HER2 Research Articles

Therapeutic Challenges in the Management of Collecting Duct Carcinoma of the Kidney: A Case Report with Review of Literature

AbstractCollecting duct carcinoma (CDC) of the kidney is a rare type of renal cell carcinoma. It is an aggressive tumor with a poor prognosis and limited treatment options. A 67-year-old man, during evaluation for hematuria, loss of appetite and weight loss, and flank pain, was found to have a left renal mass with lung and bone metastasis. He underwent a left radical nephrectomy, and histopathological examination confirmed CDC. He received palliative chemotherapy with carboplatin and gemcitabine. Computed tomography (CT) scan after three cycles showed partial response. Chemotherapy was stopped due to worsening renal function after five cycles. Immunohistochemical studies done for programmed cell death ligand 1(PDL1) SP263 and Her2 neu were negative. Next-generation sequencing for 75 therapeutically actionable gene panels showed loss of function mutation in the neurofibromatosis type 1 (NF1) gene. Missense mutations involving Platelet derived growth factor receptor alpha gene (PDGFRA), FAT atypical cadherin 1 (FAT1), and Androgen receptor (AR) genes were reported as variants of unknown significance. No clinically relevant alterations were detected in liquid biopsy. Consequently, he was started on sunitinib. After 2 months, he developed brain metastasis and was treated with whole brain radiation therapy. Systemic therapy was changed to single-agent Nab-paclitaxel. After three cycles, he developed a cutaneous metastasis in the forearm and chemotherapy was changed to single-agent doxorubicin. After three cycles of doxorubicin, he succumbed to the disease. He survived for 16 months after diagnosis. The first-line treatment for metastatic CDC is chemotherapy with gemcitabine and cisplatin. There is no established second-line treatment. In this era, next-generation sequencing for targetable genetic alterations can help us select the treatment for subsequent lines of therapy.

Interobserver Variability in HER-2 Immunostaining Interpretation of Metastatic HER2 Low Breast Cancers in Cytology Specimens.

Approximately, 55% of breast carcinomas are reported to be HER-2 low breast carcinomas. Trastuzumab-Deruxtecan is a new FDA-approved targeted therapy for HER-2 low metastatic breast carcinomas, making it essential that all efforts are made to identify these tumors in specimens submitted for pathologic examination. Cytology specimens are often the first and only modality of this assessment due to the ease of specimen procurement. This study aimed to determine the variability in HER-2 immunostaining interpretation among observers using cytologic specimens from metastatic sites. A pathology database search was made to identify metastatic breast carcinoma reported in cytology specimens. A manual search was then done to identify cases of HER-2 low category, H&E cell block and HER-2 neu immunostain slides were retrieved for a total of 50 cases. Reviewer #1 and #2 independently interpreted HER-2 immunostain of all 50 cases. Only discordant cases were sent for reviewer-3 interpretation. All three were blinded by the metastatic site, and original HER-2 interpretation. Of 50 cases, 11 cases (22%) were reported as concordant scores between reviewer #1 and reviewer #2 but had a discordant original IHC report. Additionally, 4 cases (8%) had discordant reporting of HER2 IHC stain between reviewer #1 and reviewer #2 making a total of 15 cases (30%) with overall discordant results. This study highlights the interobserver variability of HER-2 immunostain interpretation for HER-2 low category of breast carcinomas. We recommend the need for more robust laboratory techniques including molecular for uniform identification of these unique targetable metastatic breast carcinoma groups.

Expression of cancer stem cell markers (CD24, CD44 & ALDH1A3 isoform) in Breast Cancer in Indian population considering clinicopathological characteristics and response to neoadjuvant chemotherapy - a prospective analysis from a university hospital.

Cancer stem cells (CSC) are a small number of tumour propagating cells present in the bulk of tumour cells. Expression of biological markers for CSCs viz. cluster of differentiation 24 and 44 (CD24, CD44) and aldehyde dehyodeganse 1 (ALDH1) imply aggressive tumour cell behaviour and poorer outcome, particularly in breast cancer. N = 75 Tumor tissue samples from enrolled breast cancer patients were obtained and subjected to histopathological examination and immunohistochemistry (IHC) after informed consent from patients. In addition to the estrogen receptor, progesterone receptor, Her2 neu receptor, and Ki67 index; IHC was also performed for CD24, CD44 and ALDH1A3 expression. These markers' positivity was correlated with clinical parameters, therapy response and metastasis prognostication. Most patients had higher tumor stage and high nodal burden (81.3% with node positivity; N1-68%, N2 -6.6%, N3-6.6%). Study showed significant association of CD24-/CD44 + group (p = 0.021) with distant metastasis and significant association of CD24-/CD44 + /ALDH1A3 + (p = 0.008) with higher stage (T4 stage). Tumor tissues expressing CD24-/CD44 + /ALDH1A3 + group (p = 0.010) and CD24 + /CD44 + / ALDH1A3 + (p = 0.010) were significantly associated with poor response to treatment. The correlation of CD24-/CD44 + was also statistically significant (p = 0.009). Positive expression of either CD24 and/or CD44 presented with aggressive disease, larger tumours and heavy nodal burden at a younger age. Additionally, ALDH1A3 positivity signified higher metastasis rates. CD24-/CD44 + /ALDH1A3 + and CD24 + /CD44 + / ALDH1A3 + correlated with greater chances of distant metastasis, aggressive disease, limited response to chemotherapy and poorer prognosis. Thus, these observations establish the role of these CSC phenotypes as important factors for prognostic outcomes and predictors of adverse outcomes. CD24-/CD44 + /ALDH1A3 + expression could serve as an important prognostic marker and predictor of adverse outcomes in Indian breast cancer tumour biology.

Utility of PET-CT for assessment of response to neo-adjuvant chemotherapy in breast cancer.

12 Background: Response to neo-adjuvant chemotherapy (NACT) is associated with prognosis in non-metastatic breast cancer and can potentially inform further therapeutic options. The aim of this study was to correlate post NACT response on PET CT with pathological response. Methods: All patients who underwent pre- NACT (baseline) and post NACT PET CT imaging with F-18 FDG in a dose of 5-7 MBq/kg body weight with a minimum of 185 MBq given intravenously were retrospectively analyzed. Scan was performed on GE Discovery 710 whole-body PET scan with 128 slice CT. Relevant clinical and imaging related details were extracted from the treatment records. Post NACT PET response (PERCIST criteria) in the primary tumor and nodes was correlated with the pathological response on the post surgical specimen. Analysis was done using Microsoft Excel and SPSS v20 (IBM SPSS). Results: The median age was 49 years (range 30-76 years). 83.1% of patients had node positive disease on baseline PET imaging (not pathologically confirmed). Post chemotherapy PET showed complete metabolic response in the primary tumor and regional nodes in 56.3% and 74% of patients respectively. Two patients had progressive local disease. Pathological complete response rates post surgery in triple negative, Her2 neu positive and ER positive group was 50%, 34% and 12% respectively. The sensitivity, specificity, positive predictive value and negative predictive value is tabulated below. Conclusions: Overall FDG PET CT showed good specificity with limited sensitivity for post NACT response assessment in breast cancer. Our results suggest that post NACT PET CT may have limited utility for clinical decision making and at present its use cannot be recommended outside of a clinical trial.[Table: see text]

Is it time to de-escalate axillary surgery in patients with ductal carcinoma in-situ undergoing mastectomy?

IntroductionAxillary surgery has been de-escalated in invasive breast carcinoma and may be omitted in certain age groups. Up to 10–20 % of patients with ductal carcinoma in-situ (DCIS) will have an element of invasion. Therefore, SLNB is indicated to rule out nodal metastasis. Our purpose was to identify the rate and possible risk factors for lymph node metastasis in DCIS, and to measure oncological outcome of positive SLNB in this group. MethodsA retrospective analysis was performed on 113 female patients with DCIS, who underwent mastectomy and SLNB. Their clinical and radiological features, as well as pre and post-operative histopathological characteristics were evaluated and data was reported over an average follow up period of 48 months. ResultDCIS was upgraded to invasive cancer in 11 patients out of 113 (9.7 %). Five patients had positive SLNB (4.4 %), one micro-metastasis (0.8 %) and four macro-metastasis (3.5 %) All the five underwent axillary lymph node dissection (ALND) and all additional nodes retrieved were negative. High nuclear grade, Her2 neu overexpression, and palpable mass showed higher odds of association with metastasis to sentinel nodes. However, due to the low event rate, the association did not reach statistical significance. Seven patients (6.2 %) developed lymphedema, 4 of which after SLNB only. No regional recurrence was reported among our study sample. ConclusionThis study confirms the very low rate of positive SLNB in patients with DCIS. It is time to de-escalate axillary surgery for patients with DCIS undergoing mastectomy and consider delayed SLNB for high risk group of patients.

Pathological complete response rate to anthracycline versus non−anthracycline based chemotherapy regimens in localized and regional HER2 neu positive breast cancer.

e12632 Background: Debate over the need of anthracycline as part of neoadjuvant chemotherapy in HER2-neu early breast cancer was addressed in many trials with results favoring similar outcomes with or without anthracycline. This was not adopted fully in Saudi Arabia because of concern regarding ethnic differences in response to treatment. We conducted this retrospective analysis to evaluate if there is any difference in pathological complete response rate (PCR) in patients with early HER2-neu positive breast cancer depending on neoadjuvant chemotherapy regimen. Methods: Patients with HER2-neu positive early breast cancer who were treated with neoadjuvant chemotherapy at Johns Hopkins Aramco Healthcare (JHAH) facility between the year 2018 and 2022 were all evaluated for pathological subtype, HER2-neu status and type of neoadjuvant chemotherapy administered. Pathological response status was evaluated in all patients and PCR was measured to see if there was any difference depending on the use of anthracycline (AC) or non-anthracycline (non-AC) based chemotherapy regimen. Patient demographics, tumor characteristics, clinical stage, treatments and outcomes were collected via JHAH’s oncology registry. Categorical variables are reported as frequencies and percentages. The association between chemotherapy regimen AC vs non-AC based and PCR was analyzed using Fisher Exact Test. p-value <0.05 was considered statistically significant. Analyses were conducted using JMP version 15. Results: In this study 59 HER2-neu positive early breast cancer patients were identified. We examined their clinical characteristics and treatment outcomes. Median age was 57. The most prevalent histology was invasive carcinoma of no special type (79.66%), Estrogen receptor positivity was observed in 72.88% of patients, while progesterone receptor positivity was seen in 62.71% of cases. Majority of patients were alive (96.61%) at the time of data collection. There was no significant difference in clinical stage in both groups. The association between chemotherapy type and pathological response was assessed. Among patients receiving AC chemotherapy (n=29), 55.17% achieved PCR, while for patients receiving Non-AC chemotherapy (n=30), the PCR rate was 50%. However, this difference was not statistically significant (p-value = 0.8). Conclusions: In our cohort of HER-neu positive early breast cancer patients who received neoadjuvant therapy there seems to be no significant difference in PCR with AC or Non-AC based chemotherapy regimens. This is concordant with the international trends.

Evaluation of the Expression EGFR, HER2/NEU and the End Effector ERK of the RAS/RAF/MAP Kinase Pathway in Prostatic Adenocarcinoma for a Possible Role as New Target Therapy.

Immunohistochemistry- using tissue microarrays- for EGFR, HER2/neu, non-phosphorylated, and phosphor-ERK, was performed on tissues from 166 patients- with primary prostatic adenocarcinoma with no prior treatment-. The results of different markers expression were correlated with the clinical and pathological parameters and were analyzed statistically. The prostatic tissue showed EGFR, HER2 neu, phosphorylated and non-phosphorylated ERK expression in 8.4%, 1.4%, 78.2%, and 83.4% respectively whether low (patchy) or high expression (diffuse). There were no significant correlations found between patient characteristics and expression of the tested markers. The negative immune reactivity for non-phosphorylated ERK and EGFR- was significantly correlated with high tumor stage (p values 0.03 and 0.01, respectively). EGFR and HER2/neu may play a limited role in prostatic adenocarcinoma as they showed positive expression in a limited number of the examined tissues specifically HER2neu. The expression of non-phosphorylated ERK (mostly weak to moderate) and phosphorylated ERK (mostly moderate to strong)- was appreciated in most cases. Thus, we suggest that anti-EGFR drugs may have a limited role in the treatment of castrate-resistant prostate cancer, but anti-MEK/ERK drugs may have more promising role as a target therapy. It is recommended to perform further molecular testing to elucidate the exact mechanism and significance of these markers.

Abstract PO3-22-04: PMRT Decision with low prediction of genomic test score in pT3N0M0 luminal breast cancer: Protocol MF22-02: International multicenter real-world data

Abstract Background: In current guidelines, there is no definite recommendation regarding postmastectomy radiation therapy (PMRT) in patients with luminal pT3N0M0 breast cancer (BC). The goal of this study is to determine whether PMRT could be safely omitted for a specific subgroup of those patients. Methods and Materials: There were 202 women from 16 centers with pT3N0M0 hormone receptor (HR) positive, Her2 neu (-) BC who underwent mastectomy, were analyzed retrospectively. None of the patients received neoadjuvant chemotherapy. Three patients were excluded because of positive surgical margins. The patients were divided into two groups, PMRT (+) (n=130) and PMRT (-) (n=69). Groups were compared in terms of overall survival, loco-regional recurrence rate, and distant metastases regarding Magee score (MS) (< 18 are considered low risk) (https://path.upmc.edu/onlineTools/mageeequations.html), menopausal status, axillary surgery, pathology, lymphovascular invasion (LVI), adjuvant chemotherapy, and adjuvant endocrine therapy. Results: The majority of the patients had invasive ductal carcinoma (49%, n=98). There was no significant difference regarding tumor size, axillary surgery, and adjuvant endocrine therapy between the two groups (p=0.82, p=0.28, p=0.12, respectively). LVI was 49% (n=98) and it was greater in PMRT (+) group (25% vs. 10%; p=0.01). PMRT (+) patients received more chemotherap(66% vs. 30%; p< 0.001), had more grade 3 tumors (28% vs. 9%, p=0.005), and more premenopausal (49% vs. 22%; p=0.0001). At a median follow-up of 51.3 months for the PMRT (-) group and 65.9 months for the PMRT (+) group (p=0.041), 9% (n=6) of patients from the PMRT (-) group and 2% (n=3) from the PMRT (+) group developed locoregional recurrence (LRR) (p=0.047). There was no difference in local recurrence (1% in PMRT (-) group vs. 2% in PMRT (+); p=0.7) and distant recurrence (7% in PMRT (-) group vs. 3% in PMRT (+); p=0.16) between patients who received PMRT and not had PMRT. Further comparison of the LRR in the PMRT (-) and PMRT (+) groups in patients with an MS < 18 did not show a significant difference (3% vs. 4%; p=0.64). However, among patients with a Magee score ≥18, the PMRT (-) group had a higher LRR rate compared to the PMRT (+) group (11% vs. 2%; p=0.01). In patients with an MS≥18, the administration of PMRT correlates with statistically significantly better LRR-free survival (HR 0.19; 95%CI 0.05 – 0.79; p=0.02). Conclusions: Our findings imply that when considering PMRT for BC with pT3N0M0, HR (+), and Her2 neu (-), clinicians can benefit from a combination of pathological risk factors and recurrence prediction models. Patients with MS< 18 receiving PMRT or not appear to experience a comparable rate of recurrence. Citation Format: Atilla Soran, Caleb King, Parul N. Barry, Rohit Bhargava, Hasan Karanlik, Melis Gultekin, Ferah Yiıdız, Aykut Soyder, Berk Goktepe, Kazim Senol, Caglar Guzel, Ebru Sen Oran, Levent Yeniay, Ahmet Dağ, Selman Emiroglu, Didem Can Trabulus, Alper Coskun, Neslihan Cabioglu, Hagigat Veliyeva, N. Zafer Utkan, Berkay Demirors, Efe Sezgin, John A. Vargo. PMRT Decision with low prediction of genomic test score in pT3N0M0 luminal breast cancer: Protocol MF22-02: International multicenter real-world data [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 PO3-22-04.

Abstract PO5-05-12: Loco-regional Treatment in De Novo Bone Only Metastatic Breast Cancer; Prospective, Multi-Institutional Real-World Data, BOMETIN, Protocol MF14-1a

Abstract Introduction: The impact of loco-regional treatment (LRT) on survival in de novo bone-only metastatic breast cancer (BC) is controversial. The aim of this study is to assess the effect of LRT on survival utilizing international, prospectively acquired data in this cohort of patients. Materials and Methods: Patients with de novo metastatic BC with bone-only metastases were divided into two groups: those receiving systemic therapy only (ST) and those undergoing LRT. Patients who received LRT were divided into two groups: those who received ST after LRT (LRT+ST arm) and those who received ST prior to LRT (ST+LRT arm). Solitary or multiple bone metastases were classified, and factors associated with disease progression were analyzed. Results: There were a total of 744 patients with de novo bone-only metastatic BC treated at each of the participating institutions between 2014 and 2022, with 372 (50%) participants in each arm. Median follow-up was 48 months (32-66, 25-75%). Patients in the LRT group were significantly younger than the ST group [50 (42, 60) vs 55 (44, 66), p=0.0001]. There were no significant differences in grade, Her2 neu and triple negative status, receipt of hormonal therapy and intervention to metastatic sites. During follow-up, 58% (n=217) of patients in ST arm and 32% (n=120) of patients in LRT arm died (p< 0.001). Local progression was observed in 20% of the patients in the ST arm whereas it was 9% in the LRT arm (p=0.0001). Systemic progression occurred more in ST arm; 66% (n=244) compared to 41% (n=152) of patients in LRT group (p< 0.001). The Hazard of death was 64% lower in LRT group than in ST group (HR: 0.36, 95% CI: 0.29-0.45), p<0.0001). The burden of metastatic disease was significantly different between groups with the solitary bone metastasis rate higher in LRT group than the ST only group (50% vs 24%, p< 0.001). However, the LRT group had better overall survival for both solitary (HR: 0.38, 95% Cl: 0.26-0.55) and multiple (HR: 0.38, 95% Cl: 0.29-0.51) bone metastases patients. Within the LRT group, survival rates were similar whether the breast surgery was performed before or after ST.Multivariate Cox analysis showed that LRT and ER/PR positivity significantly decrease the hazard of death (p< 0.05). Conclusion: Analysis of this large multi-institutional patient cohort provides further evidence that LRT improves overall survival and lowers loco-regional recurrence in patients with de novo bone-only metastatic BC. In breast cancer patients with bone-only metastases at presentation, the decision for LRT should be made through a multidisciplinary approach with consideration of surgical therapy at the primary tumor. Citation Format: Atilla Soran, Serdar Ozbas, Lutfi Dogan, Didem Can Trabulus, Jamila El-Azrhi, Kazim Senol, Berk Goktepe, Shruti Zaveri, Salyna Meas, Umut Demirci, Hasan Karanlik, Aykut Soyder, Ahmet Dağ, Ahmet Bilici, Mutlu Dogan, Mehmet Ali Nahit Sendur, Hande Koksal, Mehmet Ali Gulcelik, Neslihan Cabıoğlu, Levent Yeniay, N. Zafer Utkan, Nuri Karadurmus, Gul Daglar, Turgay Simsek, Birol Yildiz, Cihan Uras, Mustafa Tukenmez, Cihangir Ozaslan, Niyazi Karaman, Arda Isik, Berkay Demirors, Efe Sezgin, Vahit Ozmen, Anthony Lucci. Loco-regional Treatment in De Novo Bone Only Metastatic Breast Cancer; Prospective, Multi-Institutional Real-World Data, BOMETIN, Protocol MF14-1a [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 PO5-05-12.

Abstract PO4-06-03: A comparative study between RECIST 1.1 using MRI and PERCIST 1.0 using PET/CT to evaluate the response in patients of carcinoma breast receiving neoadjuvant chemotherapy

Abstract Introduction: Breast cancer is the most common cancer in women leading to the major public health problem with an estimated new cases of 2,261,419 (11.7%). Depending upon the stage at presentation, the primary modalities vary. Presently, the primary option for HER2-positive, Triple negative cancers of size more than 2cm or nodal involvement and locally advanced breast cancer is neoadjuvant chemotherapy (NACT). Accurate assessment of the tumor response and residual cancer after undergoing NACT is considered crucial for reducing the number of local recurrence cases and to predict the prognosis as patients who achieve pathological complete response (pCR) after NACT have a longer disease free period and better overall survival as compared to non-responders. In our study we have compared the two commonly used criteria i.e. RECIST 1.0 and PERCIST 1.0. Methodology: 70 patients diagnosed with breast cancer requiring neoadjuvant chemotherapy were recruited in the study conducted in the department of surgical disciplines, AIIMS Delhi from January 2021 to December 2022. Each patient underwent a contrast enhanced MRI breast and whole body FDG PET/CT at the beginning of chemotherapy and after completion of chemotherapy within a stipuated time of two to three weeks. For RECIST 1.1 criteria, response assessment was done using MRI and PERCIST used PET/CT. The response was compared with the gold standard histopathological size. Results: Concordance between the RECIST 1.1 and PERCIST 1.0 response classifications was seen in 27 (39.1%) cases, while discordance was seen in 42 (60.8%). A significant difference was observed between RECIST 1.1 and PERCIST 1.0 (k=0.1309, p< 0.0001) for response classification. Tumor response was upgraded in 32 and downgraded in 2 patients using PERCIST 1.0 as compared to RECIST 1.1. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy to predict pCR along with comparison among different molecular subtypes is shown in the table below. Conclusion: RECIST 1.1 showed high specificity, PPV and accuracy in predicting pathological complete response but tends to underestimate it whereas PERCIST 1.0 showed higher sensitivity with a tendency to overestimate. RECIST 1.1 had a high level of specificity and NPV as compared to the PERCIST 1.0, which showed a high level of sensitivity and PPV. Thus, they act as complementary modalities for predicting pathological complete response. The accuracy to predict pCR was higher for the triple-negative phenotype and Her2 neu enriched with PERCIST 1.0 as compared to RECIST 1.1, while that of PERCIST 1.0 was lower for luminal type. Table. Comparison of RECIST 1.1 and PERCIST 1.0. Citation Format: Anita Dhar, Kanika Sharma. A comparative study between RECIST 1.1 using MRI and PERCIST 1.0 using PET/CT to evaluate the response in patients of carcinoma breast receiving neoadjuvant chemotherapy [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 PO4-06-03.

Abstract PO5-20-09: LOCOREGIONAL MANAGEMENT OF DE NOVO STAGE IV HORMONE-POSITIVE BREAST CARCINOMA AFTER CDK 4/6 INHIBITOR TREATMENT

Abstract Systemic therapy remains the backbone for treatment of metastatic breast carcinoma. Locoregional treatment of the primary tumor remains controversial. While it has an established role in the palliative setting, its survival benefit remains unclear. The rationale behind locoregional approach is the reduction of tumor burden and the removal of cancer stem cells which may propagate the disease. In previous literature, hormone-positive breast cancer seems to be the best candidate for locoregional treatment in the presence of synchronous metastases. We present a case of a 43 year-old, female, with no known comorbidities, who sought consult due to note of a hard lump on her right breast. Core needle biopsy of the right breast mass was performed which showed invasive breast carcinoma, no special type, Nottingham histologic grade 2. On immunohistochemistry, tumor was ER +8, PR +8, Ki 67 90%, Her-2 neu negative. Baseline positron emission tomography/CT (PET/CT) scan showed hypermetabolic, heterogeneously-enhancing lobulated right breast mass, 3 × 6.7 × 7.7 cm, with smaller hypermetabolic adjacent nodules. There was also note of multiple enhancing, hypermetabolic lung and pleural nodules, and lymphadenopathies in the mediastinal, right axillary, right cardiophrenic and perigastric areas. Well-defined, hypermetabolic heterogeneously hypoenhancing masses were also seen in segments II and VII of the liver. There was also note of right-sided pleural effusion. Ultrasound-guided thoracentesis was done which turned positive for malignant cells on pleural fluid analysis. She underwent 4 cycles of chemotherapy with Doxorubicin and Paclitaxel. Reevaluation PET-CT scan revealed partial response. Patient was then started on Ribociclib plus Letrozole with ovarian function suppression for 18 months. On latest reevaluation PET/CT scan, there was no evidence of hypermetabolic metastatic disease, with demonstration of hypermetabolic activity only in the right breast. The patient then underwent right total mastectomy, with histopathologic findings of residual invasive carcinoma, Nottingham histologic grade 3, residual tumor size of 3.5 cm, with 95% tumor cellularity and lymphovascular invasion identified, ypT2. All surgical margins were negative for tumor. Currently, the patient has no evidence of disease, with ribociclib and letrozole continued until disease progression or unacceptable toxicity. In this case, surgery of the primary tumor was performed in the presence of a responsive metastatic disease, with the primary tumor being the only evidence of disease. With the advent of newer therapy options like cyclin-dependent kinase 4/6 inhibitors offering outstanding survival benefit for metastatic disease, a more aggressive and synergistic approach with locoregional therapy may be done to eradicate the tumor burden, translating to better long-term survival. Locoregional management of the primary tumor should be discussed in the context of a multidisciplinary team approach and should be individualized based on the individual patient’s need. Citation Format: Raye Angeli Abella, Rubi Li. LOCOREGIONAL MANAGEMENT OF DE NOVO STAGE IV HORMONE-POSITIVE BREAST CARCINOMA AFTER CDK 4/6 INHIBITOR 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 PO5-20-09.

Study of impact of assessment of estrogen receptor, progesterone receptor, Her2 neu receptor and Ki-67 at diagnosis in management of breast cancer patient at Birat Medical College Teaching Hospital (BMCTH)

Introduction: Breast cancer is the most common cancer in Nepal. Treatment of breast cancer includes combined therapy based on hormonal receptors within breast tissue and is linked to prognosis and survival. Objective: To evaluate hormonal factors preoperatively and assess the impact of how it would change the management practices of treating breast cancer in our setup. Methodology: This descriptive prospective study was conducted from March to October 2023 in the department of surgical oncology BMCTH in patients with breast mass suggestive of carcinoma meeting inclusion criteria and willing for treatment. Patients demographic data, detailed history and clinical examination was done at the time of diagnosis entered in excel sheet and calculation done by SPSS. Ethical clearance was taken from the institutional review committee of BMCTH (Ref: IRC-PA-296/2023 ). Results: In 80 female patients with mean age 46.15 years, Left breast cancer (60%) was more common than right side (40 %). Most common site of presentation was the upper outer quadrant (UOQ- 47.%). Invasive ductal carcinoma was the commonest type (47.5%) of all histological variants. 67.5% patients had ER positive receptor, 67.5% had PR positive and 2 Her2 neu was present in 28.7 %. TNBC reported 18.75% (15 patients out of 80 patients). Ki- 67 prognostic value ranged from 10 to 70 with mean 29.91+-20.795%. Among all 36.3% underwent neoadjuvant chemotherapy prior to surgery and 63.7% underwent upfront surgery for breast cancer. Conclusion: Screening of Triple negative and luminal type B breast cancers preoperatively is essential. Evaluation of hormonal factors ER, PR, Her 2 neu and Ki-67 preoperatively is must as it changes the management practices of treating breast cancer.

Abstract LB188: PEA-15 phosphorylation mediates pro-tumor effects by promoting β-catenin activity in TNBC

Abstract Triple negative breast cancer (TNBC) is a subtype of breast cancer that is defined by a lack of estrogen receptor, progesterone receptor, and HER2-neu gene product expression. Previously, we found that TNBC cells with phosphorylated PEA-15 adaptor protein exhibited decreased clonogenic and anchorage-independent growth in vitro, and decreased growth and lung metastasis in vivo. Further, we found lower levels of phosphorylated β-catenin at S675 in PEA-15-AA (non-phosphorylatable) mutants than in PEA-15-DD (phosphomimetic) mutants. We therefore hypothesized that phosphorylated PEA-15 enhances the aggressiveness of TNBC by regulating the phosphorylation of β-catenin at S675. We first screened a panel of TNBC cells for β-catenin levels via western blot. Next to assess the biological role of β-catenin we knocked down its expression in TNBC cells (SUM149, BT549). In the β-catenin knockouts, proliferation decreased by 20%(P<0.0001) mammosphere formation by 69% (P<0.001), and clonogenic growth by 65% (P<0.0001), when compared to the vector control. To determine if PEA-15 mediates pro-tumor effects by phosphorylating β-catenin at S675, we created a nonphosphorylatable (S675A) and a phosphomimetic (S675D) form of β-catenin. We transfected BT549 cells with S675A and observed a decrease of 26% (P=0.011) in proliferation, 65% (P<0.001) in mammospheres, and 54% (P=0.0001) in clonogenic formation when compared with WT β-catenin transfected cells. Next, we transfected SUM149 cells with S675D and found an increase of 58% (P<0.001) in proliferation, 79% (P=0.001) in mammospheres, and 23% (P=0.0303) in clonogenic formation when compared with WT β-catenin transfected cells. To test if PEA-15 phosphorylation mediates β-catenin activity, we transfected the S675A and S675D form of β-catenin into MDA-MB-468 cell lines which stably express PEA-15-AA and PEA-15-DD. When we performed a rescue experiment with PEA-15-AA cells transfected with S675D we found a 78% (P=0.0008) increase in mammospheres when compared to vector transfected cells. Conversely, when PEA-15-DD cells were transfected with S675A we found a 53% (P=0.0004) decrease in mammospheres when compared to vector transfected cells. Next, we did a multiplex staining of a tissuemicroarray (n= 102 human TNBC tumors). We observed that in patients with grade 3 tumors, the percentages of cells expressing total PEA-15(P=0.005), P-PEA-15-S116(P=0.038), and p-β-catenin (P=0.0005) were significantly higher than those in patients with grade 2 tumors. Together, these results show that PEA-15 phosphorylation mediates tumor aggressiveness in TNBC by promoting β-catenin activity. Future studies will evaluate the clinical significance of PEA-15 and β-catenin and their phosphorylated forms in TNBC patients. These results will establish β-catenin and PEA-15 phosphorylation as potential markers of, and targets against TNBC progression. Citation Format: Alex W. Tan, Mohd Mughees, Wendy A. Woodward, Debu Tripathy, Natalie Fowlkes, Chandra Bartholomeusz. PEA-15 phosphorylation mediates pro-tumor effects by promoting β-catenin activity in TNBC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB188.

Abstract 114: Identification of the actionable target, LILRB4, through genetic linkage analysis of Diversity Outbred (DO) F1 mice expressing HER2(neu)

Abstract Our goal is to identify, in situ, the regulatory genes that dictate the onset age and growth rate of spontaneously arising tumors to implement new intervention strategies. For genetic linkage analysis, we crossed HER2(neu) Tg mice with Diversity Outbred (DO) mice, an outbred population comprised of 8 founding strains (A/J, C57BL/6J, 129S1/SvlmJ, NOD/ShiLtJ, NZO/HILtJ, CAST/EiJ, PWK/PhJ, WSB/EiJ) maintained by non-sibling crossing to ensure each mouse is genetically unique. Using R/QTL package, we linked Quantitative Trait Loci (QTL) in Chr 1 and X with tumor onset age, and a Chr 10 QTL with tumor growth rate. The Chr1 (=human Chr2) QTL was linked to human breast cancer diagnosis in 11 Genome-Wide Association Studies (GWAS; the human GWAS catalog, https://www.ebi.ac.uk/gwas/). Because human GWAS data is deficient in Chr X mapping and also does not assess tumor growth rate as a trait, the QTL loci identified in mouse Chr X and 10 were discoveries beyond the capacity of human GWAS. In total, we identified 26 candidate genes across the 3 QTL. For clinical validation, the genes were analyzed with CodeAI (Caris LS) which associated cancer patient clinical data with candidate gene expression. We found 21/26 genes significantly associated with the survival of patients with primary (n=3,533) and/or metastatic (n=4,870) breast cancers and 17/26 were associated with lung cancer (n=11,334) survival, with 13 overlapping genes between lung and breast cancer, indicating broad applicability of these candidate genes. We interrogated the immune status in BALB NeuT and (BALBxPWK)F1 NeuT mice because the F1 mice developed tumors around 9 wk, much earlier than the 14 wk observed in BALB NeuT mice. Surprisingly, (BALBxPWK)F1 mice responded to cancer vaccines more vigorously. Single cell RNA (scRNA) libraries from (BALBxPWK)F1 NeuT tumors showed an expanded lymphocyte cluster (12%), compared with BALB NeuT (2%) and an enrichment of T cell activation genes. These findings may reflect a deficiency in tumor cell recognition by the activated anti-tumor effectors and a window of opportunity for correction. Of the 21 candidate genes, LILRB4, a myeloid cell checkpoint molecule, was of particular interest. Expression of LILRB4 is predictive of patient survival in both breast and lung cancer. Using scRNA sequencing, we found this transmembrane receptor expressed primarily by tumor infiltrating myeloid cells. In a reported scRNA sequencing dataset (GSE161529), LILRB4 was expressed by infiltrating macrophages in human breast cancers, and is also correlated with reduced survival. In a PAN Cancer ATACseq dataset (Corces et al., 2018), promoter accessibility of LILRB4 was associated with reduced survival. Taken together, there are multiple immune regulatory mechanisms of tumor progression and LILRB4 is an important new actionable target. CA76340 (WZW), KCI TBM program (JBJ) and CCSG P30 CA022453 (GB). Citation Format: Jennifer B. Jacob, Wei-Zen Wei, Benjamin L. Kidder, Tolulope Adeyelu, Andrew Elliott, Gerold Bepler, Joyce D. Reyes. Identification of the actionable target, LILRB4, through genetic linkage analysis of Diversity Outbred (DO) F1 mice expressing HER2(neu) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 114.

Prognostic factors and survival of breast cancer in patients over 40 years of age

Aims: Breast cancer is the cancer with the highest incidence and mortality in women. There are differences in prognosis and survival between women over and under the age of 40. In this article, we aimed to examine breast cancer prognostic factors and survival results in people over the age of 40. Methods: 1187 patients aged 40 and over who underwent surgery at the Ondokuz Mayıs University Department of General Surgery between August 2005 and April 2019 and whose data were accessible were retrospectively examined. Data were obtained from the hospital automation system, the Ministry of Health’s online database, hospital archives, patients, and/or their relatives. They were classified separately in terms of type of surgery, axillary metastasis status (according to radiological status if axilla surgery is not performed), type of axilla surgery performed, pathological tumor size, number of pathological lymph nodes, pathological stage, lymphovascular and perineural invasion status, hormone receptor positivity, C-erb B2 and Ki-67 status, neoadjuvant treatment status, and molecular subgroup. Variables were analyzed individually for recurrence, mortality, and survival. Results found to be significant were subjected to multivariate analysis testing. Statistical significance was accepted as p<0.05. Results: As a result of multivariate analysis performed by excluding data that disrupted homogeneous distribution, perineural invasion, lymphovascular invasion, grade, and progesterone receptor status were determined to be independent prognostic factors in terms of recurrence. Lymphovascular invasion and progesterone receptor status were found to be independent prognostic factors for mortality. Conclusion: A lot of studies have been conducted, and criteria have been determined for breast cancer prognosis and survival. In our results, lymphovascular invasion and progesterone receptor status were found to be independent prognostic markers for both recurrence and mortality. More reliable results can be obtained with prospective study analyses.

A study on immunohistochemical expression of HER2/Neu and p63 and its association with grade and invasiveness in case of bladder carcinoma.

Bladder cancer is a global disease, ranks as the fourth most prevalent cancer. The incidence and prevalence increase with age. Grade and aggressiveness have been found to be related with different genetic expression and mutation. To evaluate any relation of grade and invasiveness of urothelial cancer with varied expression of immune histochemical marker p63 and her2/neu. The present study was a hospital based prospective cross-sectional study. This Study was conducted from July 2021 to April 2023 in the Urology department of a tertiary care hospital. Total 90 patients undergoing trans urethral resection of bladder tumour (TURBT) were included in this study. It was found that, patients who had decreased p63 expression had high grade in tumours (93.1%) compared to patients who were expressing normal p63 (32.8%) and this was statistically significant (p < 0.0001). Tumours with decreased p63 also appeared to be more invasive, 62.1% were found to be muscle invasive. Tumours with her2 neu expression found to be more aggressive in nature, 85.7% had high grade features and 53.6% were muscle invasive. Our findings suggest that immunohistochemical expression of HER2/neu positive and decreased p63 expression were associated with high grade and invasiveness in case of bladder carcinoma.

Identification of novel PPAR-γ agonist ameliorating triple negative breast cancer by in silico methods

Triple negative breast cancer (TNBC) is still considered a medical challenge as it is an aggressive cancer characterized by poor prognosis, frequent metastasis, distinct clinical and pathological features and lack of proper treatment options. In TNBC, estrogen, progesterone and Her2 neu receptors are absent, which are usually present in otherwise breast cancers. So, hormonal therapy cannot be given in case of TNBC, leaving chemotherapy as the mainstay for treatment. However, chemotherapy is an infamous therapeutic option due to several aweful side effects like loss of appetite, extreme weight loss, hair loss, vomiting, fatigue etc. Several reports have highlighted role of Peroxisome Proliferated Activated Receptor gamma (PPAR-γ) in ameliorating breast cancer, but it is still less explored receptor for TNBC. Moreover, synthetic PPAR gamma agonists like thiazolidinediones, have good capability of activating PPAR-γ receptor, but these are also gloomy therapeutic agent due to their dreadful side effects like hepatotoxicity, bladder cancer, congestive heart failure etc. So, there is serious urge among researchers to find safer therapeutic option for TNBC. Phytochemicals are nowadays grabbing attention worldwide to treat several diseases due to their fewer or no side effects. This in silico study was performed after thorough review to select a natural, potent PPAR-γ agonist Gallotanin, as a query compound for ligand based similarity searching in PubChem database with 80% filter. Top 10 obtained compounds having highest similarity index were chosen for molecular docking in AutoDock Vina, with PPAR-γ receptor (3V9T) to know their binding patterns. Further, top 5 compounds having highest dock scores underwent ADME studies in SwissADME to assess pharmacokinetic profile of these compounds. Finally, this in silico study resulted in discovery of compound called Chamuvaritin which is still not known as a PPAR-γ agonist, efficient enough to act as potent therapeutic agent against TNBC.

Invasive Solid Papillary Carcinoma of breast in an elderly male: a rare entity in an uncommon gender - case report and review of literature

Abstract Introduction/Objective Male breast cancers (MBC) account for less than 1% of all breast cancers. Papillary cancers constitute less than 3% of MBCs. Solid papillary carcinoma (SPC) is a rare subtype of papillary cancer with a solid growth pattern associated with fibrovascular cores. SPC is an indolent disease that typically presents in a post- menopausal woman as a central breast mass. Neuroendocrine differentiation, ER/PR positive status and Her-2 neu negative status are characteristic. SPC can be in situ or have invasive components. SPC is a rare entity in men and so far, approximately less than 40 cases of SPC in men have been discussed in literature. Here, we report a rare case of SPC with multiple invasive foci in an elderly male. Methods/Case Report An 84-year-old white male presented with a painless mass in his left breast. Excision biopsy revealed Solid Papillary Carcinoma. He subsequently underwent a Left Modified Radical Mastectomy with Left Sentinel Lymph Node Excision. The final histopathology report showed a background of SPC with multiple invasive foci with largest focus measuring 2 mm. Margins were negative and lymph nodes were negative for malignancy. The tumor was ER and PR positive, Her-2 neu negative and had a Ki-67 proliferation index of 42%. Negative IHC staining for Cytokeratin AE1/AE3 confirmed the absence of metastatic epithelial cells in the examined lymph nodes. Results (if a Case Study enter NA) N/A Conclusion SPC is an uncommon subtype among the papillary lesions of breast. Furthermore, only a few cases of SPC have been reported in men. Despite its rarity, it has a good prognosis and lymph node positivity, distant metastasis and local recurrence are uncommon. However, there is limited data about SPC with invasive components which may behave like other invasive breast lesions leaving management a dilemma for clinicians. We believe this case will add to the scarce existing literature about invasive SPC in men.

Lobular Carcinoma of the Breast: A Comprehensive Review with Translational Insights.

The second most common breast carcinoma, invasive lobular carcinoma, accounts for approximately 15% of tumors of breast origin. Its incidence has increased in recent times due in part to hormone replacement therapy and improvement in diagnostic modalities. Although believed to arise from the same cell type as their ductal counterpart, invasive lobular carcinomas (ILCs) are a distinct entity with different regulating genetic pathways, characteristic histologies, and different biology. The features most unique to lobular carcinomas include loss of E-Cadherin leading to discohesion and formation of a characteristic single file pattern on histology. Because most of these tumors exhibit estrogen receptor positivity and Her2 neu negativity, endocrine therapy has predominated to treat these tumors. However novel treatments like CDK4/6 inhibitors have shown importance and antibody drug conjugates may be instrumental considering newer categories of Her 2 Low breast tumors. In this narrative review, we explore multiple pathological aspects and translational features of this unique entity. In addition, due to advancement in technologies like spatial transcriptomics and other hi-plex technologies, we have tried to enlist upon the characteristics of the tumor microenvironment and the latest associated findings to better understand the new prospective therapeutic options in the current era of personalized treatment.

Comparative genomic hybridisation and transcriptome microarray analysis in triple negative breast cancer: An INDIAN study.

Triple-negative breast cancer (TNBC), which accounts for approximately 15–20% of all breast cancers, defined as lack of expression of estrogen receptor, progesterone receptor and Her-2 neu receptors. TNBC has two subtypes basal like and non-basal like, the former characterised by aggressive biology with limited therapeutic options. This study explored molecular markers involved in pathogenesis of TNBC and investigated novel potential diagnostic and therapeutic targets by CGH array and transcriptome array. aCGH analysis in TNBC demonstrated genes amplified were 3888, number of pathway hits was 1554 and major pathways amplified was found to be WNT signalling pathway and Cadherin signalling pathway. Among all metastatic sites and remission, activation of WNT signalling pathway is commonly observed. TNBC exhibited 1486 copy number variations (CNVR) which is approximately 250 times higher than controls. More than 20 CNVR was observed in all chromosomes and more than 80 CNVR was observed in Chr 1 to Chr 4, Chr 7, Chr 11 and Chr X. Common CNVR associated with amplified regions in Chr 22, Chr 14, Chr 8 and Chr 2 was observed in TNBC and CNVR associated with Chr 22q11.22–23, Chr 6p21.32–33, Chr11q12.2, Chr14q32.22–23, Chr 8p11.22–23, was observed in metastatic disease. In transcriptome array analysis a total of 11,359 differentially expressed genes with fold change 2.0 were in observed in TNBC comprise of 7639 upregulated genes and 3720 downregulated genes. Further, with fold change 10, 1526 upregulated genes and 839 down regulated genes were identified. Panther pathway analysis identified the main pathways of upregulated genes were Wnt signalling pathway, Integrin signalling pathway and Cadherin signalling pathway. The main pathways of down regulated genes were Inflammation mediated by chemokine and cytokine signalling pathways. PPI network shows that COL12A1, COL6A3, FN1, MMP3, WNT5A were key upregulated genes and ITGB7, PTPRC, ITGA4, LCK and CD247 were key down regulated genes. Cytoscape analysis followed by multiple list comparator tool identified top 5 significant hub genes were FN1, MMP3, COLL11A1, COL12A1 and COL3A1. The significant pathway genes obtained by CGH array and transcriptome array when compared, exhibited 5 common genes COL4A1, FN1, COL6A3, COL5A2 and PCDH7. These genes were not overexpressed in Controls and therefore involved in pathogenesis of TNBC. Expressions of these genes were validated by studying protein expression by immunohistochemistry. FN1 and COL6A3 protein over expression predicted worse DFS in TNBC and can be considered as therapeutic targets at diagnosis to reduce the disease metastases. These findings provide new insights into the pathogenesis of TNBC and guide for selection of targets related to diagnosis, prognosis and prediction of treatment in TNBC.