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The last UK breast cancer (BC) human epidermal growth factor receptor 2 (HER2) testing guideline recommendations were published in 2015. Since then, new data and therapeutic strategies have emerged. The American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) published a focused update in 2018 that reclassified in situ hybridisation (ISH) Group 2 (immunohistochemistry (IHC) score 2+and HER 2/chromosome enumeration probe 17 ( CEP 17) ratio ≥2.0 and HER 2 copy number <4.0 signals/cell), as well as addressed other concerns raised by previous guidelines. The present article further refines UK guidelines, with specific attention to definitions of HER2 status focusing on eight key areas: (1) HER2 equivocal (IHC 2+) and assignment of the ASCO/CAP ISH group 2 tumours; (2) the definition of the group of BCs with low IHC scores for HER2 with emphasis on the distinction between IHC score 1+ (HER2-Low) from HER2 IHC score 0 (HER2 negative); (3) reporting cases showing HER2 heterogeneity; (4) HER2 testing in specific settings, including on cytological material; (5) repeat HER2 testing, (6) HER2 testing turnaround time targets; (7) the potential role of next generation sequencing and other diagnostic molecular assays for routine testing of HER2 status in BC and (8) use of image analysis to score HER2 IHC. The two tiered system of HER2 assessment remains unchanged, with first line IHC and then ISH limited to IHC equivocal cases (IHC score 2+) but emerging data on the relationship between IHC scores and levels of response to anti-HER2 therapy are considered. Here, we present the latest UK recommendations for HER2 status evaluation in BC, and where relevant, the differences from other published guidelines., Competing Interests: Competing interests: The authors attended meetings sponsored by Roche and AstraZeneca on HER2 low and HER2 positive breast cancer. No other relevant conflict of interests., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: EPHOS-B aimed to determine whether perioperative anti-HER2 therapy inhibited proliferation and/or increased apoptosis in HER2-positive breast cancer., Patients and Methods: This randomized phase II, two-part, multicenter trial included newly diagnosed women with HER2-positive invasive breast cancer due to undergo surgery. Patients were randomized to: part 1 (1:2:2), no treatment (control), trastuzumab or lapatinib; part 2 (1:1:2) control, trastuzumab, or lapatinib and trastuzumab combination. Treatment was given for 11 days presurgery. Coprimary endpoints were change in Ki67 and apoptosis between baseline and surgery tumor samples (biologic response: ≥30% change). Central pathology review scored residual cancer burden (RCB). Relapse-free survival (RFS) explored long-term effects., Results: Between November 2010 and September 2015, 257 patients were randomized (part 1: control 22, trastuzumab 57, lapatinib 51; part 2: control 29, trastuzumab 32, combination 66). Ki67 response was evaluable for 223 patients: in part 1 Ki67 response occurred in 29/44 (66%) lapatinib versus 18/49 (37%) trastuzumab (P = 0.007) and 1/22 (5%) control (P < 0.0001); in part 2 in 36/49 (74%) combination versus 14/31 (45%) trastuzumab (P = 0.02) and 2/28 (7%) control (P < 0.0001). No significant increase in apoptosis after 11 days was seen in treatment groups. Six patients achieved complete pathologic response (pCR, RCB0) and 13 RCB1, all but two in the combination group. After 6 years median follow-up, 28 (11%) had recurrence and 19 (7%) died. No recurrences or deaths were observed among patients who achieved a pCR. Ki67% falls ≥50% associated with fewer recurrences (P = 0.002)., Conclusions: Early response after short duration anti-HER2 dual therapy identifies cancers dependent on the HER2 pathway providing a strategy for exploring risk-adapted individualized treatment de-escalation., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: Advances in breast cancer (BC) research have demonstrated differences between black and white women with regarding tumour behaviour, patient outcome and response to treatment which can be explained by underlying genetic changes. The tumour suppressor gene p53 has been speculated to be involved in tumour biology of triple negative and/or basal -like BC and more commonly observed in black than caucasian women., Materials and Methods: In this study, the protein expression of p53 was investigated in tissue samples from a series of 308 Nigerian women, prepared as a tissue microarray (TMA), using immunohistochemistry. Clinicopathological parameters, biomarkers of functional significance in BC and patient outcome of tumours expressing p53 in Nigerian women were correlated with UK grade matched series., Results: A significantly large proportion of BC from Nigerian women showed high p53 expression compared with UK women (p<0.001). In those tumours showing positive p53 in the Nigerian series, a significant proportion were premenopausal, diagnosed before 50 years, larger in size, with evidence of metastasis into lymphatic vessels ( all p<0.001). In addition, p53 positive expression was also significantly correlated with negative expression of ER and PgR (p<0.001, p<0.03 respectively), BRCA1, MDM2 (all p<0.001), p21 (p=0.006) and E-cadherin (p=0.001) and positively associated with P-cadherin (p=0.001), triple negative phenotype, basal cytokeratin (CK) 5/6 expression (p<0.04) and basal phenotype compared with the UK series (p<0.001). Survival analyses showed Nigerian women with BC were significantly associated with poor BC specific survival (p<0.001, but no significant association with disease free interval was observed., Conclusion: In this study, protein expressions of p53 pathways are different between Nigerian and UK BC women and this may also contribute to differences in tumour biology. Therefore, targeting these p53 pathways for therapeutic usage might improve the poor outcome observed in Black Nigerian women.

Although breast cancer (BC) incidence is lower in African-American women compared with White-American, in African countries such as Nigeria, BC is a common disease. Nigerian women have a higher risk for early-onset, with a high mortality rate from BC, prompting speculation that risk factors could be genetic and the molecular portrait of these tumours are different to those of western women. In this study, 308 BC samples from Nigerian women with complete clinical history and tumour characteristics were included and compared with a large series of BC from the UK as a control group. Immunoprofile of these tumours was characterised using a panel of 11 biomarkers of known relevance to BC. The immunoprofile and patients' outcome were compared with tumour grade-matched UK control group. Nigerian women presenting with BC were more frequently premenopausal, and their tumours were characterised by large primary tumour size, high tumour grade, advanced lymph node stage, and a higher rate of vascular invasion compared with UK women. In the grade-matched groups, Nigerian BC showed over representation of triple-negative and basal phenotypes and BRCA1 deficiency BC compared with UK women, but no difference was found regarding HER2 expression between the two series. Nigerian women showed significantly poorer outcome after development of BC compared with UK women. This study demonstrates that there are possible genetic and molecular differences between an indigenous Black population and a UK-based series. The basal-like, triple negative and BRCA1 dysfunction groups of tumours identified in this study may have implications in the development of screening programs and therapies for African patients and families that are likely to have a BRCA1 dysfunction, basal like and triple negative.