Human Epidermal Factor Receptor Research Articles

Abstract PO5-04-01: Inetetamab combined with sirolimus and chemotherapy in HER2 positive metastatic breast cancer patients with abnormal activation of Pi3k/Akt/mTOR pathway after trastuzumab treatment

Abstract Objective: To explore the efficacy and safety of Inetetamab Combined with Sirolimus and Chemotherapy in the treatment of human epidermal factor receptor 2 (HER2) positive metastatic breast cancer patients with abnormal activation of Pi3k/Akt/mTOR (PAM) pathway after Trastuzumab treatment. Methods: This prospective multicenter clinical study enrolled HER2 positive metastatic breast cancer patients at the National Cancer Center in China from July 2021 to September 2022 with PAM pathway mutation confirmed by histology or peripheral blood genetic testing. The inclusion criteria included: 1) Recurrent and metastatic breast cancer patients with HER2 positive confirmed histologically; 2) ECOG PS score ≤ 2; 3) Patients who have progressed after previous treatment with Trastuzumab; 4) Patients with PAM pathway mutation confirmed by Genetic testing; 5) Patients' cardiac, pulmonary, liver and bone marrow functions are basically normal; 6) Patients voluntarily sign informed consent forms. The exclusion criteria included: 1) Patients previously treated with mTOR inhibitors or pyrotinib; 2) Patients who have used chronic Corticosteroid for more than 3 months or used Immunosuppressive drug within 4 weeks; 3) Patients with symptomatic central nervous system metastasis; 4) Patients with left ventricular Ejection fraction< 50% or clinical manifestations of obvious arrhythmia, myocardial ischemia, severe atrioventricular block, cardiac insufficiency, and severe valvular disease; 5)Diagnosed with other malignant tumors within five years. Patients were randomly divided into trial group and control group. The patients in the trial group received inetetamab combined with sirolimus and chemotherapy, and control group received pyrotinib and chemotherapy. RECISTv1.1 standard was used to evaluate the efficacy of patients. Descriptive statistics are used to summarize clinical pathological features. Kaplan Meier method was used to draw survival curves. Log-rank test was used to compare progression free survival (PFS) differences between groups. P< 0.05 was considered statistically significant. Results:A total of 59 HER2 positive metastatic breast cancer patients with abnormal activation of PAM pathway were included, of which 37 patients received the treatment of inetetamab group and 22 patients received the treatment of pyrotinib group. The median follow-up time was 5.33 months. In the intent-to-treat set, the median PFS of patients in the inetetamab group was 4.64 months, which was shorter than 5.69 months in the pyrotinib group. There was no statistically significant difference between the two groups (P=0.51; HR=0.41; 95% CI, 0.12-1.45). The objective response rate (ORR) of the inetetamab group and the pyrotinib group were 28.1% and 29.4%, respectively. In terms of safety, the incidence of adverse events (AE) in the experimental group was (33/37) 89.1%, while (16/21) 76.2% in the control group. The incidence of AE above level 3 in the inetetamab group and pyrotinib group were (13/37) 35.1% and (3/21) 14.3%, respectively. Conclusion:For the metastatic HER2 positive breast cancer patients with abnormal activation of PAM pathway treated with trastuzumab previously, the combination of inetetamab with sirolimus and chemotherapy regimen are equivalent to the combination of pyrotinib and chemotherapy regimen. It demonstrated that combination of inetetamab with sirolimus and chemotherapy could be one of the treatment options for the metastatic HER2 positive breast cancer patients. Citation Format: Qiao Li, Dan Lv, Xiaoying Sun, Mengyuan Wang, Li Cai, Feng Liu, Chenghui Li, Jiuda Zhao, Jing Sun, Yehui Shi, Fei Ma. Inetetamab combined with sirolimus and chemotherapy in HER2 positive metastatic breast cancer patients with abnormal activation of Pi3k/Akt/mTOR pathway after trastuzumab treatment [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-04-01.

Abstract PD15-03: PD15-03 Incorporation of Repeated Core Needle Biopsy and Targeted Fine Needle Aspiration to Optimize Axillary Surgery After Neoadjuvant Chemotherapy in Node-positive Breast Cancer: A Prospective Feasibility Study

Abstract Background: It is of substantial importance to tailor axillary surgery after neoadjuvant chemotherapy (NAC) based on tumor biology and response to treatment. This study aimed to determine the accuracy of repeated core needle biopsy (RCNB) in breast to predict nodal response after NAC. Methods: Eligible patients with clip insertment into pathologically-proven positive node underwent RCNB during NAC. Targeted fine needle aspiration (TFNA) of clipped lymph node (CLN) was performed in a subset of patients after NAC. All patients ultimately underwent axillary surgery. RCNB and TFNA results were compared with surgical pathology. Results: Data from 189 eligible patients were analyzed. The overall axillary pCR was 57.1%. The false-negative rate (FNR) of RCNB across the whole cohort was 12.1% (95% CI, 5.3%–18.9%), and exploratory subgroup analysis revealed an excellent ability to predict the presence of residual nodal disease in estrogen receptor-positive breast cancer with a low FNR of 1.6% (95% CI, 0.0%–4.9%) (Table 1). Adopting a strategy where only patients with negative RCNB undergo targeted axillary dissection (TAD) would potentially reduce the FNR of TAD from 9.3% to 2.3%. Furthermore, combination of RCNB and TFNA demonstrated a FNR of 2.2% (95% CI, 0.0%–6.6%), and negative predictive value of 94.1% (95% CI, 81.6%–100.0%) (N = 87) (Table 2). The proposed algorithm based on RCNB and TFNA is helpful in optimizing axillary surgery by avoiding 25 unnecessary attempts as well as 2 false-negative cases in TAD and conferring 10 patients omission of axillary surgery. Conclusions: Combination of RCNB and TFNA allows for an accurate assessment of nodal response after NAC. These results may facilitate reliable identification of suitable candidates for de-escalation or elimination in axillary surgery. Table 1: Overall Cohort Diagnostic Accuracy of Repeated Core Needle Biopsy to Predict Nodal Response (N = 189) Abbreviations: ER, estrogen receptor; HER2, human epidermal factor receptor 2; NPV, negative predictive value; PPV, positive predictive value. Table 2. Diagnostic Accuracy of Repeated Core Needle Biopsy in Breast, Targeted Fine Needle Aspiration and the Combination in Cohort 2 (N = 87) Abbreviations: NPV, negative predictive value; PPV, positive predictive value; RCNB, repeated core needle biopsy; TFNA, targeted fine needle aspiration. Citation Format: Siyu Wu, Jianwei Li, Ying Zhang, Na Hu, Guangyu Liu. PD15-03 Incorporation of Repeated Core Needle Biopsy and Targeted Fine Needle Aspiration to Optimize Axillary Surgery After Neoadjuvant Chemotherapy in Node-positive Breast Cancer: A Prospective Feasibility Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD15-03.

Identification and validation of critical genes with prognostic value in gastric cancer.

Background: Gastric cancer (GC) is a digestive system tumor with high morbidity and mortality rates. Molecular targeted therapies, including those targeting human epidermal factor receptor 2 (HER2), have proven to be effective in clinical treatment. However, better identification and description of tumor-promoting genes in GC is still necessary for antitumor therapy. Methods: Gene expression and clinical data of GC patients were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Last absolute shrinkage and selection operator (LASSO) Cox regression were applied to build a prognostic model, the Prognosis Score. Functional enrichment and single-sample gene set enrichment analysis (ssGSEA) were used to explore potential mechanisms. Western blotting, RNA interference, cell migration, and wound healing assays were used to detect the expression and function of myosin light chain 9 (MYL9) in GC. Results: A four-gene prognostic model was constructed and GC patients from TCGA and meta-GEO cohorts were stratified into high-prognosis score groups or low-prognosis score groups. GC patients in the high-prognosis score group had significantly poorer overall survival (OS) than those in the low-prognosis score groups. The GC prognostic model was formulated as PrognosisScore = (0.06 × expression of BGN) - (0.008 × expression of ATP4A) + (0.12 × expression of MYL9) - (0.01 × expression of ALDH3A1). The prognosis score was identified as an independent predictor of OS. High expression of MYL9, the highest weighted gene in the prognosis score, was correlated with worse clinical outcomes. Functional analysis revealed that MYL9 is mainly associated with the biological function of epithelial-mesenchymal transition (EMT). Knockdown of MYL9 expression inhibits migration of GCcells in vitro. Conclusion: We found that PrognosisScore is potential reliable prognostic marker and verified that MYL9 promotes the migration and metastasis of GC cells.

Clinicopatholgic Characteristics to the Relapse on Ductal Carcinoma <i>In Situ</i>: Ki-67 Index as the Most Influential Prognostic Factor

Purpose: The biggest concern related to ductal carcinoma in situ (DCIS) is local recurrence and recurrence patterns. The purpose of this study was to investigate the relationship between clinicopathological factors and relapse in patients treated with DCIS.Methods: We reviewed medical records of 104 patients who were diagnosed as DCIS between January 1999 and December 2015 at a single institute. We compared and analyzed clinicopathological factors such as age at diagnosis, preoperative lesions on ultrasonography, preoperative tumor markers, operation methods in the breast, histological grade, nuclear grade, resection margin, comedonecrosis, estrogen receptor/ progesterone receptor expression, human epidermal factor receptor 2/neu expression, Ki-67, postoperative implementation of adjuvant hormonal therapy, and radiotherapy by dividing them into recurrent and non-recurrent groups.Results: Seventeen patients (16.3%) of 104 patients relapsed in the ipsilateral or contralateral breast. The median follow-up period of non-relapsed group was 4.9 years (range, 0.5–19.15) and the median follow-up period of relapsed group was 3.5 years (range, 1.4–14.13). Clinicopathological factors that were significantly related to relapse were nuclear grade (p=0.022) and Ki-67 (p=0.025) based on the results of chi-square or Fisher’s exact analysis. In multivariate analysis using logistic regression, Ki-67 (p=0.021) was significantly associated with DCIS relapse.Conclusion: This study suggested that the higher Ki-67 over 14% was strongly associated with DCIS relapse.

Abstract P2-13-41: First-line pyrotinib plus trastuzumab and nab-paclitaxel for patients with HER2-positive advanced breast cancer

Abstract Background: Overexpression of human epidermal factor receptor 2 (HER2) is seen in 15-20% of breast cancer and results in more aggressive clinical behavior and poor prognosis. This study (ChiCTR2000030618) analyzed the efficacy and safety of pyrotinib plus trastuzumab and nab-paclitaxel in patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer.Methods: Patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer received pyrotinib (400 mg, qd), trastuzumab (H, 8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) and nab-paclitaxel (260 mg/m² every 3 weeks) until disease progression or an unacceptable adverse event (AE). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and AEs.Results: A total of 28 patients (median age: 55.5 years [28-78]) were enrolled from April 2020 to June 2021. All 28 patients (100%) had Eastern Cooperative Oncology Group performance status of 1. The metastatic sites were in brain (14.29%), liver (25.00%), bone (28.57%) and lung (53.57%). HR+ and HR- for primary tumor accounted for 57.14% and 42.86%, respectively. Trastuzumab was previously administered in the (neo)adjuvant setting to 17(60.71%) patients. Eight patients with measurable lesions were evaluable for response. 5 (62.50%) patients had partial response (PR) and 3 (37.50%) patients achieved stable disease (SD), resulting in an ORR of 62.50% and DCR of 100.00%. Median PFS has not yet been reached. Twenty-one patients were included in the safety assessments. The most common AE was diarrhea (85.71%), but only 3 (14.29%) patients reported Grade ≥ 3 diarrhea which could be well controlled. The median onset of diarrhea was 1.5 days after start of treatment and the median duration was 9 days. Most diarrhea events were reported during the first cycle of treatment and the frequency persistently declined in the following cycles. Moreover, the AEs of all grades that were documented in ≥20% of patients included leukopenia (28.57%), anemia (23.81%), thrombocytopenia (19.05%), γ-glutamyltransferase increased (19.05%), vomiting (19.05%), rash (19.05%) and alanine aminotransferase increased (19.05%). No treatment-related deaths were reported.Conclusion: Pyrotinib plus trastuzumab and nab-paclitaxel showed promising efficacy in first-line HER2-positive breast cancer and were well tolerated. More data would be analyzed and reported in the future. Citation Format: Hui Xie, Wei Li, Yufeng Yao, Sujie Ni, Tongbo Yi, Jinling Cheng, Qi Fang, Lei Zhang, Jun Zhou, Xiaohong Wu, Chunbin Wang, Yanan Zhang, Jianwei Qin, Qing Shao, Tao Zhao, Xiaohong Huang, Lingyun Xu. First-line pyrotinib plus trastuzumab and nab-paclitaxel for patients with HER2-positive advanced breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-41.

P46.07 Afatinib-Related Pneumonitis in Metastatic EGFR-Positive NSCLC

Lung cancer is the third commonest cancer in Indonesia, and the first case of death in all cancer in both gender. EGFR mutation frequency in cytological sample in Indonesia was 44.4%. Afatinib is second generation epidermal growth factor receptor tyrosine kinase inhibiot, which inhibits epidermal growth factor receptor (EGFR), human epidermal factor receptor-2 (HER2) and HER4. Afatinib first introduced in Indonesia in 2016, and get approval for national health insurance program in 2018. The side effect of afatinib are skin rash, diarrhea, paronichia and pneumonitis. Here were reported a 69 yo female with diagnosis of lung adenocarcinoma T3N3M1 brain, lung EGFR mutation exon 19 deletion. She was treated with afatinib 40mg. Her condition was improved, but after 2 months of treatment, she complained of cough and shortness of breath. On chest HRCT showed bilateral pneumonitis. After inclusion of infection and heart failure, she was treated with pulse-dose steroid, but her condition deterioriated, and she passed away with respiratory failure. This is a case report, written informed consent has been obtained from her family member. HRCT of lung showed bilateral pneumonitis. Pneumonitis is a very rare adverse event of EGFR TKI, however can be devastating. We reported acute pneumonitis related to afatinib in metastatic adenocarcinoma, although already been diagnosed and treated early, but difficult to manage.

Higher-risk breast cancer in women aged 80 and older: Exploring the effect of treatment on survival

BackgroundTo understand the association between various treatments and survival for older women with higher-risk breast cancer when controlling for patient and tumor factors. Materials and methodsWe conducted a retrospective, population-based study. Women aged 80 years or older and diagnosed between 2004 and 2017 with non-metastatic, higher-risk breast cancer were identified form the provincial cancer registry in Alberta, Canada. Higher-risk was defined as any of following: T3/4, node positive, human epidermal factor receptor-2 (Her2) positive or triple negative disease. Treatments were surgery, radiotherapy and systemic therapy (hormonal therapy, and/or chemotherapy and/or trastuzumab) or a combination of the previous. Cox regression models were used to examine the association between treatments and breast cancer specific survival (BCSS) and overall survival (OS). Results1369 patients were included. The median age was 84 years. 332 (24%) of women had T3-T4 tumors, 792 (58%) had nodal involvement, 130 (10%) had Her2 positive tumors, 124 (9%) had triple negative tumors. After a median follow-up of 35 months, 29.5% of patients died of breast cancer whereas 34.2% died from other causes. Patients had a lower adjusted hazard for BCSS if they had surgery (hazard ratio [HR] = 0.37 95% confidence interval [CI]: 0.27, 0.51), or systemic therapy (HR = 0.75, 95%CI: 0.58, 0.98). Patients had an increased probability of breast cancer death in the first 5 years after diagnosis compared to death from other causes. ConclusionsSurgery and systemic therapy were associated with longer BCSS and OS. This suggests that maximizing treatments might benefit higher-risk patients.

Pleiotropic nature of curcumin in targeting multiple apoptotic-mediated factors and related strategies to treat gastric cancer: A review.

Gastric cancer (GC) is one of the major reasons for cancer-associated death and exhibits the second-highest mortality rate worldwide. Several advanced approaches have been designed to treat GC; however, these strategies possess many innate complications. In view of this, the upcoming research relying on natural products could result in designing potential anticancer agents with fewer side effects. Curcumin, isolated from the rhizomes of Curcuma longa L. has several medicinal properties like antiinflammatory, antioxidant, antiapoptotic, antitumor, and antimetastatic. Such pleiotropic nature of curcumin impedes the invasion and proliferation of GC by targeting several oncogenic factors like p23, human epidermal factor receptor2 including Helicobacter pylori. The side effect of chemotherapy, that is, chemotherapeutic resistance and radiotherapy could be reduced combination therapy of curcumin. Moreover, the photodynamic therapy of curcumin destroys the cancer cells without affecting normal cells. However, further more potential studies are required to establish the potent efficacy of curcumin in the treatment of GC. The current review details the anticancer activities of curcumin and related strategies which could be employed to treat GC with additional focus on its inhibitory properties against viability, proliferation, and migration of GC cells through cell cycle arrest and stimulation by apoptosis-mediated factors.

Neoadjuvant targeted therapy for apocrine carcinoma of the breast: A case report

BACKGROUNDApocrine carcinoma of the breast is a special type of invasive ductal carcinoma of the breast that is rare in clinical practice. Neoadjuvant therapy, especially neoadjuvant targeted therapy, has rarely been reported for apocrine carcinoma of the breast.CASE SUMMARYA 63-year-old woman presented with apocrine carcinoma of the left breast underwent core needle biopsy. The patient was diagnosed with apocrine carcinoma by immunohistochemical staining and negative hormone status (estrogen receptor and progesterone receptor) but showed overexpression of human epidermal factor receptor 2 (HER-2). Moreover, positive expression of androgen receptor (approximately 60%) and gross cystic disease fluid protein 15 was observed. The patient was treated with neoadjuvant targeted therapy consisting of the TCH regimen (docetaxel, carboplatin area under curve 6 and trastuzumab) every 21 d. The mass in the left breast was significantly reduced, and pain in the breast and left upper arm also improved.CONCLUSIONHER-2 positive apocrine carcinoma of the breast can be improved by neoadjuvant chemotherapy combined with targeted therapy.

Acetyltanshinone IIA is more potent than lapatinib in inhibiting cell growth and degrading HER2 protein in drug-resistant HER2-positive breast cancer cells

High expression of human epidermal factor receptor 2 (HER2) is directly related to tumor progression, malignancy and drug resistance in HER2-positive breast cancer (HER2-PBC). The major limitation of current anti-HER2 therapies is that they cannot reduce the levels of HER2 protein. Here, we investigated the effect of acetyltanshinone IIA (ATA) in lapatinib-resistant HER2-PBC cells. Our data showed that ATA exhibited more potent effects than lapatinib against drug-resistant HER2-PBC cells in terms of (1) inhibiting cell growth, (2) reducing phosphorylated and total HER2 levels, (3) inhibiting tumor xenograft growth in nude mice, and (4) reducing HER2 protein levels in tumor xenografts. A mechanistic study revealed that ATA promoted HER2 degradation via increasing c-Cbl and CHIP-mediated HER2 ubiquitination and subsequent HER2 degradation by the proteasome or lysosome. ATA also reduced the levels of other tyrosine kinase receptors (TKRs), such as HER3, IGF-1R and MET, in lapatinib-resistant cells. Our findings suggest that direct degradation of HER2 and other TKRs can be an effective strategy for combatting drug resistance. They also indicate the potential utilization of ATA in treating breast cancer that is resistant or nonresponsive to current HER2-targeted therapies.

In Vivo Evaluation of Dual-Targeted Nanoparticles Encapsulating Paclitaxel and Everolimus.

A synergistic combination of paclitaxel (PTX) and everolimus (EVER) can allow for lower drug doses, reducing the toxicities associated with PTX, while maintaining therapeutic efficacy. Polymeric nanoparticles (NPs) of high stability provide opportunities to modify the toxicity profile of the drugs by ensuring their delivery to the tumor site at the synergistic ratio while limiting systemic drug exposure and the toxicities that result. The goal of the current study is to evaluate the in vivo fate of human epidermal factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) dual-targeted PTX+EVER-loaded NPs (Dual-NPs) in an MDA-MB-231-H2N breast cancer (BC) tumor-bearing mouse model. The pharmacokinetic parameters, plasma area under the curve (AUC) and half-life (t1/2z) were found to be 20-fold and 3 to 4-fold higher, respectively, for the drugs when administered in the Dual-NPs in comparison to the free-drug combination (i.e., PTX+EVER) at an equivalent dose of PTX. While maintaining anti-tumor efficacy, the levels of body weight loss were significantly lower (p < 0.0001) and the overall degree of neurotoxicity was reduced with Dual-NPs treatment in comparison to the free-drug combination when administered at an equivalent dose of PTX. This study suggests that Dual-NPs present a promising platform for the delivery of the PTX and EVER combination with the potential to reduce severe PTX-induced toxicities and in turn, improve quality of life for patients with BC.

Bevacizumab in the neoadjuvant treatment of human epidermal growth factor receptor 2-negative breast cancer: A meta-analysis of randomized controlled trials.

Several randomized clinical trials have suggested the effectiveness of bevacizumab (Bev) in early and advanced breast cancer; however, due to the increased toxicity and lack of a clear long-term survival benefit, there is currently no defined role for Bev in breast cancer in the USA, while it has been approved in Europe. We herein sought to conduct a meta-analysis of large randomized trials comparing the efficacy and long-term outcome of neoadjuvant chemotherapy with Bev compared with chemotherapy without Bev in human epidermal factor receptor 2 (HER2)-negative breast cancer. A search was conducted through PubMed and Ovid Medline databases. Among the 279 articles identified, 5 met the eligibility criteria and were included in the present analysis. A total of 2,268 patients treated with Bev and 2,278 treated without Bev were analyzed. Pathological complete response (pCR) was obtained in 35% of patients treated with Bev and in 26% of those treated without Bev. A statistically significant increase (26%) in the incidence of pCR was observed in the Bev-treated group. However, patients treated with Bev exhibited no significant difference in the risk of disease recurrence or death. To the best of our knowledge, this is the first meta-analysis addressing the long-term outcomes of Bev in combination with chemotherapy in the neoadjuvant treatment of HER2-negative breast cancer. The results confirmed the significant benefit of Bev combined with chemotherapy compared with chemotherapy alone on breast cancer response, in both triple-negative and hormone receptor-positive cases. However, this benefit does not translate into a long-term disease-free or definitive overall survival advantage. Optimizing patient selection is desirable for maximizing the long-term benefits of Bev, while reducing cost and treatment-related adverse effects. Future efforts directed toward the discovery of predictive markers would be crucial for identifying the subset(s) of breast cancer patients who are most likely to benefit from Bev therapy.

Abstract 3242: Differences in stromal tumor-infiltrating lymphocytes in breast cancer from women of African and European ancestry after accounting for tumor characteristics

Abstract Background: Women of African ancestry (AA) have higher breast cancer mortality than other US racial/ethnic groups, attributed to a number of social and economic factors. However, breast tumors in AA women are more likely to present with higher grade and lacking estrogen receptor (ER) expression compared to those from women of European ancestry (EA), suggesting the importance of tumor factors in breast cancer disparities. Emerging evidence suggests that stromal tumor-infiltrating lymphocytes (TIL-str) have a role in immune response to therapy and prognosis of breast cancer. The objective of this study was to examine associations between risk factors for breast cancer and TIL-str, with consideration of tumor characteristics. Methods: We reviewed the hematoxylin and eosin slides from surgical or biopsy tumor blocks of invasive breast cancer from 1,385 cases (986 AA and 399 EA women, aged 20-75 years) in the Women's Circle of Health Study, a multicenter case-control study in New York and New Jersey. In-person interviews were conducted at diagnosis to obtain data on demographics, family histories, hormone use, and reproductive and menstrual histories. Anthropometric measurements were taken by trained staff. TIL-str were scored as 0%, 1%, and 10% to 100% in increments of 10%. Linear regressions were performed to estimate differences in TIL-str scores (β). Results: In univariate analysis, TIL-str was higher in tumors from AA than those from EA women overall (mean score = 21.5% vs. 12.5; P&amp;lt;0.001). TIL-str score was positively associated with higher grade, larger tumor size, and ER and progesterone receptor (PR) negativity in both AA and EA women (all P&amp;lt;0.05). In EA women, TIL-str score was also higher in more advanced than early stage tumors and human epidermal factor receptor 2 (HER2) positive than negative tumors (both P&amp;lt;0.05), but not in AA women. In multivariable analysis, AA compared to EA race was significantly associated with a higher TIL-str score (β = 5.7%, P&amp;lt;0.001), adjusting for age at diagnosis, body mass index, menopausal status, tumor grade, size, stage, and molecular subtypes defined by ER, PR, and HER2. There was no apparent association between TIL-str and history of breast cancer in first-degree relatives, history of benign breast disease, hormone use, reproductive factors, or body size. Conclusion: Self-reported African compared to European ancestry is independently associated with higher TIL-str scores in breast tumors. Our findings suggest that immune response may play a role in the differences in breast cancer biology and outcomes between AA and EA women. (Funding: The Breast Cancer Research Foundation; NIH P01CA151135, R01CA100598, R01CA185623, P30CA072720, K07CA201334; US Army Medical Research and Material Command DAMD-17-01-1-0334) Citation Format: Ting-Yuan D. Cheng, Rochelle Payne Ondracek, Song Yao, Warren Davis, Angela Omilian, Mateusz Opyrchal, Elisa V. Bandera, Michael J. Higgins, Christine B. Ambrosone, Thaer Khoury. Differences in stromal tumor-infiltrating lymphocytes in breast cancer from women of African and European ancestry after accounting for tumor characteristics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3242.

Indication of metronomic chemotherapy for metastatic breast cancer: Clinical outcomes and responsive subtypes.

The survival of patients with metastatic breast cancer (MBC) has not improved, despite recent advances in therapeutic strategies. This is mainly due to the fact that cytotoxic agents cannot be administered over a long period, even if they exhibit favorable activity, due to treatment-related side effects or acquisition of tumor resistance to the administered agents. Thus, the development of therapeutic strategies that may be used over a long time period is required to improve survival. We assessed the availability and clinical outcomes of metronomic chemotherapy, which is defined as continuous or frequent treatment with low doses of cytotoxic drugs. A total of 80 patients with MBC received chemotherapy in the metastatic setting, and the clinicopathological factors and clinical outcomes were retrospectively compared between 52 patients who received metronomic regimens and 28 patients who received other cytotoxic regimens. As regards clinical outcomes, the median time-to-treatment failure (TTF) and overall survival (OS) were significantly longer in the metronomic group compared with those in the non-metronomic group (TTF, 15 vs. 4 months, P=0.0001; and OS, 53 vs. 28 months P=0.0012, respectively). In the metronomic group, none of the 18 patients who responded to the regimen had triple-negative (TN) cancer (17 had luminal-type tumors and 1 had a human epidermal factor receptor 2-type tumor). Furthermore, TTF and OS were significantly longer in patients with non-TN cancer compared with those in patients with TN cancer in the metronomic group (TTF, 16 vs. 7 months, P=0.0014; and OS, 108 vs. 20 months, P=0.000007, respectively). The proportion of patients who experienced treatment-related adverse events was significantly lower in the metronomic group compared with that in the non-metronomic group (36.5 vs. 61.5%, respectively; P=0.038). In conclusion, metronomic chemotherapy is a viable option for luminal-type MBC in terms of effectiveness and minimal toxicity, regardless of metastatic sites or prior treatment. However, an alternative treatment is required for TN cancer.

HER3 over-expression and overall survival in gastrointestinal cancers.

Published studies on the association between human epidermal factor receptor 3 (HER3) expression and overall survival (OS) in gastrointestinal cancers have yielded conflicting results. The aim of this study was to explore the association of HER3 over-expression with OS in gastrointestinal cancers. A systematic search was performed through Medline/PubMed, Embase, Science Direct and Elsevier. The summary odds ratio (OR) with 95% confidence interval (CI) was calculated to estimate the strength of the association. Overall, we observed that HER3 over-expression was associated with worse OS at five years (OR = 1.38, 95% CI: 1.04-1.82); however, HER3 over-expression was not associated with worse OS at three years (OR = 1.33, 95% CI: 0.97-1.84). The cumulative meta-analysis showed similar results. In subgroup analyses by tumor type, HER3 over-expression in gastric cancers was associated with worse OS at both three years (OR = 1.69, 95% CI: 1.28-2.25) and five years (OR = 1.74, 95% CI: 1.26-2.41). In conclusion, our results suggest that HER3 over-expression may be associated with worse overall survival in gastric cancers. Well-designed studies with a large sample size are required to further confirm our findings.

Molecular heterogeneity of triple-negative breast cancer and its clinical implications

Triple-negative breast cancer (TNBC) is defined by a lack of expression of hormone receptors, oestrogen and progesterone, as well as human epidermal factor receptor 2. This review focuses on the increasing understanding of the molecular heterogeneity of TNBC subtypes and the therapeutic implications of this subclassification. Emerging evidence clearly indicates that TNBC is a heterogeneous disease with varying prognosis according to clinical, pathological and genetic factors. Some distinct histological special types within this clinically defined collection of entities have been shown to have a particularly good prognosis (e.g. medullary carcinomas), and others very poor outcome (e.g. metaplastic carcinomas), whereas the broader immunohistochemically defined 'core-basal-like' or gene expression defined 'basal' groups generally have a poor prognosis. This molecular subclassification has implicated several biological processes as potential therapeutic targets: the DNA damage response, drivers of deregulated proliferation, angiogenesis, epithelial-mesenchymal transition and immune deregulation. Molecular stratification of these prognostic groups has been critical in identifying novel therapeutic targets for future drug development. The development of poly-(ADP)ribose polymerase inhibitors for BRCA1-mutation carriers with TNBC has led the ongoing efforts to translate fundamental biological insights into improved therapies for a difficult-to-treat breast cancer subgroup.

Different Prognostic Significance of Bcl-2 Based on Cancer Molecular Subtype

Purpose: B-cell lymphoma (bcl)-2 is an anti-apoptotic gene, and it is a poor prognostic factor in various malignant tumors. However, the prognostic significance of bcl-2 expression in breast cancer remains controversial. We investigated the prognostic significance of bcl-2 according to cancer molecular subtype. Methods: We analyzed 411 patients with primary invasive breast cancer who underwent surgery at our institution between 1999 and 2001. The subtypes were classified as luminal (estrogen receptor [ER]+ and/or progesterone receptor [PR]+, irrespective of human epidermal factor receptor 2 [HER2]), triple-negative (ER-, PR-, and HER2-), or HER2 (ER- ,PR-, and HER2+). Results: A total of 236 (57.4%) cases were positive for bcl-2, and bcl-2 expression was significantly associated with earlier stage, lower grade, expression of hormone receptor positivity, and HER2 negativity. No difference in disease-free survival (DFS) was observed based on bcl-2 expression. However, the prognostic significance of bcl-2 varied with subtype; bcl-2 was not a prognosticator in patients with the luminal and HER2 subtypes. However, patients with bcl-2(+) tumors of the triple-negative subtype showed significantly worse DFS than those with bcl-2(-) tumors (p=0.048). In a multivariate analysis, bcl-2 expression remained a significant predictor of recurrence in patients with the triple-negative subtype (hazard ratio, 3.26; 95% confidence interval, 1.40-7.59; p=0.006). Conclusion: The prognostic significance of bcl-2 varied with molecular subtype; bcl-2 expression was a poor prognosticator in patients with the triple-negative subtype, but not in those with the luminal and HER2 subtypes.

Phase II Trial of Combination of Pegylated Liposomal Doxorubicin, Cisplatin, and Infusional 5-Fluorouracil (CCF) Plus Trastuzumab as Preoperative Treatment for Locally Advanced and Inflammatory Breast Cancer

Background Pegylated liposomal doxorubicin (PLD) was shown as active but less toxic compared to doxorubicin in advanced breast cancer. Given its low cardiotoxicity, the combination of PLD and trastuzumab appears most attractive in the treatment of human epidermal factor receptor 2 (HER2)-positive breast cancer. Patients and Methods: We investigated the activity of 8 courses of PLD in combination with cisplatin and infusional 5-fluorouracil (CCF) plus 3-week trastuzumab in patients with primary or recurrent cT2-T4 a-d, N0-3, M0 any estrogen receptor (ER), HER2-positive breast cancer. Patients with ER and/or progesterone receptor (PgR) ≥ 10% tumors received also letrozole (plus triptorelin if premenopausal). The principal endpoint was clinical response rate; secondary endpoints were the pathologic complete response rate (pCR) and the cardiac safety of the combination. Results: Thirty-two patients were enrolled in the study and all are evaluable for response and toxicity. Fifteen patients (47%) had ER-positive tumors, 15 patients and 2 patients had ER absent and ER poor tumors, respectively. Thirteen patients (41%) had inflammatory breast cancer (IBC) and 84% of patients had clinically positive nodes. A clinical response rate of 94% (95% CI, 79%-99%) and a pCR rate of 41% (95% CI, 24%-59%) were observed. Fifty-four percent of patients with IBC obtained a pCR. Eleven patients discontinued treatment before completing 8 courses as planned. No patient developed relevant cardiac toxicity. Conclusion: In this series of very locally advanced breast cancer, the combination of CCF and trastuzumab was very active obtaining an impressive rate of pCR, particularly in IBC, which merits further investigation in larger series.