Series of rare cases of breast tumour: 8-year review at mankweng Breast Oncology clinic, Limpopo, South Africa

Introduction: This case report describes a 54-year-old patient who developed invasive breast carcinoma in her left breast without further specifications, of the luminal B molecular subtype, concurrently with a primary breast lymphoma (diffuse large B-cell lymphoma with the germinal center B-cell subtype), which was definitively diagnosed only after surgical intervention. Synchronous occurrence of breast cancer and non-Hodgkin lymphoma (NHL) is an uncommon situation, with only 38 cases reported in the literature. It is extremely rare for both tumors to present as a collision tumor within the same breast. A collision tumor refers to the coexistence of two histologically distinct tumors occurring at the same site. The mechanisms underlying this collision are highly complex, and it remains unclear whether the pathophysiological association between them can be attributed to being induced by the same causal factor. Breast lymphoma is an uncommon hematological neoplasm originating in the breast lymphoid tissue. Its prevalence is low, ranging from 0.04%–0.7%. It is classified into primary breast lymphoma (PBL), when it occurs in the breast without concomitant widespread disease, and secondary breast lymphoma (SBL), when there is metastatic involvement of the breast. The average age of onset for PBL varies from 60 to 65 years; it does not have a specific manifestation but usually presents as a unilateral, painless, palpable mass. Most PBLs are high-grade B-cell lymphomas, with diffuse large B-cell lymphoma (DLBCL) being the most common subtype, as well as the one with the worst prognosis and highest recurrence rate. After diagnosis, treatment of breast lymphoma is based on a combination of surgery, radiotherapy, chemotherapy, and immunotherapy. It is believed that the development of breast lymphoma associated with invasive breast carcinoma could be induced by the same virus or by hormonal alterations, primarily estrogen. Another hypothesis is that breast cancer could act as a stimulating factor for lymphoma, just as the reduced immune function caused by lymphoma may promote the development of carcinoma. The association between non-Hodgkin lymphoma and breast carcinoma is extremely rare, and currently, there is no clear treatment pattern or detailed information regarding its prognosis. Methodology: In January 2022, a 54-year-old single female patient, a native and resident of São Paulo/SP, sought medical attention due to the appearance of a palpable nodule in the left breast for more than a year, accompanied by intermittent bleeding from the lesion that began a month prior. She had a diagnosis of systemic arterial hypertension and was being treated with two antihypertensive medications. The patient was nulliparous, her menarche occurred at age 12, she experienced menopause at age 46 (without hormone replacement therapy), and she denied having used combined oral contraceptives. She had a family history of esophageal cancer in her brother, who was a smoker and alcohol consumer. On physical examination of the breasts, inspection revealed an ulcerated lesion in the healing process involving the entire left breast, primarily in the lateral quadrants, without active bleeding. Palpation showed that the lesion measured approximately 15x12 cm, was hardened, and had limited mobility. In the left axillary region, a fibroelastic lymph node measuring 1.5 cm was palpated. During the first consultation, the patient brought an external breast ultrasound from December 2021, which described an infiltrative architectural distortion affecting nearly all quadrants, diffusely heterogeneous with poorly defined hypoechoic areas, involving the skin and subcutaneous tissue, especially in the lateral quadrants; presence of atypical axillary lymphadenopathies measuring up to 15x11 mm. Bilateral mammography at our institution revealed a 50 mm retroareolar nodule in the left breast, with irregular margins and poorly defined borders (Breast Imaging Reporting and Data System — BI-RADS 4); Our breast ultrasound showed a large, solid lesion in the left breast that was difficult to measure, while the right breast appeared normal. Additionally, CT scans of the chest, abdomen, and pelvis, as well as a bone scintigraphy, were performed to exclude other primary neoplastic sites; all examinations showed no abnormalities. The patient underwent an incisional biopsy of the left breast in the surgical center, and the histopathological report indicated atypical lymphocytic infiltration of mixed B and T cells, suggestive of reactive lymphoid hyperplasia. A core biopsy guided by ultrasound of the left breast nodule was also performed. The histopathological and immunohistochemical analysis of the biopsied tissue revealed mammary tissue with foci of moderate lymphocytic inflammatory infiltrate in a perivascular, periductal, and interstitial distribution, fibrosis, hyalinization of the stroma, and focal pseudoangiomatous hyperplasia of the stroma. The tissue was estrogen receptor positive in the ducts, p63 positive in myoepithelial cells, and AE1/AE3 positive in the ducts. Following the review of supplementary tests and clinical examination, a decision was made to proceed with initial surgical treatment. The patient underwent a mastectomy with left axillary approach, based on intraoperative frozen section results, and closure was achieved using a latissimus dorsi flap (performed in collaboration with the plastic surgery team). Histopathological analysis of the surgical specimens revealed areas of invasive breast carcinoma without further specification (20%), histological grade II, nuclear grade 3, multifocal (with three foci, the largest measuring 17x15 mm), no ductal carcinoma in situ (DCIS) detected, with extensive lymphovascular invasion present, associated with an extensive large cell lymphoma (80%) measuring approximately 20 cm, involving and ulcerating the skin and infiltrating muscle. Surgical margins were negative for invasive carcinoma; however, the deep margin coincided with the lymphoma. Immunohistochemical analysis of the invasive breast carcinoma showed high expression of estrogen (ER) and progesterone (PR) receptors (95%), a Ki-67 proliferation index of 80%, and HER2 was negative (score 0). The expression of AE1/AE3 cytokeratins confirmed the epithelial histogenesis of this neoplasm. The expression of GATA3 and estrogen receptor (ER) indicates the breast as the primary site of this carcinoma. Negativity for P63 confirms the absence of myoepithelial cells surrounding the tumor, thereby corroborating the diagnosis of invasive carcinoma. The expression of E-cadherin and β-catenin confirms that it is an invasive carcinoma of unspecified type (CI SOE or CINE). Meanwhile, the lymphoma component shows negativity for cytokeratins and positivity for CD20, confirming a B-cell immunophenotype lymphoma. Positivity for BCL6, along with negativity for MUM1, supports the diagnosis of a large B-cell lymphoma with an immunophenotype indicative of the germinal center B-cell (GCB) molecular subtype. Thus, the findings indicate a multifocal luminal B invasive carcinoma associated with extensive large B-cell lymphoma with an immunophenotype pointing to the GCB subtype. Pathological staging (pTNM, AJCC 8th edition): mpT1c pN1a pMx. Following surgery, the patient was referred to oncology and hematology for adjuvant treatment planning. She was indicated to receive six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone) along with adjuvant radiotherapy to the left thoracic wall at a dose of 40.05 Gy in 15 sessions. The patient is currently under regular follow-up, on endocrine therapy with anastrozole since May 2023, with good treatment tolerance and remains asymptomatic to date. Conclusion: The association between NHL and breast cancer is extremely rare. The mechanisms that lead to this tumor collision are highly complex and not yet fully understood, particularly regarding the main causal factors. Clinical diagnosis remains challenging, given the small number of reported cases to date.

Background: Breast cancer normally occurs in elderly women, although it also affects young women. In the Limpopo province, South Africa over 38% of breast cancer occurred in younger women under 50 years of age. The main objectives of the study were to identify the characteristics of breast cancer in women >50 years and <50 years and to categorise any differences (histological type, stage, grading and molecular subtype) exist between these two groups of breast cancer patients. Methods: This is a cross-sectional design study to analyse the profile of women >50 and <50 years with breast cancer who attended Mankweng Breast Oncology Clinic from July 2020 to December 2021. Patient demographics were summarised using descriptive statistics. Categorical variables were expressed as proportions and frequency. Association between categorical variables was done using a Chi-square test. Results: Total 222 patients. Age: >50 years-old: 131(59%); <50 years old: 91(41%). Age: >50 years group: Early stage: 49(37.4%), late stage: 82(62.6%). Molecular subtype: luminal A: 23(17.6%); luminal B: 67(51.2%); HER-2 overexpression: 21(16%); triple negative: 20(15.3%). Histological type: invasive ductal carcinoma: 126(96.2%). Age: <50 years group: Early stage: 31(34.1%), late stage: 60(65.9%). Molecular subtype: luminal A: 28(30.8%); luminal B: 40(44%); HER-2 overexpression: 5(5.5%); triple negative: 18(19.8%). Histological type: invasive ductal carcinoma: 89(98%). Conclusion: Majority of patients presented at an advanced stage in both groups. HER2 overexpression molecular subtype was higher in the >50-year patient group in compared to <50 years group (p-value 0.016). Health education and breast cancer awareness campaigns are essential for all women, young and elderly in the Limpopo province.

Background: Male breast cancer (MBC) is very uncommon, occurring less than 1% of all breast cancers, and has a worse survival rate compared with that of female patients. Clinical studies on male breast cancer have not been done frequently because of the rarity of the condition. The main aim of this study is to understand the profile of male breast cancer patients treated at Mankweng Hospital. Methods: A retrospective cross-sectional descriptive quantitative design was adopted to analyze the profile of all patients with histologically confirmed male breast cancer from March 2015 to May 2023 in the Mankweng Breast Oncology clinic. Results: A total of 17 patients with confirmed MBC were evaluated. Age range 23–80 years. The mean age is 62.5 years, with the majority (76%, 5%) being above the age of 50 years. Early-stage (0, I & II) comprised 6 (35%) and late-stage (III & IV) consisted of 11 (65%) patients. Invasive ductal carcinoma was 14 (82%), Colloid carcinoma 1, Papillary carcinoma 1 and Metastatic Adenocarcinoma 1. Molecular subtype: Luminal A: 7 (43.8%), Luminal B: 8 (50%) & Triple-negative: 1 (6.2%). ER Positive: 15 (93.7%), ER Negative: 1 (6.3%). Conclusions: The majority (65%) of male breast cancer were diagnosed at an advanced stage, and 76.5% were over the age of 50 years. Invasive ductal carcinoma was the most (82%) common histological type of breast cancer, and the majority (93%) are oestrogen receptor positive in this study. There is a gap that needs to be filled in terms of public knowledge about male breast cancer. Breast cancer awareness campaigns are also important for men to prevent delayed presentation. Men over 50 years old who notice a change in their breasts should report promptly to a health facility for further assessment.

BACKGROUNDPrimary breast lymphoma is a rare disease. The small number of patients and the paucity of data make large-series studies difficult. We conducted a pooled analysis to evaluate the treatment outcome and prognostic factors in patients with primary breast lymphoma.METHODSIn a search of PUBMED and MEDLINE we found 7 observational studies with 93 patients that were eligible for inclusion. Treatments included single therapy or combined surgery, chemotherapy and radiotherapy. We analyzed the correlation between treatment protocols, tumor relapse and survival. Histopathology and cancer stage were analyzed to evaluate their significance in treatment outcome.RESULTSAll 93 patients were female, with a mean age of 57 years. The histopathology of 63 patients (68%) was diffuse large cell lymphoma. According to Ann Arbor classification, 57% were stage I, 23% were stage II, 4% were stage III, and 16% were stage IV. Thirteen percent received surgery alone, 27% received chemotherapy alone, 7% received radiotherapy alone, 10% received surgery and chemotherapy, 10% received surgery and radiotherapy, 22% received chemotherapy and radiotherapy, and 11% received surgery combined with chemotherapy and radiotherapy. With a median follow-up duration of 34 months (mean, 53 months), 48% had relapse of disease, 50% had no relapse, while 2% had disease progression. The mean time to first tumor relapse after treatment was 20 months. The 3-year and 5-year overall survival rates were 70% and 56%, respectively. Radiotherapy was a significant prognostic factor predicting tumor relapse (P=0.044). Tumor stage was a significant prognostic factor affecting overall survival, disease-free survival and disease-specific survival (P=0.0231, 0.0015, 0.0124, respectively).CONCLUSIONWith a 3-year overall survival rate of 70%, the high relapse rate of 48% is a cause for concern. Patients who received chemotherapy and radiotherapy had better survival outcome and a lower relapse rate. We suggest that chemotherapy and radiotherapy be the initial treatment for patients with primary breast lymphoma.

Bilateral primary non-Hodgkin's lymphoma of breast is a rare entity because incidence wise it comprises less than 10% of all primary breast lymphoma. Here a case of bilateral breast lump is reported and reviewed, who had bilateral axillary node involvement and which trucut biopsy showed evidence of primary non-Hodgkin's lymphoma and responded satisfactory to chemotherapy. KEYWORDS: Breast tumor; Bilateral; Primary Non-Hodgkin's Lymphoma. INTRODUCTION: Primary mammary involvement in NHL is rare and representing 0.4-0.7 % of all diagnosed cases of non-Hodgkin's lymphoma. (1) Less than 0.6% of all breast malignancy is primary breast lymphoma.(2) Breast lymphoma usually presents as a painless unilateral breast mass and bilateral disease is seen in less than 10 %.(3) Such lymphomas are mostly non-Hodgkin's type representing 70-90%.(1) Primary breast lymphomas exhibit a poor prognosis and its therapeutic management is controversial and till date not fully established. We report a bilateral primary lymphoma (non-Hodgkin's) of breast due to its rarity.

Utility of Breast Magnetic Resonance Imaging in Determining Candidacy for Partial Breast Irradiation

Background: Circulating tumor cells (CTCs) have repeatedly been shown to carry independent prognostic information in metastatic breast cancer (MBC). A CTC count of 5 cells per 7.5 mL blood is a generally accepted cut-off, where MBCs with <5 CTCs are classified as MBCindolent and ≥5 CTCs as MBCaggressive. Furthermore, several studies have shown that the presence of CTC clusters add prognostic information to CTC count alone. Invasive lobular carcinoma (ILC) is the second most common histological breast cancer (BC) type (~10%). The vast majority of all BCs (~80%) are classified as invasive ductal carcinoma (IDC). Many distinguishing clinicopathological and genomic features have been identified between these two types, but in spite of this, current clinical management strategies and treatments are similar and mainly based on studies dominated by IDCs. The aim of this study was to explore potential differences in the distribution and prognostic significance of CTC count and CTC clusters in metastatic ILC vs. IDC, in a prospective observational study. Patients and methods: Between April 2011 and June 2016, 139 women with newly diagnosed metastatic ILC (N=28) and IDC (N=111) were included. CTCs and CTC clusters were detected, using CellSearch technology (Menarini Silicon Biosystems), at baseline (BL) before first-line systemic therapy, and during the first 6 months of follow-up (FU). The primary endpoint was progression-free survival (PFS) and the secondary endpoint overall survival (OS). Median FU time was 49 (27-93) months. Results: There was a highly significant (P<0.001) difference in the median CTC count between ILC (70, range 0-2598) and IDC (2, range 0-668) at BL, and presence of CTC clusters was also higher (36% vs. 18%, P=0.07). These differences between ILC and IDC persisted in the luminal A-like subgroup. The CTC count and CTC clusters declined in both ILC (median count 4, range 0-85; clusters: 4%) and IDC (median count 0, range 0-263; clusters: 12%) after 1 month of systemic treatment, but the decline was most pronounced in ILC. Seventy-nine percent of the ILCs and 46% of the IDCs were classified as MBCaggressive (CTC ≥5) at BL (P=0.003). The prognostic value of CTC ≥5 on PFS (HR 1.5, 95% CI 0.55-4.0, P=0.44) and OS (HR 2.4, 95% CI 0.71-8.3, P=0.16) in ILC was weak, whereas significant prognostic effects were seen in IDC (PFS: HR 1.7, 95% CI 1.2-2.6, P=0.007; OS: HR 2.1, 95% CI 1.3-3.3, P=0.002). With higher cut-offs the prognostic impact of CTC count on PFS/OS was significant also in ILC (CTC ≥20: HR 3.0, 95% CI 1.3-6.8, P=0.01 / HR 3.1, 95% CI 1.2-8.3, P=0.02) (CTC ≥80: HR 3.6, 95% CI 1.5-8.8, P=0.004 / HR 5.9, 95% CI 2.0-17.8, P=0.002) and the prognostic effect in IDC remained. The presence of ≥1 CTC cluster was a negative prognostic factor significantly associated with impaired survival in ILC (PFS: HR 4.6, 95% CI 1.7-12.4, P=0.003; OS: HR 4.9, 95% CI 1.7-13.8, P=0.003), whereas the effect was weaker in IDC (PFS: HR 1.2, 95% CI 0.69-2.0, P=0.55; OS: HR 1.9, 95% CI 1.1-3.3, P=0.02). First-line systemic treatment was similar in ILC vs. IDC (endocrine 46% vs. 39% and chemotherapy 54% vs. 61%) and the overall prognosis did not differ (PFS: HR 0.89, 95% CI 0.57-1.4, P=0.59; OS: HR 0.99, 95% CI 0.60-1.6, P=0.96). Conclusions: In this study of metastatic ILC and IDC, the CTC count at BL was remarkably higher in ILCs and the presence of CTC clusters was also more common, in spite of the fact that no difference in prognosis was seen. The prognostic value of the generally accepted CTC cut-off (≥5) was clearly weaker and the presence of CTC clusters stronger in ILC vs. IDC. A higher cut-off might be more suitable in ILCs in order to better discriminate between MBCindolent and MBCaggressive forms, and CTC clusters could potentially add prognostic information. Citation Format: Ulrik Christoffer Narbe, Pär-Ola Bendahl, Kristina Aaltonen, Mårten Fernö, Carina Forsare, Charlotte Levin Tykjær Jørgensen, Anna-Maria Larsson, Lisa Rydén. The distribution and prognostic significance of circulating tumor cells are different in invasive lobular carcinoma compared to invasive ductal carcinoma of the breast [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-01-04.

Background: In contrast to early stage breast cancer, the quality of care for patients with metastatic breast cancer (MBC) has been relatively understudied, as have interventions to improve care in the real-world setting. Patients with MBC face a variety of unique needs related to their disease, treatment options, and supportive care. Little attention has been focused on leveraging the strengths of academic and community-based settings to provide optimal care for these patients. To address these critical issues, we have designed and implemented a comprehensive program that combines clinical care, clinical research, physician engagement and patient education to optimize the care of MBC patients. Methods: We developed a consistent and comprehensive intake process and follow-up approach for MBC patients who were seen at least once in the Breast Oncology Clinic (BOC) at Dana-Farber Cancer Institute (DFCI). A key component of our approach is the EMBRACE coordinator who meets with each MBC patient at the first clinic visit to review the clinical program, available educational and supportive resources, and consents to research studies. Each coordinator supports the DFCI-based oncologist and follows a discrete patient panel longitudinally, for whom they are responsible for facilitating referrals to supportive care resources, identifying potential candidates for trial prescreening, tracking availability of results from molecular testing for clinical trial matching, facilitating communication between DFCI-based providers and referring providers and organizing re-consultation visits when clinically appropriate. The coordinator contacts patients every 3 months to inquire about the patient's overall health and needs and provides updates on upcoming educational and supportive care activities at our institution. Educational offerings have been expanded to include a bi-annual newsletter, quarterly email updates, webcasts and an annual educational patient forum. Results: The program was fully implemented in the BOC across 27 oncologists in August 2016, after the start of a pilot in July 2015. On average, the program enrolls 30 to 40 new MBC patients per month at their initial visit. The EMBRACE coordinators currently support the DFCI-based oncologists in the care of approximately 1500 new and existing MBC patients and facilitate collaborations with 350 referring providers. Conclusions: The EMBRACE program has made a tangible improvement in the quality of care for patients with MBC in our clinic. We have successfully established the infrastructure of the coordinator role and a robust tracking system to support the patient, DFCI-based provider, and referring provider. While the program has been solely based at DFCI, we believe that our approach has the potential for impact beyond our institution and ultimately serve as a model for enhanced academic-community-patient partnership. Citation Format: Hughes ME, Frank ES, Merrill MS, Santiago RA, Kuhnly N, Crowley LM, Gupta G, Winer EP, Lin NU. EMBRACE (Ending metastatic breast cancer for everyone): A comprehensive approach to improve the care of patients with metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-10-04.

Background:Invasive lobular carcinoma (ILC) is the second most common histology of breast cancer, accounting for approximately 10-15% of cases. Prior studies have demonstrated that loss of E-cadherin, as well as alterations in tissue including CDH1, FOXA1, TBX3 and PTEN loss, that were more commonly observed in Luminal A ILC, while GATA3 was more commonly observed in invasive ductal carcinoma (IDC) (Ciriello et al., Cell 2015). However, data regarding the characterization of circulating tumor DNA (ctDNA) in patients (pts) with metastatic ILC are limited. We hypothesized that there would be distinct mutational profiles between pts with metastatic ILC and IDC that could be characterized using ctDNA. Methods:This retrospective cohort study included de-identified clinical, pathological, and ctDNA data from pts with metastatic breast cancer (MBC) combined under a data use agreement and approved by the institutional review boards of three sites: Washington University in St. Louis (MO), Northwestern University (Chicago, IL), and Massachusetts General Hospital (Boston, MA). All pts included in the study had ctDNA testing per standard of care with plasma-based genotyping performed by Guardant360 (Redwood City, CA) between 2015-2020. Histological classification (ILC vs. IDC) was defined based on review of pathology reports from the primary tumor or from breast biopsies of de novo MBC, and additional clinical and pathological variables were obtained via electronic medical record review. Single nucleotide variants (SNVs) were annotated using OncoKB and ClinVar and only pathogenic variants were included. Mutational profiles were compared across histologic subtypes using Fisher’s exact test to assess differences in alteration frequency across subtypes. Multivariable analysis was performed. Results:A total of 994 pts with MBC underwent ctDNA testing and were included in the analysis. 10.7% of pts had ILC (N=106) and 89.3% had IDC (N=888). 89.4% of ILC cases were categorized as hormone-receptor positive (HR+) compared with 67.1% of IDC cases. Pts with ILC had a lower frequency of triple-negative (6.7% vs. 17.7%) and HER2 positive (3.9% vs. 15.2%) breast cancer compared with IDC. Pts with ILC had a significantly higher number of pathogenic SNVs compared with IDC (mean 4.45 vs. 2.77; P=0.0037). In contrast, pts with ILC had a significantly lower number of copy number alterations as compared to pts with IDC (mean 0.40 vs. 1.03; P=0.0017). No differences were observed in mutant allele frequency between pts with ILC and IDC. The 5 most common alterations observed in pts with ILC were the following: PIK3CA, TP53, ESR1, ERBB2, and ARID1A. Alterations in AR, BRAF, CDH1, ERBB2, FGFR2, IDH2, KRAS, NF1, PIK3CA, SMAD4, and TERT were significantly higher in ILC than IDC (all P<0.05). In contrast, mutations in GATA3, and amplifications in ERBB2 and MYC were significantly more common in pts with IDC (all P<0.05). In multivariable analysis, mutations in BRAF, CDH1, ERBB2, IDH2, TERT remained significantly higher in ILC, while amplification of MYC was significantly higher in IDC (all P<0.05). After restricting the analysis to pts with HR+ HER2 negative MBC, the following genes were significant in multivariate analysis: CDH1 and ERBB2 for pts with ILC and MYC amplification for pts with IDC (all P<0.05). Discussion:In this large, multi-institutional dataset, pts with metastatic ILC were characterized by a significantly higher number of SNVs in ctDNA compared to pts with IDC, suggesting higher mutational burden. We report several alterations that were significantly different in ILC vs. IDC. These results demonstrate the ctDNA profile of pts with ILC, and future studies should explore serial plasma-based genotyping to track ILC evolution to develop targeted precision medicine based therapeutic approaches for this unique subset of pts with MBC. Citation Format: Andrew A Davis, Lorenzo Gerratana, Katherine Clifton, Marko Velimirovic, Whitney L Hensing, Ami N Shah, Paolo D’Amico, Carolina Reduzzi, Qiang Zhang, Charles S Dai, Elyssa N Denault, Nusayba A Bagegni, Mateusz Opyrchal, Foluso O Ademuyiwa, Ron Bose, William J Gradishar, Amir Behdad, Cynthia X Ma, Aditya Bardia, Massimo Cristofanilli. Circulating tumor DNA characterization of invasive lobular carcinoma in patients with metastatic 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 PD14-04.

SummaryEstrogens play an important role in the development and progression of human cancers, particularly in breast cancer. Breast cancer progression depends on the malignant destabilization of adherens junctions (AJs) and disruption of tissue integrity. We found that estrogen receptor alpha (ERα) inhibition led to a striking spatial reorganization of AJs and microclustering of E-Cadherin (E-Cad) in the cell membrane of breast cancer cells. This resulted in increased stability of AJs and cell stiffness and a reduction of cell motility. These effects were actomyosin-dependent and reversible by estrogens. Detailed investigations showed that the ERα target gene and epidermal growth factor receptor (EGFR) ligand Amphiregulin (AREG) essentially regulates AJ reorganization and E-Cad microclustering. Our results not only describe a biological mechanism for the organization of AJs and the modulation of mechanical properties of cells but also provide a new perspective on how estrogens and anti-estrogens might influence the formation of breast tumors.

Introduction Breast cancer is a heterogeneous disease with distinct biological subtypes. Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) are the two most frequent histological breast cancer subtypes. With this study, we aimed to provide insight into the role of histological subtype on the characteristics, choices with respect to systemic therapy in daily practice and outcome of patients with metastatic breast cancer. Patients and methods We analyzed 815 patients diagnosed with metastatic breast cancer in eight hospitals between 2007 and 2009. All hormone receptor (HR) positive patients with either IDC or (mixed) ILC were included. Patient and tumor characteristics, outcomes and treatment data were collected. Survival curves and time to first palliative systemic therapy (either chemotherapy or endocrine therapy) were estimated using the Kaplan-Meier method and compared using log-rank tests. To explore the association of palliative systemic therapy with the survival of patients with metastatic breast cancer a Cox proportional hazards model was performed with palliative chemotherapy and endocrine therapy as a time-dependent covariates. Results A total of 568 patients with HR-positive tumors were included; 437 with IDC and 131 with (mixed) ILC. Patients with ILC were older at diagnosis of primary breast cancer, had larger primary tumors and more node-positive disease compared with IDC. Median survival was not different between the subtypes (29 months for ILC and 25 months for IDC, P=0.53). One year after diagnosis of metastatic breast cancer, less patients with HR-positive ILC received chemotherapy (33% of patients with ILC and 47% of patients with IDC) and their time to first palliative chemotherapy was significantly longer compared with HR-positive IDC (P=0.001). Time to first palliative endocrine therapy was significantly shorter for ILC compared with IDC (P=0.0001). In multivariable analysis for patients with ILC with palliative endocrine therapy and palliative chemotherapy as time-dependent covariates, palliative chemotherapy as first given systemic therapy was associated with an unfavorable outcome (hazard ratio 2.8, 95% CI 1.7-4.6, P<.0001) compared to no palliative chemotherapy and treatment with palliative endocrine therapy as first given systemic therapy was associated with a favorable outcome (hazard ratio 0.4, 95% CI 0.2-0.8, P=0.005). In multivariable analysis for patients with IDC, treatment with palliative chemotherapy as first given systemic therapy was also associated with unfavorable outcome (hazard ratio 2.1, 95% CI 1.6-2.7. P<.0001), whereas treatment with palliative endocrine therapy as first given systemic therapy was not associated with outcome for patients with IDC (hazard ratio 0.9, 95% CI 0.6-1.2, P=0.4). Conclusion There was no difference in survival of metastatic breast cancer patients with HR-positive ILC compared with those with IDC. This similar outcome was achieved with different treatment strategies, in which patients with ILC were more likely to receive endocrine therapy and less likely to receive chemotherapy. Citation Format: Lobbezoo DJA, Truin W, Voogd AC, Roumen RMH, Vreudgenhil G, Dercksen MW, van den Berkmortel F, Smilde TJ, van de Wouw AJ, van Kampen RJW, van Riel JMGH, Peters NAJB, Peer PGM, Tjan-Heijnen VCG. Does histological subtype play a role in treatment decision-making for hormone receptor positive metastatic breast cancer? A study of the Southeast Netherlands breast cancer consortium. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-13-06.

Background: Invasive lobular carcinoma (ILC) represents the second most common breast cancer (BC) subtype and is usually characterized as hormone-receptor positive, low-to-intermediate histologic grade, and human epidermal growth factor receptor (HER) 2-negative. In the early-stage setting, ILCs are associated with lower rates of pathological response to preoperative chemotherapy compared with invasive ductal carcinoma (IDC). This exploratory analysis investigated the magnitude of benefit of single-agent eribulin for the treatment of advanced ILC using data from three clinical trials in women with advanced BC. We also describe the patterns of response and survival outcomes compared with IDC. Methods: Individual patient (pt) data from the experimental arms of two phase III studies (305 and 301) and a single-arm, phase II study were pooled for the present analysis. Study 305 (EMBRACE) randomized pts treated with ≥2 lines of chemotherapy for advanced BC to receive eribulin or treatment of physician's choice. In study 301, pts treated with ≤2 lines of chemotherapy for advanced BC were randomized to receive eribulin or capecitabine. In the phase II study, pts who had received ≥3 lines of chemotherapy were treated with eribulin. Overall survival (OS) and progression-free survival (PFS) analyses were adjusted by study, estrogen receptor (ER) and HER2 status, and number of lines of therapy for advanced disease. Results: The three studies included 1353 eribulin-treated pts. Of the 1152 pts included in the present analysis, 118 were classified as ILC and 1034 as IDC. Median age of ILC and IDC pts was 58 years and 55 years, respectively. ER and/or progesterone receptor (PgR) positivity was more common in ILC (ER = 69%, PgR = 55%) than IDC (ER = 60%, PgR = 48%), while HER2 positivity was less frequent in ILC than IDC (9% vs 16%). A total of 52.5% of ILC and 61.4% of IDC pts received ≥3 lines of chemotherapy (for any stage BC) prior to eribulin. Pts with ILC and IDC had similar median OS (13.4 vs 13.5 months; hazard ratio [HR] = 1.10; 95% confidence intervals [CIs] 0.87, 1.38) and PFS (4.1 vs 3.6 months; HR = 0.91; 95% CIs 0.72, 1.14). Investigator-evaluated tumor response rates are shown in the table. Table: Best overall tumor responses (by investigator review)Response, %Invasive lobular carcinoma, n = 110Invasive ductal carcinoma, n = 985Objective response rate: CR + PR (95% CIs)15.5 (9.3, 23.6)14.8 (12.7, 17.2)Complete response (CR)00.4Partial response (PR)15.514.4Stable disease (SD)53.652.7Progressive disease (PD)26.428.9Clinical benefit rate: CR + PR + SD ≥6 months (95% CIs)29.1 (20.8, 38.5)28.6 (25.8, 31.6)Not evaluable4.53.6 Conclusions: In this exploratory, pooled analysis, magnitude of benefit from single-agent eribulin did not differ between the ILC and IDC cohorts. While there was a limited numbers of pts with ILC, response rates, PFS, and OS were similar for the two pt groups. The results with eribulin for advanced ILC contrast with data for other agents in early-stage settings, where ILC is generally less responsive to chemotherapy than IDC. These findings may, however, underline changes in the disease biology after exposure to previous therapies or changes inherent to disease progression. Citation Format: Javier Cortés, José Pérez, Yi He, Otto Metzger-Filho. Efficacy of eribulin in patients with invasive lobular carcinoma of the breast: data from a pooled analysis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-13-06.

Metastatic spread of invasive lobular breast carcinoma to stomach is rare especially before diagnosis of primary breast cancer. Incorrect diagnosis might result in delay of appropriate treatment for breast cancer. Recognition of this possibility enables better clinical management. A 62-year-old female presented with upper gastrointestinal symptoms and weight loss and was referred to a gastroenterologist for investigation. At the time of initial diagnosis of stomach cancer, patient was asymptomatic for breast cancer. Multiple gastric biopsies taken showed features suspicious of metastatic breast cancer. Consequently, the initial provisional diagnosis of stomach cancer changed into metastatic invasive lobular breast carcinoma. These findings were corroborated radiologically. The patient was treated with letrozole and zoledronic acid as first-line therapy for one year. Residual metastatic breast cancer was present in the gastric mucosa. The patient was treated with endocrine therapy containing ribociclib and treatment was ineffective confirmed by PET-CT scan. But her symptoms have resolved completely despite her presentation with stage IV. We present rare case of initial presentation of gastric metastasis before diagnosis of a primary invasive lobular breast carcinoma. Correct diagnosis and appropriate treatment were accomplished through initial clinical suspicion, accurate histological examination, and endoscopy together with analysis of disease-specific biomarkers.

Primary lymphoma of the breast is an unusual clinical entity. The coexistence in the same breast of an invasive ductal carcinoma is even rarer. We report a 69-year old woman referred for further evaluation of a palpable mass in her right breast. She was diagnosed and treated for simultaneous primary lymphoma and invasive ductal carcinoma. Primary breast lymphoma should always be considered in the differential diagnosis of breast masses. The presence of both malignancies presents a challenge in treatment decisions.

Case report and literature review: Metastatic lobular carcinoma of the breast an unusual presentation