High Expression of Trophoblast Cell Surface Antigen 2 in Triple-negative Breast Cancer Identifies a Novel Therapeutic Target

Abstract Objectives Patients with triple-negative breast cancer (TNBC) respond poorly to current therapeutic modalities. The newly FDA-approved drug conjugate, Sacituzumab Govitecan, targeting antitrophoblastic cell surface antigen 2 (Trop-2), offers a new modality to treat these subtypes of breast carcinoma (BC). Our study examines expression of Trop-2 by immunohistochemistry (IHC) in TNBC. Methods Forty cases of TNBC were selected from our files (34 ductal, 4 pleomorphic lobular, 1 metaplastic, and 1 mixed ductal and lobular carcinoma). A control group included 11 luminal A-like, 11 luminal B-like, and 8 HER2-like BC. Immunostaining for Trop-2 was performed on 4-micron-thick tissue sections using goat polyclonal antibody (R&D Systems). Three pathologists individually scored the % and intensity of membranous staining. The % of staining was defined as <10%, 10%-50%, and >50%. The intensity of staining was scored as 3+ (crisp circumferential membranous staining), 2+ (medium membranous staining), 1+ (patchy weak membranous staining), and 0 (no staining). A Kruskal-Wallis H-test and pairwise comparison with Bonferroni correction was performed to compare % and intensity of staining in TNBC to control group. Results TNBC exhibited stronger Trop-2 staining in both intensity and extent when compared to the control. The result was significantly different, χ2 (4) = 17.427, P = .001. A pairwise comparison with Bonferroni correction found significant difference between TNBC (42.55) and luminal A (16.65) (P < .001). There was significant agreement (P < .001) among 3 independent pathologists for assessing % and intensity of staining. Conclusion The extent and intensity of staining for Trop-2 is higher in TNBC than in other molecular subtypes of BC. These findings suggest that patients with TNBC may potentially benefit from this targeted therapy. Furthermore, identification of Trop-2 in other molecular subtypes may expand the therapeutic potential of this new drug. Further studies are needed to determine the efficacy of this marker.

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Inflammatory Breast Cancer: Clinical Characteristics and Influence of Molecular Subtypes on Treatment Response

Tumori Journal ◽

10.1177/03008916211012341 ◽

2021 ◽

Vol 107 (1_suppl) ◽

pp. 12-12

Author(s):

D Aissaoui ◽

M Bohli ◽

R Ben Amor ◽

J Yahyaoui ◽

A Hamdoun ◽

...

Keyword(s):

Breast Cancer ◽

Treatment Response ◽

Inflammatory Breast Cancer ◽

Hormone Receptor ◽

Triple Negative ◽

Molecular Subtypes ◽

Luminal A ◽

Her2 Positive ◽

Luminal B ◽

Significant Difference

Introduction: Inflammatory Breast Cancer (IBC) is a rare and very aggressive breast cancer with poor prognosis. The prevalence is different from a country to another. In Tunisia, it is about 5 to 7% of breast cancer. The aim of this study is to describe the epidemiological and histopathological features of patients with inflammatory breast cancer and to evaluate the treatment response according to the molecular subtypes. Methods: This retrospective review identified 31 patients with no metastatic IBC treated in our radiotherapy department between December 2019 and November 2020. IBC was confirmed using the clinical criteria. Baseline clinic-pathological and treatment information was retrieved from medical records. Statistical analysis was performed with IBM SPSS V.20. Results: Median age was 51.3 years [27-68]. 48% of tumors were grade 3. The average tumor size was 36mm [10-90]. The histological type was ductal carcinoma in 97%. Vascular invasion was noted in 24 patients (77%). Thirty patients were classified as stage IIIB and one patient was IIIC. 74% were hormone receptor positive and 45% were HER2 positive. Luminal B was the predominant subtype (52%) followed by Her2 positive (32%), Luminal A (23%), and triple negative (3%) All patients had chemotherapy: neoadjuvant for 26 patients (84%) and adjuvant for 5 patients (16%). Nine patients (29%) had tumor pathological complete response (pCR). Partial response was observed in 18 patients (58%). Lymph node pCR was noted in 16% of cases (n=5). Endocrine therapy and trastuzumab were given to 76% and 45% of patients, respectively. The influence of the molecular subtype was not statistically significant on the response to neoadjuvant treatment. The highest rate of pCR were 43% for Her2positive, then 27%, 21% and 9% for Luminal B, Luminal A and Triple negative, respectively (p=0.2). Conclusion: Our study showed a high percentage of hormone receptor and Her2+ (74% and 45% respectively) in IBC. Luminal B was the most frequent subtype. Anthracycline-based chemotherapy and trastuzumab improved the pCR rate: 44% for Her2positive. Triple negative showed poorer pCR than other breast cancer subtype without a significant difference. A larger study is warranted to confirm our findings.

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Diffusion-Weighted Imaging of Different Breast Cancer Molecular Subtypes: A Systematic Review and Meta-Analysis

Breast Care ◽

10.1159/000514407 ◽

2021 ◽

pp. 1-8

Author(s):

Hans-Jonas Meyer ◽

Andreas Wienke ◽

Alexey Surov

Keyword(s):

Breast Cancer ◽

Systematic Review ◽

Diffusion Weighted Imaging ◽

Triple Negative ◽

Molecular Subtypes ◽

Luminal A ◽

Diagnose Breast Cancer ◽

Luminal B ◽

Diffusion Weighted ◽

Adc Values

Background: Magnetic resonance imaging can be used to diagnose breast cancer (BC).Diffusion-weighted imaging (DWI) and the apparent diffusion coefficient (ADC) can be used to reflect tumor microstructure. Objectives: This analysis aimed to compare ADC values between molecular subtypes of BC based on a large sample of patients. Method: The MEDLINE library and Scopus database were screened for the associations between ADC and molecular subtypes of BC up to April 2020. The primary end point of the systematic review was the ADC value in different BC subtypes. Overall, 28 studies were included. Results: The included studies comprised a total of 2,990 tumors. Luminal A type was diagnosed in 865 cases (28.9%), luminal B in 899 (30.1%), human epidermal growth factor receptor (Her2)-enriched in 597 (20.0%), and triple-negative in 629 (21.0%). The mean ADC values of the subtypes were as follows: luminal A: 0.99 × 10–3 mm2/s (95% CI 0.94–1.04), luminal B: 0.97 × 10–3 mm2/s (95% CI 0.89–1.05), Her2-enriched: 1.02 × 10–3 mm2/s (95% CI 0.95–1.08), and triple-negative: 0.99 × 10–3 mm2/s (95% CI 0.91–1.07). Conclusions: ADC values cannot be used to discriminate between molecular subtypes of BC.

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CD44 Targeted Nanomaterials for Treatment of Triple-Negative Breast Cancer

Cancers ◽

10.3390/cancers13040898 ◽

2021 ◽

Vol 13 (4) ◽

pp. 898

Author(s):

Ghazal Nabil ◽

Rami Alzhrani ◽

Hashem Alsaab ◽

Mohammed Atef ◽

Samaresh Sau ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

In Vivo Studies ◽

High Dose ◽

Luminal A ◽

Combination Strategy ◽

Ongoing Research

Identified as the second leading cause of cancer-related deaths among American women after lung cancer, breast cancer of all types has been the focus of numerous research studies. Even though triple-negative breast cancer (TNBC) represents 15–20% of the number of breast cancer cases worldwide, its existing therapeutic options are fairly limited. Due to the pivotal role of the presence/absence of specific receptors to luminal A, luminal B, HER-2+, and TNBC in the molecular classification of breast cancer, the lack of these receptors has accounted for the aforementioned limitation. Thereupon, in an attempt to participate in the ongoing research endeavors to overcome such a limitation, the conducted study adopts a combination strategy as a therapeutic paradigm for TNBC, which has proven notable results with respect to both: improving patient outcomes and survivability rates. The study hinges upon an investigation of a promising NPs platform for CD44 mediated theranostic that can be combined with JAK/STAT inhibitors for the treatment of TNBC. The ability of momelotinib (MMB), which is a JAK/STAT inhibitor, to sensitize the TNBC to apoptosis inducer (CFM-4.16) has been evaluated in MDA-MB-231 and MDA-MB-468. MMB + CFM-4.16 combination with a combination index (CI) ≤0.5, has been selected for in vitro and in vivo studies. MMB has been combined with CD44 directed polymeric nanoparticles (PNPs) loaded with CFM-4.16, namely CD44-T-PNPs, which selectively delivered the payload to CD44 overexpressing TNBC with a significant decrease in cell viability associated with a high dose reduction index (DRI). The mechanism underlying their synergism is based on the simultaneous downregulation of P-STAT3 and the up-regulation of CARP-1, which has induced ROS-dependent apoptosis leading to caspase 3/7 elevation, cell shrinkage, DNA damage, and suppressed migration. CD44-T-PNPs showed a remarkable cellular internalization, demonstrated by uptake of a Rhodamine B dye in vitro and S0456 (NIR dye) in vivo. S0456 was conjugated to PNPs to form CD44-T-PNPs/S0456 that simultaneously delivered CFM-4.16 and S0456 parenterally with selective tumor targeting, prolonged circulation, minimized off-target distribution.

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Trends in breast cancer mortality according to molecular subtypes: A population-based study.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.572 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 572-572

Author(s):

Yunan Han ◽

Shuai Xu ◽

Graham A. Colditz ◽

Adetunji T. Toriola

Keyword(s):

Breast Cancer ◽

Cancer Mortality ◽

Triple Negative ◽

Molecular Subtypes ◽

Breast Cancer Mortality ◽

Treatment Strategies ◽

Luminal A ◽

Her2 Positive ◽

Mortality Trends ◽

Luminal B

572 Background: Breast cancer is the second leading cause of cancer death in U.S. women. On the molecular level, breast cancer is a heterogeneous disease. Heterogeneous expressions of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) are etiologically and clinically meaningful, as they map to distinct risk factors and different treatment strategies. Although breast cancer mortality has been declining since 1990, little is known about mortality trends according to molecular subtypes at the population level. Methods: We examined the incidence-based mortality rates and trends among women who were diagnosed with invasive breast cancer from 2010 through 2017 using the Surveillance, Epidemiology, and End Results (SEER) database. We defined incidence-based mortality using a moving 5-year calendar period starting in 2014. We further assessed mortality according to breast cancer molecular subtypes: luminal A (ER and/or PR positive, HER2 negative), luminal B (ER and/or PR positive, HER2 positive), HER2-enriched (HER2 over-expressed or amplified, ER and PR negative) and triple-negative (ER and PR negative, HER2 negative) tumors. We calculated annual percent changes (APC) in incidence-based mortality using joinpoint regression models. Results: Overall, incidence-based mortality for breast cancer significantly decreased by 1.5% annually from 2014 through 2017 (APC, -1.5%; 95% coefficient interval [CI], -2.3% to -0.7%; p<0.001). Incidence-based mortality decreased annually by 2.0% for luminal A breast cancer (APC, -2.0%; 95% CI, -3.7% to -0.3%; p<0.001), 2.1% for luminal B breast cancer (APC, -2.1%; 95% CI, -5.4% to 1.4%; p=0.1), 1.1% for triple-negative breast cancer (TNBC) (APC, -1.1%; 95% CI, -2.1% to -0.0%; p<0.001). However, incidence-based mortality for HER2-enriched breast cancer increased 2.3% annually during the study period (APC, 2.3%; 95% CI, -2.4% to 7.2%; p=0.2). Conclusions: Between 2014 and 2017, incidence-based mortality for luminal A, luminal B, and TNBC decreased among U.S. women, with a larger decrease observed for luminal tumors. However, incidence-based mortality for HER2-enriched breast cancer increased. The favorable incidence-based mortality trends for luminal tumors and TNBC are likely due to the continuing improvement in treatments and early detection. The increasing trend of incidence-based mortality for HER2-enriched breast cancer constitutes a priority for cancer control activities and further research.

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Low KIBRA Expression Is Associated with Poor Prognosis in Patients with Triple-Negative Breast Cancer

Medicina ◽

10.3390/medicina57080837 ◽

2021 ◽

Vol 57 (8) ◽

pp. 837

Author(s):

So-Woon Kim ◽

Jinah Chu ◽

Sung-Im Do ◽

Kiyong Na

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Poor Prognosis ◽

Triple Negative ◽

Histological Grade ◽

Growth Factor Receptor ◽

Hippo Signaling ◽

Luminal A ◽

Luminal B ◽

Epidermal Growth

Background and Objectives: Kidney and brain protein (KIBRA) is a protein encoded by the WW and C2 domain containing 1 (WWC1) gene and is involved in the Hippo signaling pathway. Recent studies have revealed the prognostic value of KIBRA expression; however, its role in breast cancer remains unclear. The aim of this study was to examine KIBRA expression in relation to the clinical and pathological characteristics of patients with breast cancer and to disease outcomes. Materials and Methods: We analyzed the expression of KIBRA and its correlation with event-free survival (EFS) outcomes in resected samples from 486 patients with breast cancer. Results: KIBRA expression was significantly different among the molecular subgroups (low KIBRA expression: luminal A, 46.7% versus 50.0%, p = 0.641; luminal B, 32.7% versus 71.7%, p < 0.001; human epidermal growth factor receptor 2 (HER2)-enriched, 64.9% versus 45.5%. p = 0.001; triple-negative, 73.6% versus 43.8%, p < 0.001). Low KIBRA expression was also associated with high nuclear grade (60.4% versus 37.8%, p < 0.001), high histologic grade (58.7% versus 37.0%, p < 0.001), and estrogen receptor (ER) negativity (54.2% versus 23.6%, p < 0.001). Low KIBRA expression was significantly associated with poor EFS (p = 0.041; hazard ratio (HR) 1.658; 95% confidence interval (CI), 1.015–2.709). Low KIBRA expression was an independent indicator of poor prognosis (p = 0.001; HR = 3.952; 95% CI = 1.542–10.133) in triple-negative breast cancer (TNBC). Conclusion: Low KIBRA expression was associated with higher histological grade, ER negativity and poor EFS of breast cancer. In particular, our data highlight KIBRA expression status as a potential prognostic marker for TNBC.

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Alteration in Steroid Hormone and HER2/neu Receptor Status Following Neoadjuvant Chemotherapy in Triple Negative Breast Cancer. Is There Any Hope?

JOURNAL FOR CLINICAL AND DIAGNOSTIC RESEARCH ◽

10.7860/jcdr/2021/45220.14439 ◽

2021 ◽

Author(s):

Rama Das ◽

Parna Basu ◽

Suman Ghosh ◽

Debasish Guha

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Triple Negative Breast Cancer ◽

Hormone Receptor ◽

Triple Negative ◽

Control Group ◽

Study Group ◽

Residual Tumour ◽

Receptor Status ◽

Platinum Based Chemotherapy

Introduction: Breast cancer continues to be the most common cancers among women in India. The Triple Negative Breast Cancer (TNBC) is a heterogeneous group of malignancy which is often aggressive and has a worse prognosis. Aim: The aim of this study was to assess the hormone receptor and HER2/neu status with platinum based chemotherapy in TNBC. Materials and Methods: The study was analysed retrospectively in a tertiary care centre of West Bengal from Januay 2017 to December 2019. Forty TNBC patients of Locally Advanced Breast Cancer (LABC) cases who received carboplatin along with neoadjuvant chemotherapy (study group) were compared with other group of 64 TNBC patients (control group) who did not receive any chemotherapy making a total of 104 cases of TNBC patients who were selected for the study. All the patients in both the groups had modified radical mastectomy. The study group of 40 TNBC patients who received chemotherapy also showed pathological partial response. Masterchart was prepared comprising patient’s age, menopausal status, family history, therapy history, histo-morphological features, hormone receptor and HER2/neu status after platinum added chemotherapy. Oestrogen Receptor (ER)/Progesterone Receptor (PR) were considered positive, if >1% tumour cell nuclei were immunoreactive and negative, if it was otherwise. HER-2/neu score of 3+ was taken as positive by Immunohistochemistry (IHC) method. Statistical analysis for descriptive purposes, percentages and mean were calculated. Comparison of both the groups was done by Pearson’s Chi-squared and Fisher’s-exact test. Significance level was considered at p-value <0.05. Results: TNBC patients (NACT group) showed hormone receptor positivity of 21 cases (52.50%) after chemotherapy along with carboplatin. HER2/neu positivity was detected in 9 (22.5%) cases. Non-NACT (64) cases were considered as control group for comparison. The effect of NACT in TNBC patients was found to be statistically significant with respect to change in HER2/neu (p=0.033, p<0.05) and ER status (p<0.05) while change in PR status was found to be statistically insignificant. Conclusion: The study showed significant alteration in hormonal and HER2/neu receptor status in TNBC patients receiving platinum added neoadjuvant chemotherapy. This study found statistical significance and justifies re-evaluation of these Hormone Receptor (HR) and HER2/neu markers in residual tumour after chemotherapy.

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Expression of Transgelin in Triple Negative and Non Triple Negative Breast Cancer: A Differential Study

Tumori Journal ◽

10.1177/0300891620914150 ◽

2020 ◽

Vol 106 (1_suppl) ◽

pp. 20-20

Author(s):

NS Tolba ◽

AS Alsedfy ◽

SW Skandar ◽

YM El-Kerm

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Molecular Subtypes ◽

High Rate ◽

Targeted Treatment ◽

Her2 Status ◽

Altered Expression ◽

Wide Range ◽

Significant Difference

Introduction: Triple negative breast cancer (TNBC) is defined by the absence of ER expression, PR expression and HER2 amplification. No targeted treatment is available for TNBC and chemotherapy remains the best therapeutic option. However, in the case of recurrence or chemo-resistance, therapeutic options are very limited. TNBC presents a high rate of proliferation and is highly aggressive having low survival rate. As the complexity of this disease is being simplified over time, new targets are also being discovered for the treatment of this disease. Therefore, there is still need for new biomarkers, which would serve for targeted treatment. Transgelin was proposed as a new potential cancer biomarker. Altered expression of Transgelin has been described in a wide range of cancers, often with contradictory results. The aim of the study was to compare Transgelin expression across molecular subtypes of breast cancer, to identify if it can be used as a future molecular targeted protein for TNBC. Material and Methods: Transgelin immunohistochemistry was applied on 60 retrospectively collected paraffin blocks of patients presenting with invasive breast carcinoma (NST) having different molecular subtypes. Blocks were collected between 2015 and 2016 from Pathology department, Medical Research Institute, Egypt. Her2 equivocal cases were excluded from the study. Results: Transgelin expression was positive in 23 cases and negative in 37 cases. There was a statistically significant difference between (Transgelin +) and (Transgelin -) cases being highly expressed in TNBC in comparison to other molecular subtypes. It was also highly expressed in tumors with large size, high grade, positive lymph-vascular invasion status & lymph node metastasis. There was no statistically significant difference between (Transgelin+) and (Transgelin-) as regards age and Her2 status. Conclusions: Transgelin is an aggressive biomarker differentially expressed among the molecular breast cancer subtypes with high expression in TNBC. Transgelin may provide a potential target for future treatment of TNBC.

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