which the study will continue for ≥5 years, allowing for a maximum follow-up of 8 years. The treating physician will determine all care and the frequency of visits. PRO measures will be completed at study enrollment and every 90 days. Clinical data will be abstracted quarterly from patient records. The first patient was enrolled in June 2012, and preliminary descriptive data based on 25% to 30% of the final study population are expected at the end of 2013, and as of April 25, 2014, 386 patients are enrolled.DiscussionSystHERs is expected to provide in-depth data on demographic, clinicopathological, and treatment patterns and their associations with clinical outcomes, PROs, and healthcare resource utilization. Tumor tissue and DNA repositories will also be established for use in future translational research.Trial registration numberNCT01615068 (ClinicalTrials.gov identifier).

Abstract Background Breast cancer risk, development, and treatment are influenced by genetic variation in certain genes, namely those involved in cell proliferation, tumor suppression, and drug metabolism. In turn, the relevance of the aforementioned genetic variation to cancer depends on the ethnic group in question, highlighting the need for population-specific association studies. Therefore, the objective of the present study was to investigate the association between certain ESR1, ESR2, HER2, UGT1A4, and UGT2B7 single nucleotide polymorphisms and breast cancer. Methods Blood samples were collected from 437 Jordanian-Arab breast cancer patients and healthy volunteers and subject to genotyping using the Sequenom MassARRAY® system (iPLEX GOLD). Results Our findings show a significant association between breast cancer and the allelic (P = 0.02486879) and genotypic (P = 0.04793066) frequencies of the ESR1 polymorphism rs3798577, a result which was confirmed in different genetic models. No other investigated polymorphism showed a significant association with breast cancer itself in Jordanian Arabs, but the Rare Hz (GG) vs Het (AG) genetic model revealed an association of the disease with the ESR1 polymorphism rs3798577. However, several associations were found between certain polymorphisms and breast cancer’s prognostic factors. Conclusion This study suggests that certain polymorphisms may increase the risk of breast cancer in the Jordanian-Arab population. Future research and clinical translation could incorporate the current results in preventative breast cancer approaches tailored for Jordanian-Arab patients.

Abstract Background Cholangiocarcinoma is a rapidly fatal cancer entity with a median survival of less than one year. In contrast to many other malignancies, no substantial therapeutic breakthrough has been made in the past few decades, thereby limiting the treatment to cytotoxic chemotherapy with little beneficial effect for most patients. Targeted therapy tailored to the individual has shown substantial success in the recent past as a promising avenue for cancer therapy. Methods In this study, we determined the frequency of amplification of the HER2 gene in a comprehensive and well-characterized European cholangiocarcinoma cohort encompassing 436 patients including intrahepatic (n = 155), proximal (n = 155) and distal (n = 126) cholangiocarcinoma by strict application of a combined immunohistochemical and in situ hybridization algorithm following the current guidelines for HER2 assessment in gastric cancer. Results We identified a proportion of 1.4% (n = 6) patients that demonstrated HER2 gene amplification, with the highest rate among the distal cholangiocarcinoma patients (2.4%). None of the patients with equivocal (2+) immunohistochemical staining results exhibited gene amplification molecularly. In four of the five patients with HER2 positivity, gene amplification was already present in concomitantly tested high-grade biliary intraepithelial neoplasia (80%). HER2 gene amplification was not significantly associated with other clinical parameters, including survival. Conclusions This study identifies HER2 gene amplification as a rare event in cholangiocarcinoma of the Western population, occurring already in high-grade BilIN in a subset of patients. Furthermore, we provide a robust testing algorithm that may be used prior to therapy administration in future clinical trials evaluating the role of HER2 as a predictive marker in cholangiocarcinoma.

Abstract Background The glutathione S-transferases (GSTs) are a superfamily of phase II detoxifying enzymes that inactivates a wide variety of potential carcinogens through glutathione conjugation. Polymorphic changes in the GST genes have been reported to be associated with increased susceptibility to cancer development and anticancer drug resistance. In this study, we investigated the association between genetic variants in GSTM1 and GSTP1 and patients’ clinicopathological parameters. The prognostic values of such associations were evaluated among bladder cancer patients. Methods Genotyping of GSTM1 and GSTP1 in bladder cancer patients was assessed using polymerase chain reaction followed by DNA sequencing. Overall survival was estimated using the Kaplan-Meier method and multiple logistic regression and correlation analysis were performed. Results The GSTM1 null genotype was significantly associated with poor overall survival compared with the wild-type GSTM1 genotype. There was a trend towards better overall survival in patients with wild-type GSTP1 allele (AA) compared with GSTP1 (AG/GG) genotype. Interestingly, Kaplan-meier survival curve for GSTM1 null patients adjusted for sub-cohort with amplified HER2 gene showed poor survival compared with the GSTM1 null/ non-amplified HER2 gene. Also the same population when adjusted with HER2 protein expression, data showed poor survival for patients harboring GSTM1 null/high HER2 protein expression compared with low protein expression. Conclusion This study focuses on the impact of GSTM1 null genotype on bladder cancer patients’ outcome. Further investigations are required to delineate the underlying mechanisms of combined GSTM −/− and HER2 status in bladder cancer.

Abstract Background Metastasis of gastric cancer commonly manifests as a malignant effusion, which presents an alternative cell source for human epidermal growth factor receptor 2 (HER2) status identification. This study aimed to compare HER2 status in primary gastric adenocarcinoma tumors and corresponding cell blocks prepared from malignant effusions (CB-MEs). Methods HER2 status was retrospectively evaluated by immunohistochemistry (IHC) in primary gastric adenocarcinomas and paired pathologically confirmed CB-MEs of 45 patients. Silver in situ hybridization (SISH) was also performed in cases with IHC 2+ for primary gastric adenocarcinomas and above IHC 1+ for CB-MEs. Results HER2 positivity was observed in 4.4% (2/45) of primary gastric adenocarcinomas and 6.7% (3/45) of CB-MEs. The HER2 concordance rate between primary gastric adenocarcinomas and CB-MEs was 88.9% (40/45) (κ = − 0.056). All five patients with HER2 positivity in the primary tumor or a CB-ME had a negative result in the corresponding paired sample. Of the 15 patients with two or more serially sampled CB-MEs, HER2 expression determined by IHC differed between each CB-ME in six (40%) patients, and all three patients with HER2 positivity in CB-MEs exhibited HER2 positivity in one of the serially sampled CB-MEs. Conclusions The HER2 positivity rate was very low in gastric cancer patients with malignant effusions. Our results suggest that HER2 positivity was discordant between the primary gastric adenocarcinoma and corresponding CB-MEs and among serially sampled CB-MEs. The possibility of detecting HER2 positivity can be improved if the primary gastric adenocarcinoma tumor as well as all the available CB-MEs from each patient are analyzed.

Abstract Background 10–20% of patients with gastric cancer (GC) have HER2+ tumors. Addition of trastuzumab (T) to cisplatin/fluoropyrimidine-based chemotherapy (CT) improved survival in metastatic, HER2+ GC. When pertuzumab (P) was added to neoadjuvant T and CT, a significant increase in histopathological complete response rate was observed in HER2+ breast cancer. This study aims to investigate the added benefit of using both HER2 targeting drugs (T alone or the combination of T + P), in combination with perioperative CT for localized HER2+ GC. Methods This is a prospective, randomized, open-label, phase II trial. HER2 status from patients with resectable GC (UICC TNM7 tumor stage Ib-III) will be centrally determined. Two hundred and-fifteen patients from 52 sites in 14 countries will be centrally randomized (1:2:2 ratio) to one of the following treatment arms:1. Standard: CT alone. CT regimens will be FLOT (5-FU, leucovorin, oxaliplatin, taxotere) CapOx (capecitabine, oxaliplatin) or FOLFOX (5-FU, leucovorin, oxaliplatin) according to investigator’s choice in Europe, and cisplatin/capecitabine in Asia.2. Experimental arm 1 : CT as in control group, plus T (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) at day 1, independent of CT chosen for 3 cycles of 3 weeks before and after surgery.3. Experimental arm 2: CT plus T as in experimental arm 1, plus P (840 mg every 3 weeks) on day 1. Adjuvant treatment with T or T + P will continue for 17 cycles in total. Stratification factors are: histology (intestinal/non-intestinal); region (Asia vs Europe); location (GEJ vs non-GEJ); HER2 immunohistochemistry score (IHC 3+ vs IHC 2+/FISH+) and chemotherapy regimen. Primary objective is to detect an increase in the major pathological response rate from 25 to 45% either with CT plus T alone, or with CT plus the combination of T and P. Discussion Depending on the results of the INNOVATION trial, the addition of HER2 targeted treatment with either T or T and P to CT may inform future study designs or become a standard in the perioperative management HER2+ GC. Trial registration This article reports a health care intervention on human participants and was registered on July 10, 2014 under ClinicalTrials.gov identifier: NCT02205047; EudraCT: 2014–000722-38.

Abstract Background The phase III EMILIA and TH3RESA trials demonstrated clinical benefits of trastuzumab emtansine (T-DM1) therapy in patients with previously treated HER2-positive metastatic breast cancer (MBC). Data from these and other trials showed that T-DM1–associated survival benefits were observed across biomarker subgroups tested in these trials. Prespecified, exploratory analyses of the phase III MARIANNE study examined the effects of HER2-related biomarkers on PFS in patients administered T-DM1 in the first-line MBC setting. Methods In MARIANNE, patients with previously untreated HER2-positive MBC were randomized (1:1:1) to trastuzumab plus taxane, T-DM1 plus placebo, or T-DM1 plus pertuzumab. Biomarker subgroups included HER2 and HER3 mRNA expression levels (≤median vs. >median), HER2 staining intensity (IHC 3+ vs. 2+ vs. 0/1+), PIK3CA status (mutated vs. non-mutated), PTEN H-score (≤median vs. >median), and PTEN protein expression level (0 vs. 1+ vs. 2+ vs. 3+ vs. 4+). PFS was analyzed descriptively for each subgroup using Kaplan–Meier methodology. Additional exploratory post-hoc analyses evaluated the effects of HER2 heterogeneity. Multivariate analyses were also performed. Results Median PFS was numerically longer for patients with HER2 mRNA levels >median versus ≤median across treatment arms. In general, there were no predictive biomarkers of benefit for either T-DM1 treatment arm; most hazard ratios were close to 1 with wide confidence intervals that included the value 1. Focal HER2 expression (IHC 3+ or IHC 2+) was present in 3.8% of patients and was associated with numerically shorter PFS in the T-DM1–containing treatment arms versus trastuzumab plus taxane. Compared with non-mutated PIK3CA, mutated PIK3CA was associated with numerically shorter median PFS across treatment groups. Post-hoc multivariate analysis showed HER2 mRNA expression and mutated PIK3CA were prognostic for PFS (P ≤ 0.001 for both biomarkers). Conclusions In MARIANNE, biomarkers related to the HER2 pathway did not have predictive value for PFS when comparing T-DM1 (with or without pertuzumab) with trastuzumab plus taxane. However, HER2 mRNA level and PIK3CA mutation status showed prognostic value. Evaluation of other potential biomarkers, including immune markers, is ongoing. Trial registration Registration number: NCT01120184. Date of registration: April 28, 2010 (registered prospectively).

Background: Trastuzumab has changed the prognosis of HER2+ breast cancer. We aimed to investigate the prognosis of ER+/HER2+ patients treated with trastuzumab, thus to guide escalation endocrine treatment in ER+ breast cancer.Methods: ER-positive early breast cancer patients operated at Ruijin Hospital between Jan. 2009 and Dec. 2017 were retrospectively included. Eligible patients were grouped as HER2-negative (HER2-neg) or HER2-positive with trastuzumab treatment (HER2-pos-T). Kaplan-Meier analysis and Cox proportional hazards model were used to compare the disease-free survival (DFS) and overall survival (OS) between these two groups.Results: A total of 3761 patients were enrolled: 3313 in the HER2-neg group and 448 in the HER2-pos-T group. Patients in the HER2-pos-T group were associated with pre/peri-menopause, higher histological grade, LVI, higher Ki-67 level, lower ER and PR levels (all P <  0.05). At a median follow-up of 62 months, 443 DFS events and 191 deaths were observed. The estimated 5-year DFS rate was 89.7% in the HER2-neg group and 90.2% in the HER2-pos-T group (P = 0.185), respectively. Multivariable analysis demonstrated that patients in the HER2-pos-T group had a better DFS than patients in the HER2-neg group (HR 0.52, 95% CI: 0.37-0.73, P <  0.001). The estimated 5-year OS rates were 96.0% and 96.3% in the two groups, respectively (P = 0.133). Multivariate analysis found that HER2-pos-T group was still associated with significantly better OS compared with the HER2-neg group (HR 0.38, 95% CI: 0.22-0.67, P = 0.037).Conclusion: ER+/HER2+ breast cancer patients treated with trastuzumab were associated with superior outcome compared with ER+/HER2- patients, indicating HER2-positivity itself may not be an adverse factor for ER+ patients in the era of trastuzumab. [ABSTRACT FROM AUTHOR]

Background: Over than one third (28-58%) of pregnancy-associated breast cancer (PABC) cases are characterized by positive epidermal growth factor receptor 2-positive (HER2) expression. Trastuzumab anti-HER2 monoclonal antibody is still the benchmark treatment of HER2-positive breast tumors. However, FDA has categorized Trastuzumab as a category D drug for pregnant patients with breast cancer. This systemic review aims to synthesize all currently available data of trastuzumab administration during pregnancy and provide an updated view of the effect of trastuzumab on fetal and maternal outcome.Methods: Eligible articles were identified by a search of MEDLINE bibliographic database and ClinicalTrials.gov for the period up to 01/09/2020; The algorithm consisted of a predefined combination of the words "breast", "cancer", "trastuzumab" and "pregnancy". This study was performed in accordance with the PRISMA guidelines.Results: A total of 28 eligible studies were identified (30 patients, 32 fetuses). In more than half of cases, trastuzumab was administered in the metastatic setting. The mean duration of trastuzumab administration during gestation was 15.7 weeks (SD: 10.8; median: 17.5; range: 1-32). Oligohydramnios or anhydramnios was the most common (58.1%) adverse event reported in all cases. There was a statistically significant decrease in oligohydramnios/anhydramnios incidence in patients receiving trastuzumab only during the first trimester (P = 0.026, Fisher's exact test). In 43.3% of cases a completely healthy neonate was born. 41.7% of fetuses exposed to trastuzumab during the second and/or third trimester were born completely healthy versus 75.0% of fetuses exposed exclusively in the first trimester. All mothers were alive at a median follow-up of 47.0 months (ranging between 9 and 100 months). Of note, there were three cases (10%) of cardiotoxicity and decreased ejection fraction during pregnancy.Conclusions: Overall, treatment with trastuzumab should be postponed until after delivery, otherwise pregnancy should be closely monitored. [ABSTRACT FROM AUTHOR]