Breast cancer is a complex and heterogeneous disease. Gene expression profiling has contributed significantly to our understanding of this heterogeneity at a molecular level, refining taxonomy based on simple measures such as histological type, tumour grade, lymph node status and the presence of predictive markers like oestrogen receptor and human epidermal growth factor receptor 2 (HER2) to a more sophisticated classification comprising luminal A, luminal B, basal-like, HER2-positive and normal subgroups. In the laboratory, breast cancer is often modelled using established cell lines. In the present review we discuss some of the issues surrounding the use of breast cancer cell lines as experimental models, in light of these revised clinical classifications, and put forward suggestions for improving their use in translational breast cancer research.

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Choosing the right cell line for breast cancer research

Massively parallel DNA sequencing technologies provide an unprecedented ability to screen entire genomes for genetic changes associated with tumour progression. Here we describe the genomic analyses of four DNA samples from an African-American patient with basal-like breast cancer: peripheral blood, the primary tumour, a brain metastasis and a xenograft derived from the primary tumour. The metastasis contained two de novo mutations and a large deletion not present in the primary tumour, and was significantly enriched for 20 shared mutations. The xenograft retained all primary tumour mutations and displayed a mutation enrichment pattern that resembled the metastasis. Two overlapping large deletions, encompassing CTNNA1, were present in all three tumour samples. The differential mutation frequencies and structural variation patterns in metastasis and xenograft compared with the primary tumour indicate that secondary tumours may arise from a minority of cells within the primary tumour.

https://cdr.lib.unc.edu/downloads/cz30pv848

Genome remodelling in a basal-like breast cancer metastasis and xenograft

Epithelial-mesenchymal transitions (EMTs) are a key requirement for cancer cells to metastasize and colonize in a new environment. Epithelial-mesenchymal plasticity is mediated by master transcription factors and is also subject to complex epigenetic regulation. This Review outlines our current understanding of the interactions between EMT-inducing transcription factors and epigenetic modulators during cancer progression and the therapeutic implications of exploiting this intricate regulatory process. During the course of malignant cancer progression, neoplastic cells undergo dynamic and reversible transitions between multiple phenotypic states, the extremes of which are defined by the expression of epithelial and mesenchymal phenotypes. This plasticity is enabled by underlying shifts in epigenetic regulation. A small cohort of pleiotropically acting transcription factors is widely recognized to effect these shifts by controlling the expression of a constituency of key target genes. These master regulators depend on complex epigenetic regulatory mechanisms, notably the induction of changes in the modifications of chromatin-associated histones, in order to achieve the widespread changes in gene expression observed during epithelial-mesenchymal transitions (EMTs). These associations indicate that an understanding of the functional interactions between such EMT-inducing transcription factors and the modulators of chromatin configuration will provide crucial insights into the fundamental mechanisms underlying cancer progression and may, in the longer term, generate new diagnostic and therapeutic modalities for treating high-grade malignancies.

The epigenetics of epithelial-mesenchymal plasticity in cancer

Remarkable progress has been made in defining a new understanding of the role of mRNA translation and protein synthesis in human cancer. Translational control is a crucial component of cancer development and progression, directing both global control of protein synthesis and selective translation of specific mRNAs that promote tumour cell survival, angiogenesis, transformation, invasion and metastasis. Translational control of cancer is multifaceted, involving alterations in translation factor levels and activities unique to different types of cancers, disease stages and the tumour microenvironment. Several clinical efforts are underway to target specific components of the translation apparatus or unique mRNA translation elements for cancer therapeutics.

Translational control in cancer.

Purpose.— To update key recommendations of the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) human epidermal growth factor receptor 2 (HER2) testing in breast ...

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Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update.


 Background The variable natural history of ductal carcinoma in situ (DCIS) is poorly understood. The aim of this retrospective cohort study was to determine the outcomes of women who were diagnosed through the English National Health Service Breast Screening Programme (NHS BSP) and had no surgery for screen-detected DCIS. Method English NHS BSP databases were searched for women diagnosed with DCIS without invasive cancer on needle biopsy between 1 April 2001 and 31 March 2018 inclusive, who had no record of surgery within 6 months of diagnosis. These were cross-referenced with cancer registry data for further treatment, event information and mortality records. Details of potentially eligible women were sent to the relevant breast screening units for verification and for completion of data forms detailing clinical, radiological and pathological findings, non-surgical treatment, subsequent clinical course and outcomes. Results Data for 311 eligible women (median age 62 years) were included, with median follow-up (primary DCIS diagnosis to either surgery, development of invasive disease, death or last known to be alive) of 4.1 years (range 0.5 to 17.4 years). The median age at diagnosis was 64 years (range 47 to 90 years). Sixty (19%) women developed invasive breast cancer, 56 ipsilateral and 4 contralateral. Twenty-two women (7%) underwent surgery for DCIS (>6 months after diagnosis) and 86 (28%) died of other causes. Women with high or intermediate grade DCIS were significantly more likely to develop ipsilateral invasive breast cancer (iIBC) than those with low grade DCIS. 28/123 (23%) with high grade DCIS, 21/105 (20%) with intermediate grade DCIS, 5/76 (7%) with low grade DCIS and 2/7 (29%) with an unknown grade of DCIS developed iIBC. Ipsilateral invasion risk increased approximately linearly with time for at least 10 years. Women who developed iIBC were significantly younger than those who did not. This was driven primarily by a strong association among those with high grade DCIS. There was no significant difference in age between those with intermediate and low grade DCIS respectively who did or did not develop iIBC. The median baseline size of DCIS in women who developed iIBC was higher than in women who did not develop iIBC, both overall and in each of the three grade categories (median sizes - high grade 38 mm vs 29 mm, p=0.19; intermediate grade 35 mm vs 18 mm, p=0.31; low grade 18 mm vs 15 mm, p=0.38). This reached statistical significance for all grades combined: 37 mm (range 3-95) v 20 mm (range 3-200), p=0.02. Of the 262 women with a known microinvasion status, 8/25 (32%) with definite or possible microinvasion were subsequently diagnosed with ipsilateral invasive cancer compared to 38/237 (16%) without microinvasion (p=0.027). There was no significant association on univariable analysis between risk of iIBC and microcalcification as the predominant radiological feature (iIBC and microcalcification 47/258 vs iIBC and other radiological feature 7/46; p=0.83), the presence of histological necrosis (iIBC and necrosis, 14/89 vs iIBC and no necrosis, 31/157; p=0.49) or the use of ET (iIBC and ET 11/67 vs iIBC and no ET 45/244; p=0.86). Of the 51 invasive cancers that developed with a known grade, 46 (90%) were grade 2 or 3. Conclusion The findings suggest that women diagnosed with high or intermediate grade DCIS and those with microinvasion should continue to be offered surgery. For those with low grade DCIS there is a need for shared decision-making in the choice of surgery or active surveillance based on a discussion of the risks and benefits of the options as currently understood, and in the light of the low reproducibility of DCIS grading.
 Citation Format: Karen Clements, Anthony Maxwell, Bridget Hilton, Matthew Wallis, Cliona Kirwan, Hilary Stobart, Elena Provenzano, Nisha Sharma, Janet Litherland, Abeer Shaaban, David Dodwell, Joanne Dulson-Cox, Elinor Sawyer, Senthurun Mylvaganam, Olive Kearins, Samantha Brace-McDonnell, Sarah Pinder, Alastair Thompson. A longitudinal cohort study of outcomes in 311 women with unresected ductal carcinoma in situ detected through the English breast screening programme [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 P1-22-06.

Abstract P1-22-06: A longitudinal cohort study of outcomes in 311 women with unresected ductal carcinoma in situ detected through the English breast screening programme

This chapter deals mainly with the two most important causes of enlargement of the male breast, namely, gynecomastia and breast cancer. Gynecomastia is the commonest cause of male breast lump. Most of the lesions are idiopathic, but enlargement due to various physiological and pathological causes may occur. The lesions histologically show florid epithelial proliferation within a cellular stroma in the early (active) phase and fibrosis with minimal epithelial proliferation in the late (fibrous) phase. Male breast cancer is a rare disease, but the incidence has been increasing worldwide. Several factors have been implicated including BRCA2 mutations, old age, liver cirrhosis, and testicular disorders. Many predisposing factors are related to increased estrogen levels relative to androgen. Male breast cancer is commonly of the ductal no special type with a high proportion of papillary carcinoma. Lobular carcinoma is extremely rare in the male breast. Management strategies are similar to and derived from the female disease.

Male Breast Lesions

e12609 Background: Patients presenting with cT1-3N1M0 breast cancer often receive NACT to enable breast and/or axillary conservation. Targeted axillary dissection (TAD) (sentinel node biopsy (SNB) + removal of marked involved node) has been proposed to reduce the false negative rate of SNB after NACT in cN1 patients. In ATNEC, cT1-3N1M0 patients receive NACT followed by SNB/TAD. If the sentinel nodes (SN) have converted to benign (ypN0), patients are randomly assigned to Axillary Treatment vs no Axillary Treatment. Node marking is recommended in the study and sites are offered training to help them adopt node marking in a standardized way. Objectives: To prospectively evaluate the practice patterns and response to NACT, uptake of node marking, marked node identification rates and breast conservation rates in the ongoing UK ATNEC trial. The trial aims to recruit 1900 patients. Methods: Data for all patients who were randomized until 01-Feb-23 across 78 UK centers were included in these analyses. Patients were cT1-3N1M0 at presentation, received NACT and were found to have no residual nodal disease (ypN0) on SNB/TAD. Results: Among the 120 randomized patients (median age 54 [range 28-77] years) (median BMI 26.4 [range 17.6-51.1]), 53% (64) were post-menopausal, 78% (94) had breast conserving surgery (BCS) and 22% (26) mastectomy. At presentation, 14% (17) were T3, 64% (77) T2 and 20% (24) T1. 70% (84) had grade 3 tumors. 62% (74) were HER2 positive, 31% (37) triple negative (TNBC) and 9% (7) HER2 negative (ER or PgR positive). 54% (65) had an anthracycline and taxane based NACT and 36%(43) had platinum containing NACT. Median of 4 nodes [interquartile range 3-5] were removed during SNB/TAD. Of 109 patients with node marking data, the involved node was marked in 73% (80). The marked node was identified and removed in 95% (76/80), marked node was the SN in 88% (67/76). Of the 109 patients with data for breast tumor post NACT, 69% (75) had pathological complete response (pCR), 7% (8) DCIS only, 24% (26) invasive cancer. Of the 63 patients with complete breast tumor response on imaging, 17% (11) had residual DCIS/invasive cancer. 50% (21/42) of patients with partial response or stable breast tumor on imaging had no residual tumor on histology (ypT0). Of the 107 patients with data on post NACT axillary imaging, 14% (15) had partial or stable disease but pCR on histology. Conclusions: Majority of UK patients having NACT have HER2 positive or TNBC. Although 69% patients had a pCR (ypT0) in the breast, BCS rates remain low. Imaging has limited accuracy in predicting pCR after NACT. 3 in 4 patients randomized had their node marked, with a 95% intra-operative identification rate; demonstrating ATNEC has successfully rolled out node marking in the UK. Clinical trial information: NCT04109079 .

Practice patterns in ongoing neoadjuvant ATNEC trial for patients with cT1-3N1M0 breast cancer: Response to neoadjuvant chemotherapy (NACT), targeted axillary dissection and breast conservation rates.

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2022-RA-1318-ESGO Immunohistochemical profiling of macrophage subtypes in the microenvironment of ovarian tumours in young women

Introduction: Inflammatory Breast cancer (IBC) is a rare, aggressive form of breast cancer accounting for 1-4% of all BCs. The definition of IBC is variable with some overlap with a locally advanced BC. There is paucity of data on UK outcomes with variability in what is defined as an IBC. We describe the initial results of the first UK multi-disciplinary IBC clinic. 

Abeer M Shaaban

Papers

Abstract P1-22-06: A longitudinal cohort study of outcomes in 311 women with unresected ductal carcinoma in situ detected through the English breast screening programme

Male Breast Lesions

Practice patterns in ongoing neoadjuvant ATNEC trial for patients with cT1-3N1M0 breast cancer: Response to neoadjuvant chemotherapy (NACT), targeted axillary dissection and breast conservation rates.

2022-RA-1318-ESGO Immunohistochemical profiling of macrophage subtypes in the microenvironment of ovarian tumours in young women

Inflammatory breast cancer clinic - Setting up a regional service