Routine resection of cavity shave margins (additional tissue circumferentially around the cavity left by partial mastectomy) may reduce the rates of positive margins (margins positive for tumor) and ...reexcision among patients undergoing partial mastectomy for breast cancer.
In this randomized, controlled trial, we assigned, in a 1:1 ratio, 235 patients with breast cancer of stage 0 to III who were undergoing partial mastectomy, with or without resection of selective margins, to have further cavity shave margins resected (shave group) or not to have further cavity shave margins resected (no-shave group). Randomization occurred intraoperatively after surgeons had completed standard partial mastectomy. Positive margins were defined as tumor touching the edge of the specimen that was removed in the case of invasive cancer and tumor that was within 1 mm of the edge of the specimen removed in the case of ductal carcinoma in situ. The rate of positive margins was the primary outcome measure; secondary outcome measures included cosmesis and the volume of tissue resected.
The median age of the patients was 61 years (range, 33 to 94). On final pathological testing, 54 patients (23%) had invasive cancer, 45 (19%) had ductal carcinoma in situ, and 125 (53%) had both; 11 patients had no further disease. The median size of the tumor in the greatest diameter was 1.1 cm (range, 0 to 6.5) in patients with invasive carcinoma and 1.0 cm (range, 0 to 9.3) in patients with ductal carcinoma in situ. Groups were well matched at baseline with respect to demographic and clinicopathological characteristics. The rate of positive margins after partial mastectomy (before randomization) was similar in the shave group and the no-shave group (36% and 34%, respectively; P=0.69). After randomization, patients in the shave group had a significantly lower rate of positive margins than did those in the no-shave group (19% vs. 34%, P=0.01), as well as a lower rate of second surgery for margin clearance (10% vs. 21%, P=0.02). There was no significant difference in complications between the two groups.
Cavity shaving halved the rates of positive margins and reexcision among patients with partial mastectomy. (Funded by the Yale Cancer Center; ClinicalTrials.gov number, NCT01452399.).
Morphological evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer is gaining momentum as evidence strengthens the clinical relevance of this immunological biomarker. TILs in the ...post-neoadjuvant residual disease setting are acquiring increasing importance as a stratifying marker in clinical trials, considering the raising interest on immunotherapeutic strategies after neoadjuvant chemotherapy. TILs in ductal carcinoma in situ, with or without invasive carcinoma, represent an emerging area of clinical breast cancer research. The aim of this report is to update pathologists, clinicians and researchers on TIL assessment in both the post-neoadjuvant residual disease and the ductal carcinoma in situ settings. The International Immuno-Oncology Working Group proposes a method for assessing TILs in these settings, based on the previously published International Guidelines on TIL Assessment in Breast Cancer. In this regard, these recommendations represent a consensus guidance for pathologists, aimed to achieve the highest possible consistency among future studies.
Although tumor-infiltrating lymphocytes (TIL) have been associated with response to neoadjuvant therapy, measurement typically is subjective, semiquantitative, and unable to differentiate among ...subpopulations. Here, we describe a quantitative objective method for analyzing lymphocyte subpopulations and assessing their predictive value.
We developed a quantitative immunofluorescence assay to measure stromal expression of CD3, CD8, and CD20 on one slide. We validated this assay by comparison with flow cytometry on tonsil specimens and assessed predictive value in breast cancer on a neoadjuvant cohort (n = 95). Then, each marker was tested for prediction of pathologic complete response (pCR) compared with pathologist estimation of the percentage of lymphocyte infiltrate.
The lymphocyte percentage and CD3, CD8, and CD20 proportions were similar between flow cytometry and quantitative immunofluorescence on tonsil specimens. Pathologist TIL count predicted pCR P = 0.043; OR, 4.77; 95% confidence interval (CI), 1.05-21.6 despite fair interobserver reproducibility (κ = 0.393). Stromal AQUA (automated quantitative analysis) scores for CD3 (P = 0.023; OR, 2.51; 95% CI, 1.13-5.57), CD8 (P = 0.029; OR, 2.00; 95% CI, 1.08-3.72), and CD20 (P = 0.005; OR, 1.80; 95% CI, 1.19-2.72) predicted pCR in univariate analysis. CD20 AQUA score predicted pCR (P = 0.019; OR, 5.37; 95% CI, 1.32-21.8) independently of age, size, nuclear grade, nodal status, ER, PR, HER2, and Ki-67, whereas CD3, CD8, and pathologist estimation did not.
We have developed and validated an objective, quantitative assay measuring TILs in breast cancer. Although this work provides analytic validity, future larger studies will be required to prove clinical utility.
Metaplastic breast cancer: A review Thomas, Horatio R.; Hu, Bonnie; Boyraz, Baris ...
Critical reviews in oncology/hematology,
February 2023, 2023-Feb, 2023-02-00, 20230201, Volume:
182
Journal Article
Peer reviewed
Metaplastic breast cancer (MpBC) is an uncommon aggressive malignancy that is associated with a poor prognosis. Due to its rarity, the relationships between the clinical and pathological features of ...MpBC, treatment approach, and clinical outcomes remain underexplored. In the following review article, we synthesize the existing data on the clinical, pathological and genomic features, management, and outcomes of MpBC. We also identify potential targets for future clinical trials.
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•Metaplastic Breast Cancer consists of epithelial and sarcoma-like mesenchymal cells.•It manifests as a large mass and usually metastasizes without nodal involvement.•Aberrant AKT and cadherin expression confer chemoresistance and metastatic potential.•Surgical resection and radiation therapy improves local control and survival.•Effective systemic agents for definitive and salvage therapy remain ill-defined.
The US Food and Drug Administration (FDA) approved the PD-L1 immunohistochemical assay, SP142, as a companion test to determine eligibility for atezolizumab therapy in patients with advanced triple ...negative breast cancer (TNBC) but data in lung cancer studies suggest the assay suffers from poor reproducibility. We sought to evaluate reproducibility and concordance in PD-L1 scoring across multiple pathologists. Full TNBC sections were stained with SP142 and SP263 assays and interpreted for percentage (%) immune cell (IC) staining by 19 pathologists from 14 academic institutions. Proportion of PD-L1 positive cases (defined as ≥1% IC) was determined for each assay as well as concordance across observers. We utilized a new method we call Observers Needed to Evaluate Subjective Tests (ONEST) to determine the minimum number of evaluators needed to estimate concordance between large numbers of readers, as occurs in the real-world setting. PD-L1 was interpreted as positive with the SP142 assay in an average 58% of cases compared with 78% with SP263 (p < 0.0001). IC positive continuous scores ranged from 1 to 95% (mean = 20%) and 1 to 90% (mean = 10%) for SP263 and SP142, respectively. With SP142, 26 cases (38%) showed complete two category (<1% vs. ≥1%) concordance; with SP263, 38 cases (50%) showed complete agreement. The intraclass correlation coefficient (ICC) for two category scoring of SP263 and SP142 was 0.513 and 0.560. ONEST plots showed decreasing overall percent agreement (OPA) as observer number increased, reaching a low plateau of 0.46 at ten observers for SP263 and 0.41 at eight observers for SP142. IC scoring with both assays showed poor reproducibility across multiple pathologists with ONEST analysis suggesting more than half of pathologists will disagree about IC scores. This could lead to many patients either receiving atezolizumab when they are unlikely to benefit, or not receiving atezolizumab when they may benefit.
Neoadjuvant systemic therapy is being used increasingly in the treatment of early-stage breast cancer. Response, in the form of pathological complete response, is a validated and evaluable surrogate ...end point of survival after neoadjuvant therapy. Thus, pathological complete response has become a primary end point for clinical trials. However, there is a current lack of uniformity in the definition of pathological complete response. A review of standard operating procedures used by 28 major neoadjuvant breast cancer trials and/or 25 sites involved in such trials identified marked variability in specimen handling and histologic reporting. An international working group was convened to develop practical recommendations for the pathologic assessment of residual disease in neoadjuvant clinical trials of breast cancer and information expected from pathology reports. Systematic sampling of areas identified by informed mapping of the specimen and close correlation with radiological findings is preferable to overly exhaustive sampling, and permits taking tissue samples for translational research. Controversial areas are discussed, including measurement of lesion size, reporting of lymphovascular space invasion and the presence of isolated tumor cells in lymph nodes after neoadjuvant therapy, and retesting of markers after treatment. If there has been a pathological complete response, this must be clearly stated, and the presence/absence of residual ductal carcinoma in situ must be described. When there is residual invasive carcinoma, a comment must be made as to the presence/absence of chemotherapy effect in the breast and lymph nodes. The Residual Cancer Burden is the preferred method for quantifying residual disease in neoadjuvant clinical trials in breast cancer; other methods can be included per trial protocols and regional preference. Posttreatment tumor staging using the Tumor-Node-Metastasis system should be included. These recommendations for standardized pathological evaluation and reporting of neoadjuvant breast cancer specimens should improve prognostication for individual patients and allow comparison of treatment outcomes within and across clinical trials.
The AJCC Cancer Staging Manual 8th edition included tumor grade in the pathologic prognostic stage for breast carcinomas. Due to the known subjectivity of tumor grading, we aimed to assess the degree ...of interobserver agreement for invasive carcinoma grade among pathologists and determine its effect on pathologic prognostic stage. One hundred consecutive cases of invasive stage II carcinomas were independently graded twice, with an 4-week intervening wash-out period, by 6 breast pathologists utilizing established Nottingham grading criteria. Inter- and intra-observer variability was determined for overall grade and for each of the 3 scoring components. Interobserver variability was good to very good (κ range = 0.582–0.850) with even better intra-observer variability (mean κ = 0.766). Tubule score was the most reproducible element (κ = 0.588). Complete concordance was reached in 54 cases and 58 cases in rounds 1 and 2 respectively. In round 1 this resulted in different pathologic prognostic stage in only 25 of discordant cases, 18 of which were stage IA versus IB. In conclusion, grading agreement between pathologists was good to very good and discordant grades resulted in small changes to pathologic prognostic stage.
•Invasive breast carcinoma grading is prognostic but subjective.•Tumor grade was included in the 8th edition AJCC prognostic staging of breast cancer.•Breast pathologists agree on grade in most tumors with only rare 2 step discordance.•Grading variability results in predominantly IA to IB prognostic stage differences.
Triple negative breast cancer (TNBC) is characterized by high proliferation, poor differentiation and a poor prognosis due to high rates of recurrence. Despite lower overall incidence African ...American (AA) patients suffer from higher breast cancer mortality in part due to the higher proportion of TNBC cases among AA patients compared to European Americans (EA). It was recently shown that the clinical heterogeneity of TNBC is reflected by distinct transcriptional programs with distinct drug response profiles in preclinical models. In this study, gene expression profiling and immunohistochemistry were used to elucidate potential differences between TNBC tumors of EA and AA patients on a molecular level. In a retrospective cohort of 136 TNBC patients, a major transcriptional signature of proliferation was found to be significantly upregulated in samples of AA ethnicity. Furthermore, transcriptional profiles of AA tumors showed differential activation of insulin-like growth factor 1 (IGF1) and a signature of BRCA1 deficiency in this cohort. Using signatures derived from the meta-analysis of TNBC gene expression carried out by Lehmann et al., tumors from AA patients were more likely of basal-like subtypes whereas transcriptional features of many EA samples corresponded to mesenchymal-like or luminal androgen receptor driven subtypes. These results were validated in The Cancer Genome Atlas mRNA and protein expression data, again showing enrichment of a basal-like phenotype in AA tumors and mesenchymal subtypes in EA tumors. In addition, increased expression of VEGF-activated genes together with elevated microvessel area determined by the AQUA method suggest that AA patients exhibit higher tumor vascularization. This study confirms the existence of distinct transcriptional programs in triple negative breast cancer in two separate cohorts and that these programs differ by racial group. Differences in TNBC subtypes and levels of tumor angiogenesis in AA versus EA patients suggest that targeted therapy choices should be considered in the context of race.
The 3-biomarker homologous recombination deficiency (HRD) assay measures the number of telomeric allelic imbalances, loss of heterozygosity, and large-scale state transitions in tumor DNA and ...combines these metrics into a single score that reflects DNA repair deficiency. The goal of this study is to assess the consistency of these HRD measures in different biopsies from distinct areas of the same cancer.
HRD scores, BRCA mutation status, and
promoter methylation were assessed in 99 samples from 33 surgically resected, stage I-III breast cancers; each cancer was biopsied in three distinct areas. Homologous recombination repair (HR) deficiency was defined as either high HRD score (≥42) or tumor BRCA mutation.
Eighty-one biopsies from 32 cancers were analyzed. Tumor BRCA status was available for all samples, HRD scores for 70, and
methylation values for 76 samples. The
mutation and promoter methylation status and HR category showed perfect concordance across all biopsies from the same cancer. All tumors with
mutations or promoter methylation had high HRD scores, as did 17% (4/24) of the
wild-type and nonmethylated tumors. The HRD scores were also highly consistent between different biopsies from the same tumor with an intraclass correlation coefficient of 0.977, indicating that only 2.3% of the variance is attributed to within-tumor biopsy-to-biopsy variation.
These results indicate that within-tumor spatial heterogeneity for HRD metrics and the technical noise in the assay are small and do not influence HRD scores and HR status.
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