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Simple Summary: Risk stratification for early breast cancer (BC) is extremely relevant for tailoring clinical decisions but challenging due to the absence of comprehensive guidelines. Traditional criteria like tumor size, lymph node involvement, histological type, grade, lymphovascular invasion, and immune cell infiltration serve as significant prognostic indicators. Alongside hormone receptor, HER2, and BRCA1/2 testing, molecular subtyping through gene expression profiling offers valuable insights for personalized clinical decisions. "Omics" technologies, applicable to tissue and liquid biopsy samples, have expanded risk evaluation capabilities, with limitations due to the lack of prospective data in early BC. This research overview paper highlights the need for standardized methodologies and integrated pathological models across multiple analytical dimensions for earlu BC risk stratification. The aim is to provide a practical guide for histopathologists and molecular pathologists involved in early BC profiling. Early breast cancer (BC) is the definition applied to breast-confined tumors with or without limited involvement of locoregional lymph nodes. While risk stratification is essential for guiding clinical decisions, it can be a complex endeavor in these patients due to the absence of comprehensive guidelines. Histopathological analysis and biomarker assessment play a pivotal role in defining patient outcomes. Traditional histological criteria such as tumor size, lymph node involvement, histological type and grade, lymphovascular invasion, and immune cell infiltration are significant prognostic indicators. In addition to the hormone receptor, HER2, and—in specific scenarios—BRCA1/2 testing, molecular subtyping through gene expression profiling provides valuable insights to tailor clinical decision-making. The emergence of "omics" technologies, applicable to both tissue and liquid biopsy samples, has broadened our arsenal for evaluating the risk of early BC. However, a pressing need remains for standardized methodologies and integrated pathological models that encompass multiple analytical dimensions. In this study, we provide a detailed examination of the existing strategies for early BC risk stratification, intending to serve as a practical guide for histopathologists and molecular pathologists. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) accounts for approximately 12% to 17% of all breast cancers and has an aggressive clinical behavior. Increased tumor-infiltrating lymphocyte counts are prognostic for survival in TNBC, making this disease a potential target for cancer immunotherapy. Research on immunophenotyping of tumor-infiltrating lymphocytes is revealing molecular and structural organization in the tumor microenvironment that may predict patient prognosis. The anti-programmed death-ligand 1 (PD-L1) antibody atezolizumab plus nab-paclitaxel was the first cancer immunotherapy combination to demonstrate progression-free survival benefit and clinically meaningful overall survival benefit in the first-line treatment of metastatic TNBC (mTNBC) in patients with PD-L1-expressing tumor-infiltrating immune cells in 1% or more of the tumor area. This led to its United States and European Union approval for mTNBC and US approval of the VENTANA PD-L1 (SP142) assay as a companion diagnostic immunohistochemistry assay. Subsequently, the anti-programmed death-1 (PD-1 ) antibody pembrolizumab plus chemotherapy was approved by the US Food and Drug Administration for mTNBC based on progression-free survival benefit in patients with a combined positive score of at least 10 by its concurrently approved 22C3 companion diagnostic assay. Treatment guidelines now recommend PD-L1 testing for patients with mTNBC, and the testing landscape will likely become increasingly complex as new anti-PD-L1 and anti-PD-1 agents and diagnostics are approved for TNBC. Integrating PD-L1 testing into current diagnostic workflows for mTNBC may provide more treatment options for these patients. Therefore, it is critical for medical oncologists and pathologists to understand the available assays and their relevance to therapeutic options to develop an appropriate workflow for immunohistochemistry testing. [ABSTRACT FROM AUTHOR]

Background: We assessed health-related quality of life (symptoms of therapy/patient functioning/global health status), in APHINITY (pertuzumab/placebo, trastuzumab, and chemotherapy as adjuvant HER2-positive early breast cancer therapy).Methods: Patients received 1 year/18 cycles of pertuzumab/placebo with trastuzumab and chemotherapy and completed EORTC QLQ-C30 and BR23 questionnaires until 36 months post-randomisation/disease recurrence. Changes ≥10 points from baseline were considered clinically meaningful.Results: 87-97% of patients completed questionnaires. In the pertuzumab versus placebo arms, mean decrease in physical function scores (baseline → end of taxane) was -10.7 (95% CI -11.4, -10.0) versus -10.6 (-11.4, -9.9), mean decrease in global health status was -11.2 (-12.2, -10.2) versus -10.2 (-11.1, -9.2), and mean increase in diarrhoea scores (baseline → end of taxane) was +22.3 (21.0, 23.6) versus +9.2 (8.2, 10.2). Diarrhoea scores remained elevated versus baseline in the pertuzumab arm throughout HER2-targeted treatment (week 25: +13.2; end of treatment: +12.2). Role functioning was maintained in both arms.Conclusions: Improved invasive disease-free survival achieved by adding pertuzumab to trastuzumab and chemotherapy did not adversely affect the ability to conduct activities of daily living versus trastuzumab and chemotherapy alone. Patient-reported diarrhoea worsened during taxane therapy in both arms, persisting during HER2-targeted treatment in the pertuzumab arm. CLINICALTRIALS.GOV: NCT01358877. [ABSTRACT FROM AUTHOR]

Background: Invasive lobular breast cancer (ILC) is the second most common histological subtype of breast cancer after invasive ductal cancer (IDC). Here, we aimed at evaluating the prevalence, levels, and composition of tumor-infiltrating lymphocytes (TILs) and their association with clinico-pathological and outcome variables in ILC, and to compare them with IDC.Methods: We considered two patient series with TIL data: a multicentric retrospective series (n = 614) and the BIG 02-98 study (n = 149 ILC and 807 IDC). We compared immune subsets identified by immuno-histochemistry in the ILC (n = 159) and IDC (n = 468) patients from the Nottingham series, as well as the CIBERSORT immune profiling of the ILC (n = 98) and IDC (n = 388) METABRIC and The Cancer Genome Atlas patients. All ILC/IDC comparisons were done in estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative tumors. All statistical tests were two-sided.Results: TIL levels were statistically significantly lower in ILC compared with IDC (fold-change = 0.79, 95% confidence interval = 0.70 to 0.88, P < .001). In ILC, high TIL levels were associated with young age, lymph node involvement, and high proliferative tumors. In the univariate analysis, high TIL levels were associated with worse prognosis in the retrospective and BIG 02-98 lobular series, although they did not reach statistical significance in the latter. The Nottingham series revealed that the levels of intratumoral but not total CD8+ were statistically significantly lower in ILC compared with IDC. Comparison of the CIBERSORT profiles highlighted statistically significant differences in terms of immune composition.Conclusions: This study shows differences between the immune infiltrates of ER-positive/HER2-negative ILC and IDC in terms of prevalence, levels, localization, composition, and clinical associations. [ABSTRACT FROM AUTHOR]

Background. Biomarkers are crucial for decisions regarding adjuvant therapy in primary breast cancer, and their correct assessment is therefore of the utmost importance. Aims. To investigate the concordance between Swedish pathology departments and a reference laboratory, for routine analysis of oestrogen receptor (ER), progesterone receptor (PR), Ki67, and human epidermal growth factor receptor 2 (HER2), alone, and in combination (St Gallen subtypes). Methods. This survey included 27 of the 28 pathology laboratories in Sweden, covering 98% of cases of primary breast cancer surgery in Sweden. Paraffin-embedded tumour blocks (n = 270) were collected and sent to the central reference laboratory, together with the originally stained slides, for re-analysis. The primary evaluations were previously performed according to national Swedish guidelines, without any knowledge of the subsequent central assessment. Results. The agreement for ER, PR, and Ki67 was 99% [kappa value (κ) = 0.95], 95% (κ = 0.85), and 85% (κ = 0.70), respectively. The agreement for HER2 (0/1 + vs. 2+/3+) was 85% (κ = 0.64), but when equivocal tumours were further analysed with in situ hybridisation, only one discrepancy was observed. Discrepancies between results for ER and PR seem to be explained by analytical differences, whereas the interpretation of staining seems to be more critical for Ki67 and HER2 immunohistochemistry. The agreement between the results from the Swedish laboratories and the reference laboratory, based on the St Gallen subtypes, was 88% (κ = 0.81). Conclusions. When applying national guidelines, highly reproducible results were obtained in routine assessment of breast cancer biomarkers, and the results of this study confirm the clinical utility of these markers for decisions regarding the treatment of primary breast cancer. [ABSTRACT FROM AUTHOR]

Rational We retrospectively analyzed 232 patients affected by well differentiated ductal intraepithelial neoplasia (DIN1c or DCIS G1) treated with conservative surgery without adjuvant radiotherapy. Results 25 invasive and 18 non-invasive local recurrences were observed (median follow-up 80 months; 5-year cumulative incidence: 12.2%). Seven of the 15 young patients (<40 y) developed local recurrence (2 in situ, 5 invasive). Age <50 (HR 1.89, 95% C.I. 1.01–3.45), multifocality (HR 3.21, 95% C.I. 1.46–7.06), Ki-67 > 7% (HR 2.33, 95% C.I. 1.20–4.55) and surgical margins <10 mm (HR 2.00, 95% C.I. 1.06–3.76) were significantly associated with an increased risk of local recurrence. Conclusions Young age, multifocality and small margins appeared as clear risk factors of local recurrence in DIN1c (DCIS G1) population. The presence of multiple poor prognostic features warrant a thorough discussion regarding local treatment. [ABSTRACT FROM AUTHOR]

BACKGROUND: The primary objectives of this study on carcinomas with equivocal HER2 expression were to assess the impact of distinct recommendations with regard to identifying patients eligible for anti-HER2 agents by fluorescence in situ hybridization (FISH) and to elucidate whether multiplex ligation-dependent probe amplification (MLPA) may be of support in assessing HER2 gene status. METHODS: A cohort of 957 immunohistochemistry-evaluated HER2-equivocal cases was analyzed by dual-color FISH. The results were assessed according to U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines and American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) 2007 and 2013 guidelines for dual- and single-signal in situ hybridization (ISH) assays. A subgroup of 112 cases was subjected to MLPA. RESULTS: HER2 amplification varied from 15% (ASCO/CAP 2007 HER2/CEP17 ratio) to 29.5% (FDA/EMA HER2 copy number). According to the ASCO/CAP 2013 interpretation of the dual-signal HER2 assay, ISH-positive carcinomas accounted for 19.7%. In contrast with the ASCO/CAP 2007 ratio, this approach labeled as positive all 32 cases (3.34%) with a HER2/CEP17 ratio <2 and an average HER2 copy number ≥6.0 signals per cell. In contrast, only one case showing a HER2 copy number <4 but a ratio ≥2 was diagnosed as positive. MLPA data correlated poorly with FISH results because of the presence of heterogeneous HER2 amplification in 33.9% of all amplified carcinomas; however, MLPA ruled out HER2 amplification in 75% of ISH-evaluated HER2-equivocal carcinomas. CONCLUSION: The ASCO/CAP 2013 guidelines seem to improve the identification of HER2-positive carcinomas. Polymerase chain reaction-based methods such as MLPA can be of help, provided that heterogeneous amplification has been ruled out by ISH. [ABSTRACT FROM AUTHOR]

Background. Breast cancer during pregnancy (BCP) is relatively rare and is associated with controversies about its biology and prognosis. Hence, we designed a case-control study to examine tumor features and outcome in a series of BCP patients diagnosed and treated in a single institution. Material and methods. We identified 65 patients diagnosed with BCP and for each; we selected two non-pregnant breast cancer patients, who were matched for age, year of surgery, stage, and neoadjuvant chemotherapy. We then compared the differences in pathology, immunohistochemical features (ER, PR, HER2 and ki-67), disease-free (DFS) and overall survival (OS). Results. We did not find any significant differences in tumor characteristics between the two groups. However, at a median follow-up of four years, BCP patients had an inferior DFS (HR 2.3; 95% CI 1.3-4.2), after adjustment for possible confounding covariates. No difference in OS was observed. However, upon restricting the analysis to patients who did not receive neoadjuvant chemotherapy, patients with BCP had inferior OS as well (HR 2.6; 95% CI 1.0-6.5). No association between induction of abortion and prognosis was observed. Conclusions. While we did not observe any differences in tumor features, BCP patients have poorer prognosis compared to age and stage-matched control. Further studies should try to elucidate reasons for such poor outcome. [ABSTRACT FROM AUTHOR]

Introduction. In recent decades, a steady improvement in imaging diagnostics has been observed together with a rising adherence to regular clinical breast examinations. As a result, the detection of small clinically occult (nonpalpable) lesions has progressively increased. At present in our institution some 20% of the cases are treated when nonpalpable. The aim of the present study is to analyze the characteristics and prognosis of such tumors treated in a single institution. Methods. The analysis focused on 1,258 women who presented at the European Institute of Oncology with a primary clinically occult carcinoma between 2000 and 2006. All patients underwent radioguided occult lesion localization (ROLL), axillary dissection when appropriate, whole breast radiotherapy, or partial breast intraoperative irradiation and received tailored adjuvant systemic treatment. Results. Median age was 56 years. Imaging showed a breast nodule in half of the cases and a breast nodule accompanied by microcalcifications in 9%. Microcalcifications alone were present in 17.1% of the cases, whereas suspicious opacity, distortion, or thickening represented the remaining 24.6%. Most tumors were characterized by low proliferative rates (68.9%), positive estrogen receptors (92.3%), and non-overexpressed Her2/neu (91.3%). After a median follow-up of 60 months, we observed 19 local events (1.5%), 12 regional events (1%), and 20 distant metastases (1.6%). Five-year overall survival was 98.6%. Conclusions. Clinically occult (nonpalpable) carcinomas show very favorable prognostic features and high survival rates, showing the important role of modern imaging techniques. [ABSTRACT FROM AUTHOR]

Discordance in estrogen receptor and human epidermal growth factor receptor 2 receptor status between the primary tumor and recurrence is frequently reported in the literature. This is frequently interpreted as evidence for a change in the biology of breast cancer during the course of the disease. This commentary discusses some of the caveats of this interpretation. Discordant receptor results can be caused by any of 3 factors: (a) a genuine switch in the biology of the disease, (b) sampling error in focally receptor-positive cancers, and (c) limited accuracy and reproducibility of receptor assays. The relative contribution of each of these factors to discordant results is unknown. A switch in molecular class between primary and recurrent cancer (or residual cancer after therapy) appears to be a rare event based on the available limited molecular profiling data. Small pockets of strongly focally receptor-positive tumor nests in a larger receptor-negative cancer are also relatively infrequently seen. Discordance resulting from inherent limitations in assay reproducibility is evident from the frequently discordant receptor results even when the same samples are assessed in different laboratories (e.g., central versus local laboratory). A repeat tumor biopsy is clearly justified when it is suspected, on clinical grounds, that the original receptor results may have been false negative or when the diagnosis of metastatic disease is in question. However, routine repeat biopsy for receptor re-evaluation does not necessarily improve diagnostic accuracy and have a potential to harm through a false-negative result. For patients with clinical courses consistent with hormone responsiveness, or with prior positive hormone receptor results, a course of endocrine therapy is reasonable regardless of the most recent hormone receptor assay result. [ABSTRACT FROM AUTHOR]

Abstract: Breast lesions defined C3 at ultrasound (US)-guided fine needle aspiration cytology (FNAC) are probably benign, but exhibit atypias. We evaluate the results of US-guided vacuum assisted breast biopsy (VABB) of these lesions. Patients diagnosed C3 by US-FNAC, submitted to US-VABB and with a minimum follow-up of 36months or surgery were enrolled. Cost outcome of this diagnostic protocol was evaluated. We evaluated 138 patients with non-palpable C3 lesions. In 2/138 (1.4%) cases VABB results were inadequate. VABB diagnosed: 17/138 (12.3%) malignant and 119/138 (86.2%) benign lesions. In 28/138 cases (20.3%) surgery retrieved 18/28 (64.3%) malignant lesions. One false negative result of VABB was observed. Sensitivity and specificity of VABB resulted 94.4% and 100%. Our diagnostic algorithm estimated a 45% mean decrease of costs using VABB when compared with surgical biopsy of all C3 lesions. [Copyright &y& Elsevier]

Summary: Mammoscintigraphy (MMS) has been indicated as a useful tool in predicting response to therapy in cancer. However, contrasting results have been reported in the literature for breast cancer patients. The aim of this study was to explore the role of MMS in locally advanced breast cancer (LABC) patients. Fifty-one patients affected by LABC and scheduled for neoadjuvant therapy were enrolled. Breast tumor status was evaluated at baseline, during therapy and at the completion of therapy by radiological techniques and by MMS. Pre-therapy (MMS1) and post-therapy MIBI (2-methoxyisobutilysonitrile) images (MMS2–3) were analyzed. MMS1 was performed in all pts, 41 carried out MMS2 and 27 had MMS3. Tumor uptake and washout in MMS1 did not show any correlation with the therapy response. The absence of any association between tumor uptake and washout with respect to therapy response suggests that MMS is not a reliable technique to predict therapy response in LABC. [Copyright &y& Elsevier]

Several controversial aspects of sentinel lymph node biopsy (SLNB) for patients with early-stage, node-negative breast carcinoma have been dealt with and resolved in the past decade since its introduction. Unfortunately, however, there is still no consensus on how best to examine sentinel lymph nodes (SLN) histologically. As a consequence, the protocols for SLN examination are remarkably variable in different institutions, leading to a very poor reproducibility of the data stemming from investigations on series of patients whose SLNs have been evaluated according to diverse protocols. Patient outcomes, however, can be optimised only by standardization of the whole procedure of SLNB, with particular reference to the histopathologic scrutiny. Lack of a standardized histopathologic protocol likely derives also from the uncertainties about the clinical implications of minimal lymph node involvement (isolated tumour cells and micrometastases) with regard both to the risk of additional metastases to non-sentinel lymph nodes of the same basin and to the prognostic value for patients' survival. This review aims at highlighting some of the controversial issues of the histopathologic examination of the SLNs, including the number of sections and cutting intervals, the use of immunohistochemistry and the role of molecular biology assays. [ABSTRACT FROM AUTHOR]

Simple Summary: Four biomarkers [estrogen receptor (ER), progesterone receptor (PgR), Ki-67, and HER2], are used to stratify breast cancer (BC) into subtypes predictive of therapy response. In a Europe-wide external quality assessment, we compared performance of an mRNA-based method [Xpert® Breast Cancer STRAT4 (CE-IVD)] for determining ESR1, PGR, ERBB2, and MKI67 expression against the gold standard [immunohistochemistry (IHC)/HER2 in situ hybridization (ISH)]. The coordinating center (CC) and five European laboratories tested ten breast cancer samples. STRAT4 binary (positive or negative) results of each marker were compared with the gold standard. ESR1 and ERBB2 mRNA results were concordant with IHC/ISH in all single analyses. In contrast, PGR and MKI67 results were discordant in a few cases, which had STRAT4 expression values close to assay cut-offs and immunohistochemically presented heterogeneous low positive PgR and heterogeneous Ki-67. STRAT4 assay may be a reproducible method. However, cases with expression values close to cut-offs should be carefully reviewed. Estrogen receptor (ER), progesterone receptor (PgR), Ki-67, and HER2 immunohistochemistry (IHC) together with HER2 in situ hybridization (ISH) are utilized to classify invasive breast cancer (IBC) into predictive molecular subtypes. As IHC evaluation may be hampered by analytical errors, gene expression assays could offer a reliable alternative. In this first Europe-wide external quality assessment (EQA) study, we investigated performance of mRNA-based Xpert® Breast Cancer STRAT4 (CE-IVD) in five European laboratories. The cohort comprised ten pre-therapy IBC core biopsies diagnosed in the coordinating center (CC). STRAT4 binary (positive or negative) mRNA results of each marker (ESR1, PGR, ERBB2, MKI67) were compared with the gold standard IHC/ISH performed by the CC. Sensitivity, specificity, and accuracy of ESR1 and ERBB2 mRNA were 100% for all samples. In contrast, PGR expression was falsely negative for one case by two sites and MKI67 falsely negative for two cases (respectively by four and one sites). These cases had STRAT4 expression values close to assay cut-offs and immunohistochemically presented heterogeneous low positive PgR and heterogeneous Ki-67. Our EQA shows that STRAT4 mRNA assay may be a reproducible method to evaluate ER, PgR, HER2, and Ki-67 status. However, cases with expression values close to assay cut-offs should be carefully reviewed. [ABSTRACT FROM AUTHOR]

BACKGROUND: Patients with ERBB2 (HER2)-positive breast cancer experience high pathologic complete response (pCR) rates after standard neoadjuvant anti-HER2 systemic therapy. We examined axillary pathologic nodal response to neoadjuvant dual HER2-targeted therapy alone, based on breast pathologic response, in a multi-institution clinical trial. STUDY DESIGN: Patients with HER2-positive breast cancer were enrolled to a phase II single-arm trial, which administered 6 cycles of neoadjuvant trastuzumab emtansine (T-DM1) plus pertuzumab. Rates of pathologic nodal disease (ypN) in patients who were clinically node-negative (cN0) and node-positive (cN1) were analyzed, by residual breast disease (pCR and residual cancer burden [RCB] I to III). RESULTS: One hundred fifty-eight patients completed preoperative treatment and proceeded to surgery. Of 92 patients who were cN0, 48 (52.2%) and 10 (10.9%) experienced breast pCR and RCB I, respectively. Of these, 100% were ypN0. Of 34 with RCB II to III, 26 (76.5%) were ypN0. Of 30 patients who were cN1 with breast pCR, 100% were ypN0; of the 12 patients who were cN1 with RCB I, 66.7% were ypN0; and of the 24 patients who were cN1 with RCB II to III, 25% were ypN0. ypN0 rates were significantly different between patients who did and did not experience a pCR, in both cN0 (p = 0.002) and cN1 (p < 0.001) subgroups. CONCLUSIONS: Patients with HER2-positive breast cancer treated with dual HER2-targeted therapy who experienced a breast pCR or RCB I response were frequently ypN0. These findings support future trials considering omission of axillary surgical staging for patients with HER2- positive breast cancer in neoadjuvant trials of active HER2-targeted regimens, particularly if they experience breast pCR or RCB I. (J Am Coll Surg 2024;238:303-311. © 2023 by the American College of Surgeons. [ABSTRACT FROM AUTHOR]

Background: Single nucleotide polymorphisms (SNPs) in the estrogen receptor 1 (ESR1) and cytochrome P450 19A1 (CYP19A1) genes have been associated with breast cancer risk, endocrine therapy response and side effects, mainly in postmenopausal women with early breast cancer. This analysis aimed to assess the association of selected germline CYP19A1 and ESR1 SNPs with early-onset hot flashes, sweating and musculoskeletal symptoms in premenopausal patients enrolled in the Tamoxifen and Exemestane Trial (TEXT).Methods: Blood was collected from consenting premenopausal women with hormone-responsive early breast cancer, randomly assigned to 5-years of tamoxifen plus ovarian suppression (OFS) or exemestane plus OFS. DNA was extracted with QIAamp kits and genotyped for two CYP19A1 (rs4646 and rs10046) and three ESR1 (rs2077647, rs2234693 and rs9340799) SNPs by a real-time pyrosequencing technique. Adverse events (AEs) were recorded at baseline and 3-monthly during the first year. Associations of the genotype variants with grade ≥2 early-onset targeted AEs of hot flashes/sweating or musculoskeletal events were assessed using logistic regression models.Results: There were 2660 premenopausal patients with breast cancer in the intention-to-treat population of TEXT, and 1967 (74 %) are included in this translational study. The CYP19A1 rs10046 variant T/T, represented in 23 % of women, was associated with a reduced incidence of grade ≥2 hot flashes/sweating (univariate odds ratio (OR) = 0.78; 95 % CI 0.63-0.97; P = 0.03), more strongly in patients assigned exemestane + OFS (TT vs CT/CC: OR = 0.65, 95 % CI = 0.48-0.89) than assigned tamoxifen + OFS (OR = 0.94, 95 % CI = 0.69-1.27, interaction P = 0.03). No association with any of the CYP19A1/ESR1 genotypes and musculoskeletal AEs was found.Conclusion: The CYP19A1 rs10046 variant T/T favors lower incidence of hot flashes/sweating under exemestane + OFS treatment, suggesting endocrine-mediated effects. Based on findings from others, this SNP may potentially enhance treatment adherence and treatment efficacy. We plan to evaluate the clinical impact of this polymorphism during time, pending sufficient median follow up.Trial Registration: ClinicalTrials.gov NCT00066703, registered August 6, 2003. [ABSTRACT FROM AUTHOR]

Background: We previously reported the 5-year results of the phase 3 IBCSG 23-01 trial comparing disease-free survival in patients with breast cancer with one or more micrometastatic (≤2 mm) sentinel nodes randomly assigned to either axillary dissection or no axillary dissection. The results showed no difference in disease-free survival between the groups and showed non-inferiority of no axillary dissection relative to axillary dissection. The current analysis presents the results of the study after a median follow-up of 9·7 years (IQR 7·8-12·7).Methods: In this multicentre, randomised, controlled, open-label, non-inferiority, phase 3 trial, participants were recruited from 27 hospitals and cancer centres in nine countries. Eligible women could be of any age with clinical, mammographic, ultrasonographic, or pathological diagnosis of breast cancer with largest lesion diameter of 5 cm or smaller, and one or more metastatic sentinel nodes, all of which were 2 mm or smaller and with no extracapsular extension. Patients were randomly assigned (1:1) before surgery (mastectomy or breast-conserving surgery) to no axillary dissection or axillary dissection using permuted blocks generated by a web-based congruence algorithm, with stratification by centre and menopausal status. The protocol-specified primary endpoint was disease-free survival, analysed in the intention-to-treat population (as randomly assigned). Safety was assessed in all randomly assigned patients who received their allocated treatment (as treated). We did a one-sided test for non-inferiority of no axillary dissection by comparing the observed hazard ratios (HRs) for disease-free survival with a margin of 1·25. This 10-year follow-up analysis was not prespecified in the trial's protocol and thus was not adjusted for multiple, sequential testing. This trial is registered with ClinicalTrials.gov, number NCT00072293.Findings: Between April 1, 2001, and Feb 8, 2010, 6681 patients were screened and 934 randomly assigned to no axillary dissection (n=469) or axillary dissection (n=465). Three patients were ineligible and were excluded from the trial after randomisation. Disease-free survival at 10 years was 76·8% (95% CI 72·5-81·0) in the no axillary dissection group, compared with 74·9% (70·5-79·3) in the axillary dissection group (HR 0·85, 95% CI 0·65-1·11; log-rank p=0·24; p=0·0024 for non-inferiority). Long-term surgical complications included lymphoedema of any grade in 16 (4%) of 453 patients in the no axillary dissection group and 60 (13%) of 447 in the axillary dissection group, sensory neuropathy of any grade in 57 (13%) in the no axillary dissection group versus 85 (19%) in the axillary dissection group, and motor neuropathy of any grade (14 [3%] in the no axillary dissection group vs 40 [9%] in the axillary dissection group). One serious adverse event (postoperative infection and inflamed axilla requiring hospital admission) was attributed to axillary dissection; the event resolved without sequelae.Interpretation: The findings of the IBCSG 23-01 trial after a median follow-up of 9·7 years (IQR 7·8-12·7) corroborate those obtained at 5 years and are consistent with those of the 10-year follow-up analysis of the Z0011 trial. Together, these findings support the current practice of not doing an axillary dissection when the tumour burden in the sentinel nodes is minimal or moderate in patients with early breast cancer.Funding: International Breast Cancer Study Group. [ABSTRACT FROM AUTHOR]

The article discusses case study of a 53-year-old woman with metastatic serous carcinoma of the ovary in an intraparenchimal breast lymph-node that on radiologic examination was interpreted as primary mammary carcinoma. Histological examination revealed a lymph node parenchyma with a thin capsule and follicular arrangements typical of germinal center. Treatment provided to this patient is also included.

The article presents a case study of a 66-year-old woman who was presented with a little carcinoma in her left breast. The patients underwent a surgical lumpectomy with sentinel lymph-adenectomy, and was diagnosed with an infiltrating duct carcinoma. The article discusses the presence of salivary gland choristoma of the breast.

Summary: The primary tumour of patients with early breast cancer is the main source of information to assess the risk of disease recurrence and to inform the choice of the most appropriate systemic treatment. Accordingly, it is the main responsibility of the pathologists to ensure the patients and treating physicians that all the relevant information is derived from the primary tumour with the highest accuracy and reproducibility. The morphological changes of the tumour cells reflect the aggregate effects of changes occurring in hundreds of genes and may be a very faithful mirror of the biological and clinical behaviour of breast cancer. According to the 2009 St. Gallen Consensus, the systemic therapy of early breast cancer is mainly informed by the expression of hormone receptors and by the HER2 status, and the assessment of Ki67 has been included among the useful parameters to inform the choice of adding chemotherapy to endocrine therapies for patients with ER-positive and HER2-negative disease. A comprehensive approach that includes the accurate evaluation of the morphological features of the tumour, with special reference to the histological type and grade, and the assessment of the main prognostic and predictive parameters (ER, PgR, HER2 and Ki67) should offer to the patients and the treating physicians a robust background upon which the final therapeutic decisions can be safely taken. [Copyright &y& Elsevier]

The promising effect of antibody–drug conjugates on breast cancer with low expression of HER2 (HER2-low) raises many questions regarding the optimal selection of patients for this treatment. A key question is whether HER2 immunohistochemistry, an assay optimised to detect HER2 amplification, is reliable enough to assess HER2 protein levels to select patients with HER2-low breast cancer in daily pathology practices worldwide. Moreover, whether this assessment can be performed with sufficient reproducibility between pathologists in daily practices is debatable. Herein, we address the historical track record of the CAP-ASCO HER2 Guidelines, the reported limited reproducibility by pathologists of HER2 immunohistochemistry in the non-amplified cases, and the performance variation of different antibodies. Based on this summary, we propose solutions to improve the robustness to enable reliable identification of patients with HER2-low breast cancer. • The definitions of HER2 0 and 1+ by IHC need to be redefined by the ASCO/CAP. • HER2 IHC assays are not calibrated to detect low-levels of HER2. • Other issues include reproducibility, different HER2-assay performance, etc. • The errors of the PDL1-saga are currently being repeated in the HER2-low narrative. • Solutions are proposed to industry, regulators, and academia (Table 1). [ABSTRACT FROM AUTHOR]

Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer with highly variable clinical behavior, but risk stratification is still challenging. We sought to identify immune-related gene expression signatures of pure DCIS associated with different risks of breast cancer recurrence. A retrospective nested case-control study of 143 pure DCIS was performed including 70 women with subsequent ipsilateral breast event (IBE, in situ or invasive; cases) and 73 DCIS women with no IBE and matched for age, tumor size, treatment, hormone receptors/HER2 status, and follow-up time (controls). RNA was extracted from DCIS samples and subjected to next-generation sequencing gene expression analysis of 395 immune-related genes. Correlations between DCIS immune-related gene expression and IBE were analyzed using weighted Cox regression for nested case-control data. Eight immune-related genes were differentially expressed between cases and controls. MAGEA10 expression (present vs. absent) and high expression levels of IFNA17 and CBLB (Q4 vs. Q1) were observed more frequently in DCIS of women with subsequent IBE, mainly invasive (p-value FDR < 0.05). Conversely, expression of IL3RA1 , TAGAP, TNFAIP8 , and high expression levels of CCL2 and LRP1 were associated with a lower risk of IBE (p-value FDR < 0.05). This exploratory analysis of pure DCIS showed significant differences in immune-related gene expression profiles between women with and with no subsequent IBE, particularly as invasive IBE. These results, after additional validation, could improve risk stratification and management of DCIS patients. • Risk stratification is fundamental for the clinical management of women with DCIS. • DCIS shows differences in the expression of immune-related genes. • Immune-related genes are associated with different recurrence risks in DCIS. • Immune gene expression analysis may improve risk stratification in women with DCIS. [ABSTRACT FROM AUTHOR]

Molecular tests predicting the risk of distant recurrence (DR) can be used to assist therapy decision-making in oestrogen receptor–positive (ER+) and human epidermal growth factor receptor 2–negative (HER2-) breast cancer patients after considerations of standard clinical markers. The Oncotype DX Recurrence Score (RS) is a widespread tool used for this purpose. Here, we compared the RS with the StemPrintER Risk Score (SPRS), a novel genomic predictor with a unique biological basis in its ability to measure the expression of cancer stemness genes. We benchmarked the SPRS vs. RS, alone or in combination with clinicopathological variables expressed by the Clinical Treatment Score (CTS), for the prognostication of DR in a retrospective cohort of 776 postmenopausal patients with ER+/HER2-breast cancer enrolled in the translational arm of the randomised Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial. Likelihood ratio (LR) with χ2 test and C-index were used to assess prognostic performance for the entire ten-year follow-up period and in early (0–5 years) and late (5–10 years) intervals. In all patients, the SPRS provided significantly more prognostic information than the RS for ten-year DR prognostication (C-index = 0.688, LR-χ2 = 33.4 vs. C-index = 0.641, LR-χ2 = 22.1) and for late (5–10 years) DR prognostication (C-index = 0.689, LR-χ2 = 18.8 vs. C-index = 0.571, LR-χ2 = 4.7). The SPRS also provided more prognostic information than the RS when added to the CTS in all patients (CTS + SPRS: LR-Δχ2 = 14.9; CTS + RS: LR-Δχ2 = 9.7) and in node-negative patients (CTS + SPRS: LR-Δχ2 = 11.7; CTS + RS: LR-Δχ2 = 6.6). In postmenopausal ER+/HER2- breast cancer patients, SPRS provided more prognostic information than RS for DR when used alone or in combination with the CTS. The SPRS could therefore potentially identify high-risk patients, who might benefit from aggressive treatments, from low-risk patients who might safely avoid adjuvant chemotherapy or prolongation of endocrine therapy. • The StemPrintER Risk Score (SPRS) is a stem cell–based prognostic test for breast cancer. • The SPRS was validated in ER+/HER2-postmenopausal women from the TransATAC cohort. • The SPRS was highly prognostic for early (0–5 yr) and late (5–10 yr) distant recurrence. • The SPRS was benchmarked against the Oncotype DX Breast Cancer Recurrence Score (RS). • The SPRS has the potential to help guide clinical decision-making in breast cancer. [ABSTRACT FROM AUTHOR]

Low human epidermal growth factor receptor 2 (HER2) expression is emerging as an actionable biomarker for the treatment of breast cancer (BC) with novel anti-HER2 drugs. However, the evolution of this biomarker during the course of disease is still poorly characterised, and controversial data exist on its prognostic implications. We reviewed data of patients with HER2-negative BC according to the latest ASCO/CAP guidelines referred between January 2014 and December 2020. We grouped patients based on the immunohistochemistry (IHC) expression of HER2, HER2-zero (IHC 0) and HER2-low subgroup (IHC 1+ or 2+/ISH-negative) and evaluated the evolution of HER2 expression between the primary tumour and the first biopsy collected in the advanced setting. Disease-free survival, overall survival and progression-free survival were compared between patients with HER2-zero and HER2-low expression on the primary tumour. 232 patients were included in the analysis. Among the overall population, there was a relevant discordance in HER2 expression between the primary tumour and the matched biopsy (K = 0.33, 95%CI 0.21–0.44): 44% of the HER2-zero primary tumour showed an increased HER2 score on biopsy, and 22% of the HER2-low primary tumours turned into HER2-IHC 0. The findings in the sub-populations of hormone-receptors positive (K = 0.32, 95%CI 0.19–0.45) and triple-negative tumours (K = 0.18, 95%CI -0.09-0.46) were consistent with the primary analysis. No difference in survival outcomes was observed between HER2-low and HER2-zero primary tumours. HER2-low expression is dynamic in BC and may be enriched in the advanced-stage setting. No prognostic significance was demonstrated for HER2-low expression. • HER2-low expression is emerging as an actionable biomarker in breast cancer. • HER2 IHC score increased from primary to metastatic tumour in 44% of the patients. • HER2-low to HER2-zero evolution was observed in 22% of the patients. • HER2-low expression is dynamic and may be enriched in the advanced-stage setting. [ABSTRACT FROM AUTHOR]

Background: In the randomised, phase 3 equivalence trial on electron intraoperative radiotherapy (ELIOT), accelerated partial breast irradiation (APBI) with the use of intraoperative radiotherapy was associated with a higher rate of ipsilateral breast tumour recurrence (IBTR) than whole-breast irradiation (WBI) in patients with early-stage breast cancer. Here, we aimed to examine the planned long-term recurrence and survival outcomes from the ELIOT trial.Methods: This single-centre, randomised, phase 3 equivalence trial was done at the European Institute of Oncology (Milan, Italy). Eligible women, aged 48-75 years with a clinical diagnosis of a unicentric breast carcinoma with an ultrasound diameter not exceeding 25 mm, clinically negative axillary lymph nodes, and who were suitable for breast-conserving surgery, were randomly assigned (1:1) via a web-based system, with a random permuted block design (block size of 16) and stratified by clinical tumour size, to receive post-operative WBI with conventional fractionation (50 Gy given as 25 fractions of 2 Gy, plus a 10 Gy boost), or 21 Gy intraoperative radiotherapy with electrons (ELIOT) in a single dose to the tumour bed during surgery. The trial was open label and no-one was masked to treatment group assignment. The primary endpoint was the occurrence of IBTR. The trial was designed assuming a 5-year IBTR rate of 3% in the WBI group and equivalence of the two groups, if the 5-year IBTR rate in the ELIOT group did not exceed a 2·5 times excess, corresponding to 7·5%. Overall survival was the secondary endpoint. The main analysis was done by intention to treat. The cumulative incidence of IBTR events and overall survival were assessed at 5, 10, and 15 years of follow-up. This trial is registered with ClinicalTrials.gov, NCT01849133.Findings: Between Nov 20, 2000, and Dec 27, 2007, 1305 women were enrolled and randomly assigned: 654 to the WBI group and 651 to the ELIOT group. After a median follow-up of 12·4 years (IQR 9·7-14·7), 86 (7%) patients developed IBTR, with 70 (11%) cases in the ELIOT group and 16 (2%) in the WBI group, corresponding to an absolute excess of 54 IBTRs in the ELIOT group (HR 4·62, 95% CI 2·68-7·95, p<0·0001). In the ELIOT group, the 5-year IBTR rate was 4·2% (95% CI 2·8-5·9), the 10-year rate was 8·1% (6·1-10·3), and the 15-year rate was 12·6% (9·8-15·9). In the WBI group, the 5-year IBTR rate was 0·5% (95% CI 0·1-1·3), the 10-year rate was 1·1% (0·5-2·2), and the 15-year rate was 2·4% (1·4-4·0). At final follow-up on March 11, 2019, 193 (15%) women had died from any cause, with no difference between the two groups (98 deaths in the ELIOT group vs 95 in the WBI group; HR 1·03, 95% CI 0·77-1·36, p=0·85). In the ELIOT group, the overall survival rate was 96·8% (95% CI 95·1-97·9) at 5 years, 90·7% (88·2-92·7) at 10 years, and 83·4% (79·7-86·4) at 15 years; and in the WBI group, the overall survival rate was 96·8% (95·1-97·9) at 5 years, 92·7% (90·4-94·4) at 10 years, and 82·4% (78·5-85·6) at 15 years. We did not collect long-term data on adverse events.Interpretation: The long-term results of this trial confirmed the higher rate of IBTR in the ELIOT group than in the WBI group, without any differences in overall survival. ELIOT should be offered to selected patients at low-risk of IBTR.Funding: Italian Association for Cancer Research, Jacqueline Seroussi Memorial Foundation for Cancer Research, Umberto Veronesi Foundation, American Italian Cancer Foundation, The Lombardy Region, and Italian Ministry of Health. [ABSTRACT FROM AUTHOR]

Background: The MINDACT trial showed excellent 5-year distant metastasis-free survival of 94·7% (95% CI 92·5-96·2) in patients with breast cancer of high clinical and low genomic risk who did not receive chemotherapy. We present long-term follow-up results together with an exploratory analysis by age.Methods: MINDACT was a multicentre, randomised, phase 3 trial done in 112 academic and community hospitals in nine European countries. Patients aged 18-70 years, with histologically confirmed primary invasive breast cancer (stage T1, T2, or operable T3) with up to three positive lymph nodes, no distant metastases, and a WHO performance status of 0-1 were enrolled and their genomic risk (using the MammaPrint 70-gene signature) and clinical risk (using a modified version of Adjuvant! Online) were determined. Patients with low clinical and low genomic risk results did not receive chemotherapy, and patients with high clinical and high genomic risk did receive chemotherapy (mostly anthracycline-based or taxane-based, or a combination thereof). Patients with discordant risk results (ie, patients with high clinical risk but low genomic risk, and those with low clinical risk but high genomic risk) were randomly assigned (1:1) to receive chemotherapy or not based on either the clinical risk or the genomic risk. Randomisation was done centrally and used a minimisation technique that was stratified by institution, risk group, and clinical-pathological characteristics. Treatment allocation was not masked. The primary endpoint was to test whether the distant metastasis-free survival rate at 5 years in patients with high clinical risk and low genomic risk not receiving chemotherapy had a lower boundary of the 95% CI above the predefined non-inferiority boundary of 92%. In the primary test population of patients with high clinical risk and low genomic risk who adhered to the treatment allocation of no chemotherapy and had no change in risk post-enrolment. Here, we present updated follow-up as well as an exploratory analysis of a potential age effect (≤50 years vs >50 years) and an analysis by nodal status for patients with hormone receptor-positive and HER2-negative disease. These analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT00433589, and the European Clinical Trials database, EudraCT2005-002625-31. Recruitment is complete and further long-term follow-up is ongoing.Findings: Between Feb 8, 2007, and July 11, 2011, 6693 patients were enrolled. On Feb 26, 2020, median follow-up was 8·7 years (IQR 7·8-9·7). The updated 5-year distant metastasis-free survival rate for patients with high clinical risk and low genomic risk receiving no chemotherapy (primary test population, n=644) was 95·1% (95% CI 93·1-96·6), which is above the predefined non-inferiority boundary of 92%, supporting the previous analysis and proving MINDACT as a positive de-escalation trial. Patients with high clinical risk and low genomic risk were randomly assigned to receive chemotherapy (n=749) or not (n=748); this was the intention-to-treat population. The 8-year estimates for distant metastasis-free survival in the intention-to-treat population were 92·0% (95% CI 89·6-93·8) for chemotherapy versus 89·4% (86·8-91·5) for no chemotherapy (hazard ratio 0·66; 95% CI 0·48-0·92). An exploratory analysis confined to the subset of patients with hormone receptor-positive, HER2-negative disease (1358 [90.7%] of 1497 randomly assigned patients, of whom 676 received chemotherapy and 682 did not) shows different effects of chemotherapy administration on 8-year distant metastasis-free survival according to age: 93·6% (95% CI 89·3-96·3) with chemotherapy versus 88·6% (83·5-92·3) without chemotherapy in 464 women aged 50 years or younger (absolute difference 5·0 percentage points [SE 2·8, 95% CI -0·5 to 10·4]) and 90·2% (86·8-92·7) versus 90·0% (86·6-92·6) in 894 women older than 50 years (absolute difference 0·2 percentage points [2·1, -4·0 to 4·4]). The 8-year distant metastasis-free survival in the exploratory analysis by nodal status in these patients was 91·7% (95% CI 88·1-94·3) with chemotherapy and 89·2% (85·2-92·2) without chemotherapy in 699 node-negative patients (absolute difference 2·5 percentage points [SE 2·3, 95% CI -2·1 to 7·2]) and 91·2% (87·2-94·0) versus 89·9% (85·8-92·8) for 658 patients with one to three positive nodes (absolute difference 1·3 percentage points [2·4, -3·5 to 6·1]).Interpretation: With a more mature follow-up approaching 9 years, the 70-gene signature shows an intact ability of identifying among women with high clinical risk, a subgroup, namely patients with a low genomic risk, with an excellent distant metastasis-free survival when treated with endocrine therapy alone. For these women the magnitude of the benefit from adding chemotherapy to endocrine therapy remains small (2·6 percentage points) and is not enhanced by nodal positivity. However, in an underpowered exploratory analysis this benefit appears to be age-dependent, as it is only seen in women younger than 50 years where it reaches a clinically relevant threshold of 5 percentage points. Although, possibly due to chemotherapy-induced ovarian function suppression, it should be part of informed, shared decision making. Further study is needed in younger women, who might need reinforced endocrine therapy to forego chemotherapy.Funding: European Commission Sixth Framework Programme. [ABSTRACT FROM AUTHOR]

* 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 cancer guideline. Methods.--Based on the signals approach, an Expert Panel reviewed published literature and research survey results on the observed frequency of less common in situ hybridization (ISH) patterns to update the recommendations. Recommendations.--Two recommendations addressed via correspondence in 2015 are included. First, immunohistochemistry (IHC) 2+ is defined as invasive breast cancer with weak to moderate complete membrane staining observed in .10% of tumor cells. Second, if the initial HER2 test result in a core needle biopsy specimen of a primary breast cancer is negative, a new HER2 test may (not "must") be ordered on the excision specimen based on specific clinical criteria. The HER2 testing algorithm for breast cancer is updated to address the recommended workup for less common clinical scenarios (approximately 5% of cases) observed when using a dual-probe ISH assay. These scenarios are described as ISH group 2 (HER2/chromosome enumeration probe 17 [CEP17] ratio ≥2.0; average HER2 copy number <4.0 signals per cell), ISH group 3 (HER2/CEP17 ratio <2.0; average HER2 copy number ≥6.0 signals per cell), and ISH group 4 (HER2/CEP17 ratio,2.0; average HER2 copy number ≥4.0 and <6.0 signals per cell). The diagnostic approach includes more rigorous interpretation criteria for ISH and requires concomitant IHC review for dual-probe ISH groups 2 to 4 to arrive at the most accurate HER2 status designation (positive or negative) based on combined interpretation of the ISH and IHC assays. The Expert Panel recommends that laboratories using single-probe ISH assays include concomitant IHC review as part of the interpretation of all single-probe ISH assay results. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the local outcome of patients after accelerated partial breast irradiation with intraoperative electrons (IORT) for invasive lobular carcinoma (ILC) compared with invasive ductal carcinoma (IDC).Methods and Materials: From 1999 to 2007, 2173 patients were treated with breast-conserving surgery and IORT (21 Gy/1 fraction) as the sole local treatment: 252 patients with ILC (11.6%) were compared with 1921 patients with IDC in terms of local control.Results: Compared with the IDC subgroup, patients with ILC had a low-risk profile and were more hormone responsive. The 5- and 10-year in-breast tumor reappearance (IBTR) rates were 5.5% and 14.4%, respectively, for the IDC group and 7.5% and 21.8%, respectively, for the ILC group (log-rank P=.03). The excess risk of IBTR associated with ILC was particularly high for small tumors (≤1 cm: hazard ratio [HR], 2.24; 95% confidence interval [CI], 1.03-4.85), elderly patients (60-69 years: HR, 2.27; 95% CI, 1.11-4.63; ≥70 years: HR, 3.28; 95% CI, 1.08-10.0), low-grade tumors (grade 1: HR, 3.50; 95% CI, 1.05-11.7), and luminal A molecular subtype (HR, 3.18; 95% CI, 1.49-6.77). Among the ILC histologic variants, no difference between classic and nonclassic subgroups was observed, although the signet ring cell and solid variants had the worst local control.Conclusions: Despite a favorable tumor profile, accelerated partial breast irradiation with IORT led to a higher incidence of IBTRs in patients with ILC compared with those with IDC. Our institutional experience emphasized the importance of the size of the irradiation field, pointing to the use of larger collimators, even when dealing with small tumors, to improve local control. [ABSTRACT FROM AUTHOR]

Background: Pertuzumab increases the rate of pathological complete response in the preoperative context and increases overall survival among patients with metastatic disease when it is added to trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. In this trial, we investigated whether pertuzumab, when added to adjuvant trastuzumab and chemotherapy, improves outcomes among patients with HER2-positive early breast cancer.Methods: We randomly assigned patients with node-positive or high-risk node-negative HER2-positive, operable breast cancer to receive either pertuzumab or placebo added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab. We assumed a 3-year invasive-disease-free survival rate of 91.8% with pertuzumab and 89.2% with placebo.Results: In the trial population, 63% of the patients who were randomly assigned to receive pertuzumab (2400 patients) or placebo (2405 patients) had node-positive disease and 36% had hormone-receptor-negative disease. Disease recurrence occurred in 171 patients (7.1%) in the pertuzumab group and 210 patients (8.7%) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.66 to 1.00; P=0.045). The estimates of the 3-year rates of invasive-disease-free survival were 94.1% in the pertuzumab group and 93.2% in the placebo group. In the cohort of patients with node-positive disease, the 3-year rate of invasive-disease-free survival was 92.0% in the pertuzumab group, as compared with 90.2% in the placebo group (hazard ratio for an invasive-disease event, 0.77; 95% CI, 0.62 to 0.96; P=0.02). In the cohort of patients with node-negative disease, the 3-year rate of invasive-disease-free survival was 97.5% in the pertuzumab group and 98.4% in the placebo group (hazard ratio for an invasive-disease event, 1.13; 95% CI, 0.68 to 1.86; P=0.64). Heart failure, cardiac death, and cardiac dysfunction were infrequent in both treatment groups. Diarrhea of grade 3 or higher occurred almost exclusively during chemotherapy and was more frequent with pertuzumab than with placebo (9.8% vs. 3.7%).Conclusions: Pertuzumab significantly improved the rates of invasive-disease-free survival among patients with HER2-positive, operable breast cancer when it was added to trastuzumab and chemotherapy. Diarrhea was more common with pertuzumab than with placebo. (Funded by F. Hoffmann-La Roche/Genentech; APHINITY ClinicalTrials.gov number, NCT01358877 .). [ABSTRACT FROM AUTHOR]

Purpose. To update the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer to improve the accuracy of HER2 testing and its utility as a predictive marker in invasive breast cancer. Methods. ASCO/CAP convened an Update Committee that included coauthors of the 2007 guideline to conduct a systematic literature review and update recommendations for optimal HER2 testing. Results. The Update Committee identified criteria and areas requiring clarification to improve the accuracy of HER2 testing by immunohistochemistry (IHC) or in situ hybridization (ISH). The guideline was reviewed and approved by both organizations. Recommendations. The Update Committee recommends that HER2 status (HER2 negative or positive) be determined in all patients with invasive (early stage or recurrence) breast cancer on the basis of one or more HER2 test results (negative, equivocal, or positive). Testing criteria define HER2-positive status when (on observing within an area of tumor that amounts to >10% of contiguous and homogeneous tumor cells) there is evidence of protein overexpression (IHC) or gene amplification (HER2 copy number or HER2/CEP17 ratio by ISH based on counting at least 20 cells within the area). If results are equivocal (revised criteria), reflex testing should be performed using an alternative assay (IHC or ISH). Repeat testing should be considered if results seem discordant with other histopathologic findings. Laboratories should demonstrate high concordance with a validated HER2 test on a sufficiently large and representative set of specimens. Testing must be performed in a laboratory accredited by CAP or another accrediting entity. The Update Committee urges providers and health systems to cooperate to ensure the highest quality testing. INSET: The Bottom Line. [ABSTRACT FROM AUTHOR]

Abstract: Background: The discordance in oestrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) status between primary and recurrent breast cancer is being intensively investigated and a large amount of data have been produced. However, results from different studies are heterogeneous and often conflicting. To highlight this issue, a meta-analysis of published data was performed. Methods: A literature search was performed using Medline, and all the studies published from 1983 to 2011 comparing changes in ER, PgR and/or HER2 status in patients with matched breast primary and recurrent tumours were included. We used random-effects models to estimate pooled discordance proportions. Results: We selected 48 articles, mostly reporting retrospective studies. Thirty-three, 24 and 31 articles were focused on ER, PgR and HER2 changes, respectively. A total of 4200, 2739 and 2987 tumours were evaluated for ER, PgR and HER2 discordance, respectively. The heterogeneity between study-specific discordance proportions was high for ER (I 2 =91%, p <0.0001), PgR (I 2 =79%, p <0.0001) and HER2 (I 2 =77%, p <0.0001). Pooled discordance proportions were 20% (95% confidence interval (CI): 16–35%) for ER, 33% (95% CI: 29–38%) for PgR and 8% (95% CI: 6–10%) for HER2. Pooled proportions of tumours shifting from positive to negative and from negative to positive were 24% and 14% for ER (p =0.0183), respectively. The same figures were 46% and 15% for PgR (p <0.0001), and 13% and 5% for HER2 (p =0.0004). Conclusion: Our findings strengthen the concept that changes in receptor expression may occur during the natural history of breast cancer, suggesting clinical implications and a possible impact on treatment choice. [Copyright &y& Elsevier]

Abstract: Purpose: Complete surgical resection is the standard treatment for localized breast phyllodes tumors. Post-surgical treatments are still a matter of debate. We carried out an overview of the literature to investigate the clinical outcome of patients with phyllodes tumor. A retrospective analysis of mono-institutional series has been included as well. Methods: We reviewed all the retrospective series reported from 1951 until April 2012. We analyzed cases treated at our institution from 1999 to 2010. Results: Eighty-three articles (5530 patients; 1956 malignant tumors) were reviewed. Local recurrences were independent of histology. Distant recurrences were more frequent in the malignant tumors (22%). A total of 172 phyllodes tumors were included in the retrospective analysis. Discussion: Prognosis of phyllodes tumors is excellent. There are no convincing data to recommend any adjuvant treatment after surgery. Molecular characterization may well provide new clues to permit identification of active treatments for the rare poor prognosis cases. [Copyright &y& Elsevier]

Abstract: Background: The MINDACT (Microarray In Node-negative and 1–3 node positive Disease may Avoid ChemoTherapy) trial investigates the clinical utility of the 70-gene profile (MammaPrint) for the selection of breast cancer patients for adjuvant chemotherapy (CT) together with standard clinicopathological criteria. We present the results of the pilot phase consisting of first 800 patients included. Methods: MINDACT has enrolled 6600 patients, classified into high or low risk by MammaPrint and clinicopathological risk through Adjuvant! Online. Patients with both clinical (C) and genomic (G) high risks are offered adjuvant CT; those with both C and G low risks do not receive CT; patients with discordant risk are randomised for the decision of adjuvant CT based on C or G risk. CT randomisation of anthracycline-based versus docetaxel/capecitabine and endocrine therapy randomisation between letrozole and tamoxifen→letrozole are offered. Results: During the pilot phase 46% of screened patients were enrolled. Main reasons for non-enrolment were node positivity before trial amendment, sample quality problems and failure to meet logistic settings. Among the 800 patients, 386 (48%) were C-low/G-low, 198 (24.8%) as C-high/G-high, 75 (9.4%) as C-low/G-high and 141 (17.6%) as C-high/G-low. In total 216 (27%) cases were discordant. The difference between patients with C-high (42%) and G-high risk (34%) is 8.25% (95% confidence interval (CI), 4.7–11.8%; P <.0001). Compliance with the treatment decision was high (>92%). Conclusions: The logistically complex MINDACT trial is feasible in a multinational setting. The proportion of discordant patients, the potential reduction in CT by using the genomic signature and compliance to treatment assignment are in accordance with the trial hypotheses. [Copyright &y& Elsevier]