DNA aneuploidy identifies a subset of Luminal subtype breast carcinoma patients with worse clinical outcome.

AIM: In breast carcinoma (BC), the relationship between the ploidy pattern and molecular subtyping is still unknown. We aim to investigate the prognostic impact of DNA ploidy within molecular subtypes of a large cohort of BC patients. METHODS: The series involved 520 BC patients with no neoadjuvant therapy and a median follow-up of 115.5 months. Immunohistochemical assessment of hormonal receptors, ERBB2 (HER2) status and Ki67 proliferative activity was the basis of the surrogate molecular subtyping. Ploidy was evaluated by DNA flow cytometry in fresh/frozen tumour samples. Kaplan-Meier (K-M) survival estimation was used for prognostic statistical analysis. RESULTS: Luminal A subtype had the lowest prevalence of disease recurrences (23.6 %) and deaths from disease (18.3 %), while Luminal B (42.2 %/37.9 %), Triple-negative (46.4 %/40.6 %), and HER2-positive (55.9 %/50.0 %) subtypes had the highest. The Triple-positive subtype shows an intermediate/low frequency of adverse events (29.4 % of disease recurrences and 17.6 % of deaths from disease). Luminal A tumours were mostly diploid (55.3 %), while Triple-negative and HER2-positive tumours showed a high incidence of aneuploidy (82.6 % and 88.2 %, respectively). Luminal B and Triple-positive tumours had an intermediate percentage of aneuploidy (63.8 % and 70.6 %, respectively). K-M survival curves showed that DNA aneuploidy is significantly associated with shorter disease-free survival and overall survival in Luminal A and Luminal B molecular subtypes. CONCLUSION: DNA aneuploidy identifies a subset of Luminal BC patients with worse clinical outcome, potentially eligible for more aggressive adjuvant therapy.

Noninferiority of Artificial Intelligence-Assisted Analysis of Ki-67 and Estrogen/Progesterone Receptor in Breast Cancer Routine Diagnostics.

Image analysis assistance with artificial intelligence (AI) has become one of the great promises over recent years in pathology, with many scientific studies being published each year. Nonetheless, and perhaps surprisingly, only few image AI systems are already in routine clinical use. A major reason for this is the missing validation of the robustness of many AI systems: beyond a narrow context, the large variability in digital images due to differences in preanalytical laboratory procedures, staining procedures, and scanners can be challenging for the subsequent image analysis. Resulting faulty AI analysis may bias the pathologist and contribute to incorrect diagnoses and, therefore, may lead to inappropriate therapy or prognosis. In this study, a pretrained AI assistance tool for the quantification of Ki-67, estrogen receptor (ER), and progesterone receptor (PR) in breast cancer was evaluated within a realistic study set representative of clinical routine on a total of 204 slides (72 Ki-67, 66 ER, and 66 PR slides). This represents the cohort with the largest image variance for AI tool evaluation to date, including 3 staining systems, 5 whole-slide scanners, and 1 microscope camera. These routine cases were collected without manual preselection and analyzed by 10 participant pathologists from 8 sites. Agreement rates for individual pathologists were found to be 87.6% for Ki-67 and 89.4% for ER/PR, respectively, between scoring with and without the assistance of the AI tool regarding clinical categories. Individual AI analysis results were confirmed by the majority of pathologists in 95.8% of Ki-67 cases and 93.2% of ER/PR cases. The statistical analysis provides evidence for high interobserver variance between pathologists (Krippendorff's α, 0.69) in conventional immunohistochemical quantification. Pathologist agreement increased slightly when using AI support (Krippendorff α, 0.72). Agreement rates of pathologist scores with and without AI assistance provide evidence for the reliability of immunohistochemical scoring with the support of the investigated AI tool under a large number of environmental variables that influence the quality of the diagnosed tissue images.

A logarithmic model for hormone receptor-positive and breast cancer patients treated with neoadjuvant chemotherapy.

OBJECTIVE: The aim of this study was to investigate the predictive importance of the previously validated log(ER)*log(PgR)/Ki-67 predictive model in a larger patient population. METHODS: Patients with hormone receptor positive/HER-2 negative and clinical node positive before chemotherapy were included. Log(ER)*log(PgR)/Ki-67 values of the patients were determined, and the ideal cutoff value was calculated using a receiver operating characteristic curve analysis. It was analyzed with a logistic regression model along with other clinical and pathological characteristics. RESULTS: A total of 181 patients were included in the study. The ideal cutoff value for pathological response was 0.12 (area under the curve=0.585, p=0.032). In the univariate analysis, no statistical correlation was observed between luminal subtype (p=0.294), histological type (p=0.238), clinical t-stage (p=0.927), progesterone receptor level (p=0.261), Ki-67 cutoff value (p=0.425), and pathological complete response. There was a positive relationship between numerical increase in age and residual disease. As the grade of the patients increased, the probability of residual disease decreased. Patients with log(ER)*log(PgR)/Ki-67 above 0.12 had an approximately threefold increased risk of residual disease when compared to patients with 0.12 and below (odds ratio: 3.17, 95% confidence interval: 1.48-6.75, p=0.003). When age, grade, and logarithmic formula were assessed together, the logarithmic formula maintained its statistical significance (odds ratio: 2.47, 95% confidence interval: 1.07-5.69, p=0.034). CONCLUSION: In hormone receptor-positive breast cancer patients receiving neoadjuvant chemotherapy, the logarithmic model has been shown in a larger patient population to be an inexpensive, easy, and rapidly applicable predictive marker that can be used to predict response.

Yassir Alaa Muhammed Hassan Shubbar CORRELATION BETWEEN DIFFERENT CLINICOPATHOLOGICAL PARAMETERS AND MOLECULAR SUBTYPES OF FEMALE BREAST CARCINOMA IN SOUTH REGION OF IRAQ.

OBJECTIVE: The aim: To correlate variable clincopathological parameters with molecular subtypes of the breast carcinoma, which affect the prognosis and management of breast malignancy. PATIENTS AND METHODS: Materials and methods: In this study a total of 511 female patients with breast carcinoma were included, ranging from 32 to 85 years of age, with 35.8% premenopausal and 64.1% being post-menopausal. The sample slides were stained immunohistochemically for estrogen receptors (ER), progesterone receptors (PR), ki67 and HER2, the tumors were graded histologically using the Nottingham criteria system. RESULTS: Results: Most tumors (72.8%) ranged between 2 and 5 cm in size; the most common histological type of breast carcinoma (49.7%) was invasive ductal carcinoma of no special type, with grade 2 presented in 51.8% cases; most frequent stage at time of presentation was stage 3A, found in 39.9%; the most frequent molecular subtype was ER and/or PR+, Her2- with low proliferation rate ki67<14% subtype in 48.5%, and those group were more likely (statistically significant) to be older, have stage 3 breast cancer, present with tumor size between 2 and 5 cm and tend to be well differentiated histological grade (grade1), mostly with lymph node positive, and most likely have tumor type of invasive ductal carcinoma of no special type. CONCLUSION: Conclusions: the most common histological type of breast carcinoma in Iraq south was invasive ductal carcinoma of no special type and most cases showed (ER and/or PR+, HER 2-, low ki67) as the most common molecular subtype.

[Expression of estrogen and progesterone receptors in vestibular schwannomas]. / Analiz ekspressii retseptorov estrogena i progesterona v vestibulyarnykh shvannomakh.

INTRODUCTION: Stereotactic radiosurgery is one of the main treatments for vestibular schwannomas (VS). Their feature is frequent post-radiation pseudoprogression. This may be due to hormonal status of patients. OBJECTIVE: To analyze expression of progesterone and estrogen receptors in women and men with VS. MATERIAL AND METHODS: Immunohistochemical analysis of expression of progesterone (PR) and estrogen receptors (ER) after biopsy was performed in 240 patients with VS between 2018 and 2021. ER/PR expression was assessed in men (n=120) and women (n=120) in 3 age subgroups: young age (18-44 years), middle age (45-59 years) and old age (60-79 years). Each subgroup included 40 patients. Statistical analysis was performed using the Mann-Whitney test and MedCalc software. RESULTS: ER expression is not typical for VS (men - 1 (0.01%), women - 3 (2.5%)). At the same time, PR expression was found in 29 (24.2%) men and 21 (17.5%) women. We found no significant difference in expression of ER and PR between men and women. However, variability in PR expression was revealed, i.e. predominance of this indicator in young women (p=0.0463) and middle-aged men (p=0.0110). Expression of PR was similar in elderly patients (p=0.2382). CONCLUSION: The established incidence of PR expression may be one of the probable causes affecting development and duration of VS pseudoprogression after radiosurgery without clear relationship between sex and age. Further prospective research is needed to predict the risks of pseudoprogression.

Annual cost-savings with the implementation of estrogen-receptor-only testing on Ductal Carcinoma in Situ specimens.

BACKGROUND: In DCIS, ER status is an important marker. The utility of concomitant PR testing remains unclear. METHODS: A single-institution retrospective cohort study was performed with a comparative analysis of the NCDB to assess annual cost-savings with omission of routine PR testing. National Medicare payment standards determined PR staining costs to be $124.92. RESULTS: 150 institutional DCIS cases with receptor data were identified. 104 (69%) were ER+/PR+, 16 (11%) were ER+/PR-, and none were ER-/PR+. Omission of routine PR testing would have resulted in $18,738 saved annually. Within the NCDB, 34,100 DCIS cases had receptor data: 29,277 (85.9%) patients were ER+, and 26,008 (76%) were both ER/PR+. 211 (0.6%) patients were ER-/PR+. Annual national cost-savings with omission of routine PR-testing would have been $4.3 million. CONCLUSION: PR testing for DCIS should be reserved only for patients with ER- DCIS undergoing breast conservation to determine the utility of adjuvant endocrine therapy.

[Clinicopathological features and prognosis of hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer].

OBJECTIVE: To investigate the clinicopathological features and prognosis of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2 -) breast cancer. METHODS: In the study, 3 035 consecutive breast cancer patients diagnosed in Breast Disease Center, Peking University First Hospital from January 2008 to December 2017 were collected. The prognostic signi-ficance of important pathological factors in HR +/HER2 - patients with complete clinicopathological information was analyzed. RESULTS: Within the 1 920 (63.26%) cases of HR +/HER2 - breast cancer, there were 1 624 cases with complete clinicopathological data, of which, 124 cases (7.64%) recurred and/or metastasized and 63 cases died of the disease, and the 5-year overall survival (OS) rate and disease-free survival (DFS) rate was 93.0% and 92.6% respectively. The stage of pT1-2 was 92.80%, while pN0 was 69.03%. 89.66% cases belonged to histologically non-specific type and 30.11%, 55.60%, 14.29% were credited to Grade 1, 2 and 3 respectively. The distribution of ER negative, low or high expression groups were 1.60%, 2.09% and 96.31%, while PR were 6.83%, 10.47%, 82.70%, respectively. The group of Ki67 index < 10% was 19.52%, ≥10% & < 20% for 32.02%, ≥20% for 48.46%. Survival analysis showed that cases with pT1 stage had lower risk of recurrence than those with pT3, while cases with pT2 and pT3 had shorter DFS than those with pT1, with higher risk of recurrence and metastasis. Analysis proved that both pN stage and histological grade were negatively correlated with DFS. The cases with pN0, pN1 and pN2 were lower risk of recurrence than those with pN3, while cases with Grade 1 and 2 had lower risk of recurrence than cases with Grade 3. And the group of Ki67 index ≥20% showed higher risk of recurrence and metastasis. The prognostic significance of ER expression in HR+/HER2- breast cancer was not significant. However, the negative/low PR expression groups showed higher risk of recurrence and metastasis, of which PR < 10% group had shortest DFS and OS, followed by 10%-60% group and then > 60% group. The most common site of metastasis was bone (55 cases, 44.35%), while cases with liver metastasis (30 cases, 24.20%) had the worst outcome. CONCLUSION: Our study revealed that pT, pN, Grade, HR expression level and Ki67 index were important prognostic factors for HR +/HER2 - breast cancer, although there are variables in prognostic value. Factors of pN and Grade showed independent prognostic significance. PR expression level had prognostic significance for the risk of recurrence and metastasis. The stratified level of PR expression (< 10%, 10%-60%, >60%) had independent prognostic value, showing successively longer DFS and OS, lower risk of recurrence. PR>60% group had the longest DFS and OS as well as the lowest risk of recurrence.

Her2/EGFR-PDGFR pathway aberrations associated with tamoxifen response in metastatic breast cancer patients.

BACKGROUND: Metastatic breast cancer (MBC) is a major health problem worldwide. Some patients improve on tamoxifen and others do not respond to treatment. Therefore, the aim of the current study is to assess genetic aberrations in the Her2/EGFR-PDGFR pathway associated with tamoxifen response in MBC patients. METHODS: This is a retrospective cohort study, including 157 hormone receptors positive, locally recurrent inoperable and/or MBC patients on tamoxifen treatment. Patients were categorized into 78 (49.7%) tamoxifen responders and 79 (50.3%) tamoxifen non-responder patients. Genetic aberrations of 84 genes involved in the Her2/EGFR-PDGFR pathway were assessed in the tumor tissue samples obtained from the patients using SA-Bioscience assay. The identified panel was correlated to patients' response to treatment, to detect the differentially expressed genes in tamoxifen responders and non-responders. RESULTS: One hundred twenty-three (78.3%) patients were estrogen receptor (ER) and progesterone receptor (PR) positive, 108 (68.8%) were ER only positive, and 78 (49.7%) were PR only positive. There were 56 genes overexpressed in the refractory group compared to responders. However, only five out of these 56 genes, Janus kinase 1 (JAK1), collagen type I alpha 1 (COL1A1), GRB2-associated binding protein 1 (GAB1), fibronectin-1 (FN1), and MAP kinase-interacting serine/threonine-protein kinase (MKNK1), showed statistical significance between the two groups. Patients with bone metastasis showed a better response to treatment compared to those with metastatic deposits in other sites such as visceral metastasis (P < 0.005). CONCLUSIONS: Genetic profiling using simple quantitative real-time polymerase chain reaction (qRT-PCR) protocols could be used to assess response to tamoxifen treatment in MBC patients. According to our data, a five-gene panel in the EGFR pathway (JAK1, COL1A1, GAB1, FN1 and MKNK1) could be used to categorize MBC patients into groups according to treatment response.

Distinct Neoadjuvant Chemotherapy Response and 5-Year Outcome in Patients With Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Tumors That Reclassify as Basal-Type by the 80-Gene Signature.

PURPOSE: The 80-gene molecular subtyping signature (80-GS) reclassifies a proportion of immunohistochemistry (IHC)-defined luminal breast cancers (estrogen receptor-positive [ER+], human epidermal growth factor receptor 2-negative [HER2-]) as Basal-Type. We report the association of 80-GS reclassification with neoadjuvant treatment response and 5-year outcome in patients with breast cancer. METHODS: Neoadjuvant Breast Registry Symphony Trial (NBRST; NCT01479101) is an observational, prospective study that included 1,069 patients with early-stage breast cancer age 18-90 years who received neoadjuvant therapy. Pathologic complete response (pCR) and 5-year distant metastasis-free survival (DMFS) and overall survival (OS) were assessed in 477 patients with IHC-defined ER+, HER2- tumors and in a reference group of 229 patients with IHC-defined triple-negative breast cancer (TNBC). RESULTS: 80-GS reclassified 15% of ER+, HER2- tumors (n = 73) as Basal-Type (ER+/Basal), which had similar pCR compared with TNBC/Basal tumors (34% v 38%; P = .52), and significantly higher pCR than ER+/Luminal A (2%; P < .001) and ER+/Luminal B (6%; P < .001) tumors. The 5-year DMFS (%, [95% CI]) was significantly lower for patients with ER+/Basal tumors (66% [52.6 to 77.3]), compared with those with ER+/Luminal A tumors (92.3% [85.2 to 96.1]) and ER+/Luminal B tumors (73.5% [44.5 to 79.3]). Importantly, patients with ER+/Basal or TNBC/Basal tumors that had a pCR exhibited significantly improved DMFS and OS compared with those with residual disease. By contrast, patients with ER+/Luminal B tumors had comparable 5-year DMFS and OS whether or not they achieved pCR. CONCLUSION: Significant differences in chemosensitivity and 5-year outcome suggest patients with ER+/Basal molecular subtype may benefit from neoadjuvant regimens optimized for patients with TNBC/Basal tumors compared with patients with ER+/Luminal subtype. These data highlight the importance of identifying this subset of patients to improve treatment planning and long-term survival.

Pathological underestimation and biomarkers concordance rates in breast cancer patients diagnosed with ductal carcinoma in situ at preoperative biopsy.

Ductal carcinoma in situ (DCIS) often upgrade to invasive breast cancer at surgery. The current study aimed to identify factors associated with pathological underestimation and evaluate concordance rates of biomarkers between biopsy and surgery. Patients diagnosed with DCIS at needle biopsy from 2009 to 2020 were retrospectively reviewed. Univariate and multivariate analyses were performed to identify factors associated with pathological underestimation. Concordance rates between paired biopsy samples and surgical specimens were evaluated. A total of 735 patients with pure DCIS at biopsy were included, and 392 patients (53.3%) underwent pathological underestimation at surgery. Multivariate analysis demonstrated that tumor size > 5.0 cm [odds ratio (OR) 1.79], MRI BI-RADS ≥ 5 categories (OR 2.03), and high nuclear grade (OR 2.01) were significantly associated with pathological underestimation. Concordance rates of ER, PR, HER2 status and Ki-67 between biopsy and surgery were 89.6%, 91.9%, 94.8%, and 76.4% in lesions without pathological underestimation, and were 86.4%, 93.2%, 98.2% and 76.3% for in situ components in lesions with pathological underestimation. Meanwhile, in situ components and invasive components at surgery had concordance rates of 92.9%, 93.8%, 97.4%, and 86.5% for those biomarkers, respectively. In conclusion, lesions diagnosed as DCIS at biopsy have a high rate of pathological underestimation, which was associated with larger tumor size, higher MRI BI-RADS category, and higher nuclear grade. High concordances were found in terms of ER, PR, and HER2 status evaluation between biopsy and surgery, regardless of the pathological underestimation.

Treatment Exposure and Discontinuation in the PALbociclib CoLlaborative Adjuvant Study of Palbociclib With Adjuvant Endocrine Therapy for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer (PALLAS/AFT-05/ABCSG-42/BIG-14-03).

PURPOSE: The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS. METHODS: Patients with stage II-III HR+, HER2- disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS. RESULTS: Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non-protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or ≥ 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11). CONCLUSION: Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS difference between arms was not directly related to inadequate palbociclib exposure. However, the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies.

Estrogen and Progesterone Therapy and Meningiomas.

Meningiomas are common intracranial tumors with a female predominance. Their etiology is still poorly documented. The role of sexual hormones has long been evoked, and data have been conflicting across studies. However, a dose-dependent relationship between the incidence and growth of meningiomas and hormonal treatment with the progestin cyproterone acetate (CPA) has recently been established. CPA-associated meningiomas seem to be mainly located in the anterior and middle skull base, are more likely to be multiple, may harbor P1K3CA mutations in up to one-third of cases, and are more common with a longer duration of treatment. A similar but lower risk of meningiomas has been recently reported with the use of chlormadinone acetate and nomegestrol acetate as progestin treatments. Concerning hormonal replacement therapy (HRT) in menopausal patients, evidence from epidemiological studies seem to favor an increased risk of meningiomas in treated patients although a recent study failed to show an increased growth of meningiomas in HRT treated vs nontreated patients. Until larger studies are available, it seems wise to recommend avoiding HRT in patients with meningiomas. Evidence from published data does not seem to support an increased risk of meningiomas with oral contraceptive oral contraceptive (OR) use. Data are too scarce to conclude on fertility treatments. Based on studies demonstrating the expression of hormonal receptors in meningiomas, therapies targeting these receptors have been tried but have failed to show an overall favorable clinical outcome in meningioma treatment.

Unique Transcriptomic Changes Underlie Hormonal Interactions During Mammary Histomorphogenesis in Female Pigs.

Successful lactation and the risk for developing breast cancer depend on growth and differentiation of the mammary gland (MG) epithelium that is regulated by ovarian steroids (17ß-estradiol [E] and progesterone [P]) and pituitary-derived prolactin (PRL). Given that the MG of pigs share histomorphogenic features present in the normal human breast, we sought to define the transcriptional responses within the MG of pigs following exposure to all combinations of these hormones. Hormone-ablated female pigs were administered combinations of E, medroxyprogesterone 17-acetate (source of P), and either haloperidol (to induce PRL) or 2-bromo-α-ergocryptine. We subsequently monitored phenotypic changes in the MG including mitosis, receptors for E and P (ESR1 and PGR), level of phosphorylated STAT5 (pSTAT5), and the frequency of terminal ductal lobular unit (TDLU) subtypes; these changes were then associated with all transcriptomic changes. Estrogen altered the expression of approximately 20% of all genes that were mostly associated with mitosis, whereas PRL stimulated elements of fatty acid metabolism and an inflammatory response. Several outcomes, including increased pSTAT5, highlighted the ability of E to enhance PRL action. Regression of transcriptomic changes against several MG phenotypes revealed 1669 genes correlated with proliferation, among which 29 were E inducible. Additional gene expression signatures were associated with TDLU formation and the frequency of ESR1 or PGR. These data provide a link between the hormone-regulated genome and phenome of the MG in a species having a complex histoarchitecture like that in the human breast, and highlight an underexplored synergy between the actions of E and PRL during MG development.

Comparison of the Modified Immunohistochemical Marker Score and 21-Gene Recurrence Score Assay in Patients with Estrogen Receptor-Positive Breast Cancer.

INTRODUCTION: Not only the 21-gene recurrence score (RS) assay but also online prognostic tools and immunohistochemical prognostic models predict chemotherapy benefits for women with early breast cancer (BC). Multigene assays, including Oncotype DX, are expensive and not covered by insurance in some countries Methods: In this study, we retrospectively analyzed a series of 155 patients with estrogen receptor-positive primary BC for whom an Oncotype DX assay was performed between January 2016 and August 2021. The patients' modified immunohistochemical marker (mIHC4) scores were calculated on the basis of their pathological reports. The correlations of the RS with the online tool PREDICT and mIHC4 scores were evaluated. RESULTS: Of the patients, 43.9% were premenopausal, 147 (94.8%) had T1 or T2 tumor, and 55.5% had no positive lymph nodes. Low (0-10), intermediate (11-25), and high RSs (26-100) were obtained in 16.1%, 61.9%, and 21.9% of the patients, respectively. The RS showed no correlation with the PREDICT score (r = 0.2720) but correlated with the mIHC4 score (r = 0.6356). In addition, a stronger correlation was observed in the patients with no node involvement and in the postmenopausal patients (r = 0.6609 and r = 0.7277, respectively). CONCLUSIONS: A relatively strong correlation was observed between the RS and the mIHC4 score. The mIHC4 score is a potentially easy and useful tool to guide adjuvant chemotherapy decision making, especially for postmenopausal patients with no node involvement if a genomic test could not be performed for some reason.

Real-world treatment of patients with palbociclib for HR+/HER2-advanced/metastatic breast cancer: the Europe IRIS study.

Aim: To report the Europe Ibrance Real World Insights study findings. Methods: Physicians abstracted demographic/clinical characteristics, treatment and outcomes data for women with HR+/HER2- locally advanced breast cancer (ABC) or metastatic  breast cancer (MBC) receiving palbociclib + aromatase inhibitor (AI) or palbociclib + fulvestrant. Kaplan-Meier analysis estimated progression-free rates (PFRs) and survival rates (SRs). Results: 238 physicians abstracted data for 1723 patients. For patients (>90%) initiating at 125 mg/day, dose was reduced in 18.9% of palbociclib + AI and 12.3% of palbociclib + fulvestrant patients. At 12 months, PFR for palbociclib + AI was 88.1%, and SR was 97.3%; PFR for palbociclib + fulvestrant was 79.8%, and SR was 97.5%. Conclusion: Low dose-reduction rates and favorable PFRs and SRs suggest that palbociclib + AI/fulvestrant is well tolerated and effective for HR+/HER2- ABC/MBC in real-world clinical practice.

Lay abstract We describe findings of the Europe Ibrance Real World Insights study. Patients were women with a common type of breast cancer that had worsened but not spread or that had spread. Doctors collected medical information about the women and looked at their progress while on treatment. The treatment was either palbociclib + an aromatase inhibitor or palbociclib + fulvestrant. Two hundred thirty-eight doctors collected information on 1723 women. More than 90% of women started this treatment at a dose of 125 mg/day; the dose was reduced for fewer than 20% of women. At 12 months, more than 80% of women survived without their breast cancer worsening, and more than 97% of women survived. These good results suggest that this treatment is safe and effective for women with breast cancer that had worsened but not spread or that had spread.

Digital validation of breast biomarkers (ER, PR, AR, and HER2) in cytology specimens using three different scanners.

Progression in digital pathology has yielded new opportunities for a remote work environment. We evaluated the utility of digital review of breast cancer immunohistochemical prognostic markers (IHC) using whole slide images (WSI) from formalin fixed paraffin embedded (FFPE) cytology cell block specimens (CB) using three different scanners.CB from 20 patients with breast cancer diagnosis and available IHC were included. Glass slides including 20 Hematoxylin and eosin (H&E), 20 Estrogen Receptor (ER), 20 Progesterone Receptor (PR), 16 Androgen Receptor (AR), and 20 Human Epidermal Growth Factor Receptor 2 (HER2) were scanned on 3 different scanners. Four breast pathologists reviewed the WSI and recorded their semi-quantitative scoring for each marker. Kappa concordance was defined as complete agreement between glass/digital pairs. Discordances between microscopic and digital reads were classified as a major when a clinically relevant change was seen. Minor discordances were defined as differences in scoring percentages/staining pattern that would not have resulted in a clinical implication. Scanner precision was tabulated according to the success rate of each scan on all three scanners.In total, we had 228 paired glass/digital IHC reads on all 3 scanners. There was strong concordance kappa ≥0.85 for all pathologists when comparing paired microscopic/digital reads. Strong concordance (kappa ≥0.86) was also seen when comparing reads between scanners.Twenty-three percent of the WSI required rescanning due to barcode detection failures, 14% due to tissue detection failures, and 2% due to focus issues. Scanner 1 had the best average precision of 92%. HER2 IHC had the lowest intra-scanner precision (64%) among all stains.This study is the first to address the utility of WSI in breast cancer IHC in CB and to validate its reporting using 3 different scanners. Digital images are reliable for breast IHC assessment in CB and offer similar reproducibility to microscope reads.

Quantitative Mammographic Density Measurements and Molecular Subtypes in Chinese Women With Breast Cancer.

Background: Studies investigating associations between mammographic density (MD) and breast cancer subtypes have generated mixed results. We previously showed that having extremely dense breasts was associated with the human epidermal growth factor receptor-2 (HER2)-enriched subtype in Chinese breast cancer patients. Methods: In this study, we reevaluated the MD-subtype association in 1549 Chinese breast cancer patients, using VolparaDensity software to obtain quantitative MD measures. All statistical tests were 2-sided. Results: Compared with women with luminal A tumors, women with luminal B/HER2- (odds ratio [OR] = 1.20, 95% confidence interval [CI] = 1.04 to 1.38; P = .01), luminal B/HER2+ (OR = 1.22, 95% CI = 1.03 to 1.46; P = .03), and HER2-enriched tumors (OR = 1.30, 95% CI = 1.06 to 1.59; P = .01) had higher fibroglandular dense volume. These associations were stronger in patients with smaller tumors (<2 cm). In contrast, the triple-negative subtype was associated with lower nondense volume (OR = 0.82, 95% CI = 0.68 to 0.99; P = .04), and the association was only seen among older women (age 50 years or older). Conclusion: Although biological mechanisms remain to be investigated, the associations for the HER2-enriched and luminal B subtypes with increasing MD may partially explain the higher prevalence of luminal B and HER2+ breast cancers previously reported in Asian women.

Relationship of established risk factors with breast cancer subtypes.

BACKGROUND: Breast cancer is a heterogeneous disease, divided into subtypes based on the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Subtypes have different biology and prognosis, with accumulating evidence of different risk factors. The purpose of this study was to compare breast cancer risk factors across tumor subtypes in a large, diverse mammography population. METHODS: Women aged 40-84 without a history of breast cancer with a screening mammogram at three United States health systems from 2006 to 2015 were included. Risk factor questionnaires were completed at mammogram visit, supplemented by electronic health records. Invasive tumor subtype was defined by immunohistochemistry as ER/PR+HER2-, ER/PR+HER2+, ER, and PR-HER2+, or triple-negative breast cancer (TNBC). Cox proportional hazards models were run for each subtype. Associations of race, reproductive history, prior breast problems, family history, breast density, and body mass index (BMI) were assessed. The association of tumor subtypes with screen detection and interval cancer was assessed using logistic regression among invasive cases. RESULTS: The study population included 198,278 women with a median of 6.5 years of follow-up (IQR 4.2-9.0 years). There were 4002 invasive cancers, including 3077 (77%) ER/PR+HER2-, 300 (8%) TNBC, 342 (9%) ER/PR+HER2+, and 126 (3%) ER/PR-HER2+ subtype. In multivariate models, Black women had 2.7 times higher risk of TNBC than white women (HR = 2.67, 95% CI 1.99-3.58). Breast density was associated with increased risk of all subtypes. BMI was more strongly associated with ER/PR+HER2- and HER2+ subtypes among postmenopausal women than premenopausal women. Breast density was more strongly associated with ER/PR+HER2- and TNBC among premenopausal than postmenopausal women. TNBC was more likely to be interval cancer than other subtypes. CONCLUSIONS: These results have implications for risk assessment and understanding of the etiology of breast cancer subtypes. More research is needed to determine what factors explain the higher risk of TNBC for Black women.

The additional value of ONEST (Observers Needed to Evaluate Subjective Tests) in assessing reproducibility of oestrogen receptor, progesterone receptor, and Ki67 classification in breast cancer.

The reproducibility of assessing potential biomarkers is crucial for their implementation. ONEST (Observers Needed to Evaluate Subjective Tests) has been recently introduced as a new additive evaluation method for the assessment of reliability, by demonstrating how the number of observers impact on interobserver agreement. Oestrogen receptor (ER), progesterone receptor (PR), and Ki67 proliferation marker immunohistochemical stainings were assessed on 50 core needle biopsy and 50 excision samples from breast cancers by 9 pathologists according to daily practice. ER and PR statuses based on the percentages of stained nuclei were the most consistently assessed parameters (intraclass correlation coefficients, ICC 0.918-0.996), whereas Ki67 with 5 different theoretical or St Gallen Consensus Conference-proposed cut-off values demonstrated moderate to good reproducibility (ICC: 0.625-0.760). ONEST highlighted that consistent tests like ER and PR assessment needed only 2 or 3 observers for optimal evaluation of reproducibility, and the width between plots of the best and worst overall percent agreement values for 100 randomly selected permutations of observers was narrow. In contrast, with less consistently evaluated tests of Ki67 categorization, ONEST suggested at least 5 observers required for more trustful assessment of reliability, and the bandwidth of the best and worst plots was wider (up to 34% difference between two observers). ONEST has additional value to traditional calculations of the interobserver agreement by not only highlighting the number of observers needed to trustfully evaluate reproducibility but also by highlighting the rate of agreement with an increasing number of observers and disagreement between the better and worse ratings.

Effect of EDTA decalcification on estrogen receptor and progesterone receptor immunohistochemistry and HER2/neu fluorescence in situ hybridization in breast carcinoma.

Bone is the most common site of metastasis in breast carcinoma (BC). Treatments for metastatic BC depend on various factors, including the tumor's estrogen receptor (ER), progesterone receptor (PR), and HER2 status. Bone biopsies require decalcification which may affect the accuracy of ER and PR immunohistochemistry (IHC) and HER2 situ hybridization (FISH) studies. Ethylenediaminetetraacetic acid (EDTA) decalcifying solutions have been theorized to have no significant impact on ER and PR IHC or HER2 FISH analyses. We completed a prospective study of the effect of EDTA decalcification on ER and PR IHC and HER2 FISH in 29 cases of BC. Samples from 29 BC resections were collected and formalin fixed between 12 and 24 h. Control samples were routinely processed, whereas test samples were placed in EDTA for 48 h. ER and PR slides were blinded, randomized, and evaluated. Blinded samples underwent HER2 FISH assays where an average HER2 copy number and HER2/CEP17 ratio were calculated. Paired differences between EDTA and control samples were compared for ER and PR positivity, average HER2 copy number, and HER2/CEP17 ratios using paired-samples t-tests (PST) and Wilcoxon signed-rank test (WSR). PST and WSR tests yielded no significant difference between EDTA and control tissue for ER% (PST: P = 1; WSR: P = 0.916), PR% (PST: P = 0.973; WSR: P = 0.984), HER2 copy number (PST: P = 0.124; WSR: P = 0.103), and HER2/CEP17 ratio (PST: P = 0.25; WSR: P = 0.105). The use of EDTA in bony tissue is therefore a valid decalcification method to ensure accurate assessment of ER and PR IHC and HER2 FISH in metastatic BC.