Tumor microenvironment and immune system preservation in early-stage breast cancer: routes for early recurrence after mastectomy and treatment for lobular and ductal forms of disease.

BACKGROUND: Intra-ductal cancer (IDC) is the most common type of breast cancer, with intra-lobular cancer (ILC) coming in second. Surgery is the primary treatment for early stage breast cancer. There are now irrefutable data demonstrating that the immune context of breast tumors can influence growth and metastasis. Adjuvant chemotherapy may be administered in patients who are at a high risk of recurrence. Our goal was to identify the processes underlying both types of early local recurrences. METHODS: This was a case-control observational study. Within 2 years of receiving adjuvant taxan and anthracycline-based chemotherapy, as well as modified radical mastectomy (MRM), early stage IDC and ILC recurred. Vimentin, α-smooth muscle actin (SMA), platelet-derived growth factor (PDGF), matrix metalloproteinase (MMP1), and clustered differentiation (CD95) were investigated. RESULTS: Of the samples in the ductal type group, 25 showed local recurrence, and 25 did not. Six individuals in the lobular-type group did not experience recurrence, whereas seven did. Vimentin (p = 0.000 and 0.021), PDGF (p = 0.000 and 0.002), and CD95 (p = 0.000 and 0.045) expressions were significantly different in ductal and lobular carcinoma types, respectively. Measurement of ductal type was the sole significant difference found in MMP1 (p = 0.000) and α-SMA (p = 0.000). α-SMA and CD95 were two variables that helped the recurrence mechanism in the ductal type according to the pathway analysis. In contrast, the CD95 route is a recurrent mechanism for the lobular form. CONCLUSIONS: While the immune system plays a larger role in ILC, the tumor microenvironment and immune system both influence the recurrence of IDC. According to this study, improving the immune system may be a viable cancer treatment option.

Gastric Metastasis Mimicking Early Gastric Cancer from Invasive Ductal Carcinoma of the Breast: Case Report and Literature Review.

Backgound and Objectives: Gastric metastasis from invasive ductal breast cancer (BC) is rare. It mainly occurs in patients with lobular BC. The occurrence of multiple metastases is typically observed several years after the primary diagnosis. Endoscopic findings of gastric metastasis of the BC were usually the linitis plastic type. Case presentation: A 72-year-old women who underwent right modified radical mastectomy (MRM) 10 month ago was referred after being diagnosed with early gastric cancer (EGC) during systemic chemotherapy. EGC type I was found at gastric fundus, and pathologic finding showed poorly differentiated adenocarcinoma. Metachronous double primary tumor EGC was considered. Management and Outcome: A laparoscopic total gastrectomy was performed, and postoperative pathology revealed submucosa invasion and two lymph node metastases. A pathologic review that focused on immunohistochemical studies of selected antibodies such as GATA binding protein 3 (GATA3), gross cystic disease fluid protein-15 (GCDFP-15), cytokeratin 7 (CK7) was performed again, comparing previous results. As a result, gastric metastasis from BC was diagnosed. After totally laparoscopic total gastrectomy, palliative first-line chemotherapy with paclitaxel/CDDP was performed. Two months after gastrectomy, she was diagnosed with para-aortic lymph node metastasis and multiple bone metastases. She expired six months after gastrectomy. Conclusions: Gastric metastasis from invasive ductal carcinoma of the breast, which is clinically manifested as EGC, is a very rare condition. If there is a history of BC, careful pathological review will be required.

[A Long-Surviving Case of Locally Advanced Breast Cancer with Multiple Lung Metastasis].

We report a case of right advanced breast cancer with multiple lung metastases in a 66-year-old woman. Her breast cancer( invasive ductal carcinoma, cT4bN1M1, Stage Ⅳ)was resected in October 2007(mastectomy plus axillary lymph node dissection)after local arterial infusion therapy(total dose 5-FU 4,735 mg plus adriamycin 180 mg), which caused bilateral lung arterial embolism due to deep vein thrombosis in right her leg. She had to be treated by anticoagulant therapy, mechanical ventilation and placement of IVC filter before her operation. Subsequent chemo-endocrine therapy(docetaxel 6 courses plus anastrozole)was continued. In October 2008, a CT scan showed disappearance of multiple lung metastases (complete response). In November 2015 (8 years after her operation), a CT scan showed recurrence of multiple lung metastases and endocrine therapy was changed to tamoxifen. A year later, a CT scan showed disappearance of multiple lung metastases(complete response)again and keep a condition of complete response in her breast cancer until May 2023 (15 years after her operation).

Distant metastasis and prognostic factors in patients with invasive ductal carcinoma of the breast.

OBJECTIVE: To explore the risk factors and prognostic factors of invasive ductal carcinoma (IDC) and to predict the survival of IDC patients with metastasis. METHOD: We used multivariate logistic regression to identify independent risk factors affecting metastasis in IDC patients and used Cox regression to identify independent prognostic factors affecting the overall survival of patients with metastasis. Nomogram was used to predict survival, while C-index and calibration curves were used to measure the performance of nomogram. Kaplan-Meier method was used to calculate the survival curves of patients with different independent prognostics factors and different metastatic sites, and the differences were compared by log-rank test. The data of our study were obtained from the Surveillance, Epidemiology and End Results cancer registry. RESULT: Our study included 226,094 patients with IDC. In multivariate analysis, independent risk factors of metastasis included age, race, marital status, income, geographic region, grade, T stage, N stage, subtype, surgery and radiotherapy. Independent prognostic factors included age, race, marital status, income, geographic region, grade, T stage, N stage, subtype, surgery and chemotherapy. We established a nomogram, of which the C-index was 0.701 (0.693, 0.709), with the calibration curves showing that the disease-specific survival between actual observation and prediction had a good consistency. The survival curves of different metastatic patterns were significantly different (log-rank test: χ2  = 18784, p < 0.001; χ2  = 47.1, p < 0.001; χ2  = 20, p < 0.001). CONCLUSION: The nomogram we established may provide risk assessment and survival prediction for IDC patients with metastasis, which can be used for clinical decision-making and reference.

Toward developing a metastatic breast cancer treatment strategy that incorporates history of response to previous treatments.

BACKGROUND: Information regarding response to past treatments may provide clues concerning the classes of drugs most or least likely to work for a particular metastatic or neoadjuvant early stage breast cancer patient. However, currently there is no systematized knowledge base that would support clinical treatment decision-making that takes response history into account. METHODS: To model history-dependent response data we leveraged a published in vitro breast cancer viability dataset (84 cell lines, 90 therapeutic compounds) to calculate the odds ratios (log (OR)) of responding to each drug given knowledge of (intrinsic/prior) response to all other agents. This OR matrix assumes (1) response is based on intrinsic rather than acquired characteristics, and (2) intrinsic sensitivity remains unchanged at the time of the next decision point. Fisher's exact test is used to identify predictive pairs and groups of agents (BH p < 0.05). Recommendation systems are used to make further drug recommendations based on past 'history' of response. RESULTS: Of the 90 compounds, 57 have sensitivity profiles significantly associated with those of at least one other agent, mostly targeted drugs. Nearly all associations are positive, with (intrinsic/prior) sensitivity to one agent predicting sensitivity to others in the same or a related class (OR > 1). In vitro conditional response patterns clustered compounds into five predictive classes: (1) DNA damaging agents, (2) Aurora A kinase and cell cycle checkpoint inhibitors; (3) microtubule poisons; (4) HER2/EGFR inhibitors; and (5) PIK3C catalytic subunit inhibitors. The apriori algorithm implementation made further predictions including a directional association between resistance to HER2 inhibition and sensitivity to proteasome inhibitors. CONCLUSIONS: Investigating drug sensitivity conditioned on observed sensitivity or resistance to prior drugs may be pivotal in informing clinicians deciding on the next line of breast cancer treatments for patients who have progressed on their current treatment. This study supports a strategy of treating patients with different agents in the same class where an associated sensitivity was observed, likely after one or more intervening treatments.

Risk and prognostic factors of breast cancer with liver metastases.

BACKGROUND: Liver metastasis is a significant adverse predictor of overall survival (OS) among breast cancer patients. The purpose of this study was to determine the risk and prognostic factors of breast cancer with liver metastases (BCLM). METHODS: Data on 311,573 breast cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database and 1728 BCLM patients from Fudan University Shanghai Cancer Center (FUSCC) were included. Logistic regression was used to identify risk factors for liver metastasis. Cox proportional hazards regression model was adopted to determine independent prognostic factors in BCLM patients. RESULTS: Young age, invasive ductal carcinoma, higher pathological grade, and subtype of triple-negative and human epidermal growth factor receptor 2 positive (HER2+) were risk factors for developing liver metastasis. The median OS after liver metastasis was 20.0 months in the SEER database and 27.3 months in the FUSCC dataset. Molecular subtypes also played a critical role in the survival of BCLM patients. We observed that hormone receptor-positive (HR+)/HER2+ patients had the longest median OS (38.0 for SEER vs. 34.0 months for FUSCC), whereas triple-negative breast cancer had the shortest OS (9.0 vs. 15.6 months) in both SEER and FUSCC. According to the results from the FUSCC, the subtype of HR+/HER2+ (hazard ratio (HR) = 2.62; 95% confidence interval (CI) = 1.88-3.66; P < 0.001) and HR-/HER2+ (HR = 3.43; 95% CI = 2.28-5.15; P < 0.001) were associated with a significantly increased death risk in comparison with HR+/HER2- patients if these patients did not receive HER2-targeted therapy. For those who underwent HER2-targeted therapy, however, HR+/HER2+ subtype reduced death risk compared with HR+/HER2- subtype (HR = 0.74; 95% CI = 0.58-0.95; P < 0.001). CONCLUSIONS: Breast cancer patients at a high risk for developing liver metastasis deserve more attention during the follow-up. BCLM patients with HR+/HER2+ subtype displayed the longest median survival than HR+/HER2- and triple-negative patients due to the introduction of HER2-targeted therapy and therefore it should be recommended for HER2+ BCLM patients.

Predicting Nonsentinel Lymph Node Metastasis in Breast Cancer: A Multicenter Retrospective Study.

BACKGROUND: Sentinel lymph node (SLN) biopsy has been the standard modality for breast cancer patients with clinically node negative disease. In patients who undergo axillary lymph node dissection (ALND) due to SLN metastasis, the harvested nodes (non-SLNs) often contain no metastasis. Here, we evaluated the predictive factors associated with non-SLN metastasis in breast cancer patients. MATERIALS AND METHODS: This was a retrospective study of patients with operable cT1-3, cN0 invasive breast cancer who underwent SLN biopsy followed by ALND due to SLN metastasis. The clinicopathologic factors and predictive factors of non-SLN metastasis were analyzed. The optimal cutoff for the Ki67 index and the number of positive and negative SLNs that were predictive of non-SLN metastasis were evaluated using receiver operating characteristic curves. RESULTS: The median number of SLN and non-SLN was 3 and 11, respectively. Of the 150 patients, 52 (35.0%) had metastases in non-SLNs. The optimal cutoffs for the Ki67 index and the number of positive and negative SLNs were of 12%, 2, and 1, respectively. In the univariate analysis, the Ki67 index and the number of positive SLNs≥2 and negative SLNs≤1 were higher in the non-SLN + group than that in the non-SLN - group. The number of negative SLNs was as a predictive factor for non-SLNs metastasis in the multivariate analysis. CONCLUSIONS: The number of negative SLNs predicts the risk of non-SLN metastasis in breast cancer. When deciding on whether to omit ALND, the number of positive and negative SLNs should be considered.

Leveraging the increased rates of pathologic complete response after neoadjuvant treatment in breast cancer to de-escalate surgical treatments.

INTRODUCTION: Breast conservative surgery (BCS) and sentinel lymph node biopsy (SLNB) after neoadjuvant treatment (NAT) is safe and effective for selected patients. This aim of this study is to evaluate the impact of anatomic site of response on outcomes and to assess the real population who may benefit from nonsurgical approaches after NAT. MATERIAL AND METHODS: From a prospectively maintained database, patients with T1-4 N0-2 breast cancer undergoing NAT were identified. Clinicopathological and survival rates were compared in relation to response and anatomic site of response. RESULTS: Six hundred and forty-six patients were included in the study. Pathologic complete response (pCR) was an independent factor for BCS and SLN. HER2 positive and TN tumors with cN0 achieving a breast pCR remain ypN0 (p = .002). Residual axillary disease was associated with breast residual tumor (p = .05) and subtype (p = .001). With a median follow up of 35.25 months, patients with any pCR had improved survival when compared with partial response, but not significant differences between pCR, axillary pCR, or breast pCR. CONCLUSION: Achieving a pCR increases BCS and SLN. In selected subgroups, sparing any axillary surgery after NAT maybe feasible. In cN+ patients, any pCR was associated with survival, but not the anatomic site of response.

Integrin alpha-2 and beta-1 expression increases through multiple generations of the EDW01 patient-derived xenograft model of breast cancer-insight into their role in epithelial mesenchymal transition in vivo gained from an in vitro model system.

BACKGROUND: Breast cancers acquire aggressive capabilities via epithelial to mesenchymal transition (EMT), in which various integrins/integrin-linked kinase signalling are upregulated. METHODS: We investigated this in two patient-derived xenografts (PDXs) developed from breast-to-bone metastases, and its functional significance in a breast cancer cell line system. ED03 and EDW01 PDXs were grown subcutaneously in immunocompromised SCID mice through 11 passages and 7 passages, respectively. Tumour tissue was assessed using immunohistochemistry (IHC) for oestrogen receptor (ER)-alpha, E-cadherin, vimentin, Twist1, beta-catenin, P120-RasGAP, CD44, CD24 and Ki67, and RT-qPCR of EMT-related factors (CDH1, VIM, CD44, CD24), integrins beta 1 (ITGB1), alpha 2 (ITGA2) and ILK. Integrin and ILK expression in epidermal growth factor (EGF)-induced EMT of the PMC42-ET breast cancer cell line was assessed by RT-qPCR and Western blotting, as were the effects of their transient knockdown via small interfering RNA +/- EGF. Cell migration, changes in cell morphology and adhesion of siRNA-transfected PMC42-ET cells to various extracellular matrix (ECM) substrates was assessed. RESULTS: The ED03 (ER+/PR-/HER2-/lobular) and EDW01 (ER+/PR-/HER2-/ductal) PDXs were both classified as molecular subtype luminal A. ED03 xenografts exhibited mutated E-cadherin with minimal expression, but remained vimentin-negative across all passages. In EDW01, the hypoxic indicator gene CAIX and Twist1 were co-ordinately upregulated at passages 4-5, corresponding with a decrease in E-cadherin. At passages 6-7, VIM was upregulated along with ITGB1 and ITGA2, consistent with an increasing EMT. The ED03 PDX displayed minimal change over passages in mice, for all genes examined. ILK, ITGB1 and ITGA2 mRNAs were also increased in the EGF-induced EMT of PMC42-ET cells (in which CDH1 was downregulated) although siRNA against these targets revealed that this induction was not necessary for the observed EMT. However, their knockdown significantly reduced EMT-associated adhesion and Transwell migration. CONCLUSION: Our data suggest that despite an increase in ITGA2 and ITGB1 gene expression in the EMT exhibited by EDW01 PDX over multiple generations, this pathway may not necessarily drive the EMT process.

Chemotherapy use near the end-of-life in patients with metastatic breast cancer.

INTRODUCTION: Very few data are available regarding the use of chemotherapy in patients with metastatic breast cancer (MBC) near the end-of-life, i.e., the final month. The aim of this study was to provide a descriptive analysis of its use in two different European geographic areas (Sweden and Greece). MATERIALS AND METHODS: We retrospectively collected data regarding clinicopathologic characteristics, survival, and use of chemotherapy during the final 30 days of life using two sources: for the Swedish cohort, patients who were diagnosed with MBC in 2010-2015 were identified from the Stockholm-Gotland population-based Breast Cancer Registry and treatment data were collected using hospital charts. For the Greek cohort, patients with MBC were identified from hospital charts at two hospitals in Athens and Crete. RESULTS: In the Swedish cohort, 1571 patients were identified; median overall survival was 16.96 months (95% CI 15.4-18.4). 23.2% of patients were treated with chemotherapy during the final month of life, with higher rates among patients ≤ 60 years (p < 0.001). Per OS monotherapy such as capecitabine or vinorelbine was most commonly used. In contrast, median OS in the Greek cohort (n = 966) was 49.8 months (95% CI 45.6-54.1) and 46.5% of patients received chemotherapy at the end-of-life, most commonly intravenous drug combinations. In multivariable analysis, age and albumin levels were statistically significantly associated with chemotherapy use in the Swedish cohort. CONCLUSION: Chemotherapy use near the end-of-life was common, which might negatively impact patient quality of life.

High expression of OSR1 as a predictive biomarker for poor prognosis and lymph node metastasis in breast cancer.

PURPOSE: Oxidative stress-responsive kinase 1 (OSR1) plays a crucial role in regulating diverse cellular pathophysiologic functions, including ion homeostasis, development, differentiation, angiogenesis, invasive migration, and metastasis. Regardless, the clinical significance of OSR1 in breast cancer is scarce. The current study was conducted to evaluate the effect of OSR1 on the prognosis of patients with breast cancer with a long-term follow-up. METHODS: OSR1 expression in formalin-fixed and paraffin-embedded tissue specimens was analyzed. These specimens were collected from 551 evaluable breast cancer cases by immunohistochemistry (IHC). OSR1 expression was dichotomized based on the H-score in IHC. The effects of OSR1 levels on the clinicopathological attributes and survival prediction in patients with breast cancer were explored. RESULTS: Among 551 specimens, 183 (33.2%) exhibited high expression of OSR1 in tumor cells. High OSR1 levels were markedly correlated with histologic grade (P = 0.035), ER (P < 0.001) and PgR (P = 0.043) expression, lymph node involvement (P < 0.001), TNM stage (P < 0.001), and axillary surgery procedures (P = 0.003). Univariate analysis results indicate that patients with high OSR1 expression had significantly poor overall survival (P < 0.001), distant disease-free survival (P < 0.001), and breast cancer-specific survival (P < 0.001). Multivariable Cox regression analyses suggest that OSR1 expression was an independent predictive marker of poor prognosis and lymph node metastasis (HR 3.224, 95% CI 1.182-8.702, P = 0.023) in patients with breast cancer. CONCLUSIONS: Our findings indicate that OSR1 is a significantly independent prognosis index for patients with breast cancer with respect to distant disease-free survival, overall survival, and breast cancer-specific survival. High OSR1 expression caused an increase in deaths specifically attributed to breast cancer and was related to increased lymph node metastasis. However, the precise cellular mechanisms for OSR1 in breast cancer require further research.

Axillary lymph node dissection is not obligatory in breast cancer patients with biopsy-proven axillary lymph node metastasis.

PURPOSE: The ACOSOG Z0011 trial demonstrated that axillary lymph node dissection (ALND) is unnecessary in select patients with cT1-2N0 tumors undergoing breast-conserving therapy with 1-2 positive sentinel lymph nodes (SLNs). However, patients with preoperatively confirmed ALN metastasis were not included and may be subjected to unnecessary ALND. The aim of this study is to identify patients who can be considered for ALND omission when the preoperative ALN biopsy results are positive. METHODS: Breast cancer patients who underwent preoperative ALN biopsy and primary surgery were retrospectively reviewed. Among patients with positive ALN biopsy results, clinicopathological and imaging characteristics were compared according to LN disease burden (1-2 positive LNs vs. ≥ 3 positive LNs). RESULTS: A total of 542 patients were included in the analysis. Among them, 225 (41.5%) patients had a preoperative positive ALN biopsy. More than 40% of the patients (n = 99, 44.0%) with a positive biopsy had only 1-2 positive ALNs. The association between nodal burden and imaging factors was strongest when ≥ 2 suspicious LNs were identified on PET/CT images (HR 8.795, 95% CI 4.756 to 13.262). More than one imaging modality showing ≥ 2 suspicious LNs was also strongly correlated with ≥ 3 positive ALNs (HR 5.148, 95% CI 2.881 to 9.200). CONCLUSIONS: Nearly half of patients with a preoperative biopsy-proven ALN metastasis had only 1-2 positive LNs on ALND. Patients meeting ACOSOG Z0011 criteria with only one suspicious LN on PET/CT or those presenting with few abnormal ALNs on only one imaging modality appear appropriate for SLNB and consideration of ALND omission.

ABREAST: a prospective, real-world study on the effect of nab-paclitaxel treatment on clinical outcomes and quality of life of patients with metastatic breast cancer.

PURPOSE: The efficacy of nab-paclitaxel in patients with metastatic breast cancer (MBC) has been demonstrated in randomized clinical trials. However, real-world evidence on effectiveness remains limited. PATIENTS AND METHODS: The primary objective of this multicenter prospective study was to assess the overall response rate (ORR) of patients with MBC treated with nab-paclitaxel. Secondary objectives included progression-free survival (PFS), overall survival (OS) and quality of life, assessed with the Functional Assessment of Cancer Therapy-Breast (FACT-B) instrument. RESULTS: Eligible patients (N = 150; 36% with de novo MBC presentation) with a median age of 64.5 years were enrolled (86% were ER+, 33.3% (50/150) were ≥ 70 years of age and 53% were treated in the third or later line of treatment). A median of 6 cycles were administered but 26% of patients required dose reduction due to toxicity. The ORR was 26.7% [95% confidence interval (CI) 19.6-33.7], the median PFS was 6.2 months (95% CI 5.2-7.3), and the median OS 21.1 months (95% CI 17.2-not estimable). There was no statistical significant difference in the median PFS of patients < and ≥ 70 years of age. The patients' baseline FACT-B total score remained unchanged. The serious and non-serious adverse event incidence rates were 13% and 48%, respectively. CONCLUSIONS: This prospective study provides further evidence on quality of life, efficacy, and safety of nab-paclitaxel in patients with MBC and sheds more light in special subpopulations such as the elderly and those treated beyond the second line.

Invasive apocrine carcinoma of the breast: clinicopathologic features and comprehensive genomic profiling of 18 pure triple-negative apocrine carcinomas.

Pure invasive apocrine carcinoma is a rare type of primary breast cancer, constituting ~1% of all breast cancers. Since most pure invasive apocrine carcinomas are triple negative, the lack of targeted therapies for triple-negative breast cancer has fostered efforts to discover actionable molecular targets in these tumors. In this study, we analyzed the clinicopathologic characteristics and comprehensive genomic profiling of 18 patients with pure triple-negative apocrine carcinomas (TNACs) using a 324-gene panel assay (FoundationOne CDx). The median age of these patients was 55.5 years, and the postmenopausal status rate was 77.8%. In total, 83.3% of patients were diagnosed with histological grade II, and 16.7% were diagnosed with grade III. The majority of patients presented at an early tumor-node-metastasis (TNM) stage (I: 38.9%; II: 50.0%; and III: 11.1%). The mean Ki-67 index was 9.7%, and the percent of PD-L1 positivity was 11.7%. With a median follow-up period of 76.5 months, one patient died, and two experienced distant metastases. There were 61 clinically relevant genomic alterations among all 18 pure TNACs, and the mean tumor mutation burden (TMB) was 3 Mut/Mb. The top ranked altered genes were PIK3CA (72.2%), PTEN (33.3%) and TP53 (27.8%). There were four novel mutations found in PTEN and an actionable rearrangement involving FGFR2-TACC2 that has not been reported in breast cancer before. In total, 88.9%, 50%, 44.4%, and 16.7% of TNACs had at least one clinically relevant genomic alteration in genes involved in the PI3K/mTOR, cell cycle, RAS/RAF/MEK and growth factor receptor-related pathways, respectively. All patients had at least one clinically relevant genomic alteration, and 94.4% had at least one actionable alteration. To the best of our knowledge, this study is the largest genomic sequencing cohort of pure TNACs. Incorporation of comprehensive genomic profiling into TNACs might shed light on potential therapeutic opportunities for both targeted drugs and immune checkpoint inhibitors.

The role of different lymph node staging systems in predicting prognosis and determining indications for postmastectomy radiotherapy in patients with T1-T2pN1 breast carcinoma.

PURPOSE: Based on the risk of locoregional recurrence (LRR), postmastectomy radiotherapy (PMRT) is recommended in T1-T2pN1 breast carcinoma (BC). We aimed to elucidate our institutional strategies underlying selection of these patients for PMRT. In the no-PMRT subset, we compared various lymph node (LN) staging systems' abilities to predict 5­year overall and locoregional-free survival (OS/LRFS). METHODS: We retrospectively enrolled 548 women with T1-T2pN1 BC undergoing mastectomy and axillary LN dissection. Depending on PMRT delivery, the participants were divided into the PMRT and no-PMRT groups. Predictors of OS/LRFS were calculated for the no-PMRT group only. Based on Cox regression modelling, the number of positive LNs (PLN), negative LNs (NLN), LN ratio (LNR), log odds of PLN (LODDS), and modified LNR (mLNR) were modelled, each respectively, with OS model covariates (age, grade III, lymphovascular invasion [LVI], tumor size, hormone receptor [HR] status) and LRFS model covariates (age, grade III, LVI). The C­statistic, Akaike information criterion, and likelihood ratio χ2 of the models were compared. RESULTS: Median follow-up was 60.5 (18-82), 61 (28-82), and 60 (18-80) months for the entire cohort, PMRT, and no-PMRT group, respectively. The PMRT and no-PMRT groups had comparable OS (p = 0.235). LRFS was better (p = 0.030) in the PMRT group comprising 105 subjects (19.16%) who were younger, more likely to have a higher-grade, HR-, HER2+ tumors, more PLNs, fewer NLNs, Ki-67 ≥ 20%, LVI, and extranodal extension (p ≤ 0.001). In the no-PMRT group, LNR-based OS/LRFS models exhibited superior prognostic performance. CONCLUSION: In early-stage BC patients undergoing mastectomies, LN dissections and no PMRT, we propose LNR-based multivariable models to predict OS/LRFS with superior accuracy.

Intratumoral heterogeneity of second-harmonic generation scattering from tumor collagen and its effects on metastatic risk prediction.

BACKGROUND: Metastases are the leading cause of breast cancer-related deaths. The tumor microenvironment impacts cancer progression and metastatic ability. Fibrillar collagen, a major extracellular matrix component, can be studied using the light scattering phenomenon known as second-harmonic generation (SHG). The ratio of forward- to backward-scattered SHG photons (F/B) is sensitive to collagen fiber internal structure and has been shown to be an independent prognostic indicator of metastasis-free survival time (MFS). Here we assess the effects of heterogeneity in the tumor matrix on the possible use of F/B as a prognostic tool. METHODS: SHG imaging was performed on sectioned primary tumor excisions from 95 untreated, estrogen receptor-positive, lymph node negative invasive ductal carcinoma patients. We identified two distinct regions whose collagen displayed different average F/B values, indicative of spatial heterogeneity: the cellular tumor bulk and surrounding tumor-stroma interface. To evaluate the impact of heterogeneity on F/B's prognostic ability, we performed SHG imaging in the tumor bulk and tumor-stroma interface, calculated a 21-gene recurrence score (surrogate for OncotypeDX®, or S-ODX) for each patient and evaluated their combined prognostic ability. RESULTS: We found that F/B measured in tumor-stroma interface, but not tumor bulk, is prognostic of MFS using three methods to select pixels for analysis: an intensity threshold selected by a blinded observer, a histogram-based thresholding method, and an adaptive thresholding method. Using both regression trees and Random Survival Forests for MFS outcome, we obtained data-driven prediction rules that show F/B from tumor-stroma interface, but not tumor bulk, and S-ODX both contribute to predicting MFS in this patient cohort. We also separated patients into low-intermediate (S-ODX < 26) and high risk (S-ODX ≥26) groups. In the low-intermediate risk group, comprised of patients not typically recommended for adjuvant chemotherapy, we find that F/B from the tumor-stroma interface is prognostic of MFS and can identify a patient cohort with poor outcomes. CONCLUSIONS: These data demonstrate that intratumoral heterogeneity in F/B values can play an important role in its possible use as a prognostic marker, and that F/B from tumor-stroma interface of primary tumor excisions may provide useful information to stratify patients by metastatic risk.

Prognostic factors and survival according to tumour subtype in women presenting with breast cancer bone metastases at initial diagnosis: a SEER-based study.

BACKGROUND: Tumour subtype has a significant effect on bone metastasis in breast cancer, but population-based estimates of the prognosis of patients with bone metastases at breast cancer diagnosis are lacking. The aim of this study was to analyse the influence of tumour subtype and other factors on the prognosis and survival of patients with bone metastases of breast cancer. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) Program data from 2012 to 2016, a retrospective cohort study was conducted to investigate stage IV breast cancer patients with bone metastases. Stage IV patient characteristics according to subtype were compared using chi-square tests. Overall survival (OS) and prognostic factors were compared using the Kaplan-Meier method and the Cox proportional hazards model, respectively. RESULTS: A total of 3384 stage IV patients were included in this study; 63.42% were HR+/HER2-, 19.86% were HR+/HER2+, 9.34% were HR-/HER2-, and 7.39% were HR-/HER2+. The median OS for the whole population was 38 months, and 33.9% of the patients were alive at 5 years. The median OS and five-year survival rate were significantly different among stage IV breast cancer patients with different molecular subtypes (p < 0.05). Multivariate Cox regression analysis showed that age of 55-59 (HR = 1.270), black race (HR = 1.317), grade III or IV (HR = 1.960), HR-/HER2- (HR = 2.808), lung metastases (HR = 1.378), liver metastases (HR = 2.085), and brain metastases (HR = 1.903) were independent risk factors for prognosis; married status (HR = 0.819), HR+/HER2+ (HR = 0.631), HR-/HER2+ (HR = 0.716), insurance (HR = 0.587) and surgery (HR = 0.504) were independent protection factors of prognosis. There was an interaction between the HR+/HER2+ subtype and other metastases (except bone metastases, HR = 0.694, 95% CI: 0.485-0.992), but the interaction between race and subtype did not reach significance for prognosis. CONCLUSIONS: There were substantial differences in OS according to tumour subtype. In addition to tumour subtype, other independent predictors of OS were age at diagnosis, race, marital status, insurance, grade, surgery and visceral metastases. There was an interaction between the HR+/HER2+ subtype and other metastases (except bone metastases) for prognosis. Tumour subtype, as a significant prognostic factor, warrants further investigation.

Can a machine-learning model improve the prediction of nodal stage after a positive sentinel lymph node biopsy in breast cancer?

Background: The current standard for evaluating axillary nodal burden in clinically node negative breast cancer is sentinel lymph node biopsy (SLNB). However, the accuracy of SLNB to detect nodal stage N2-3 remains debatable. Nomograms can help the decision-making process between axillary treatment options. The aim of this study was to create a new model to predict the nodal stage N2-3 after a positive SLNB using machine learning methods that are rarely seen in nomogram development.Material and methods: Primary breast cancer patients who underwent SLNB and axillary lymph node dissection (ALND) between 2012 and 2017 formed cohorts for nomogram development (training cohort, N = 460) and for nomogram validation (validation cohort, N = 70). A machine learning method known as the gradient boosted trees model (XGBoost) was used to determine the variables associated with nodal stage N2-3 and to create a predictive model. Multivariate logistic regression analysis was used for comparison.Results: The best combination of variables associated with nodal stage N2-3 in XGBoost modeling included tumor size, histological type, multifocality, lymphovascular invasion, percentage of ER positive cells, number of positive sentinel lymph nodes (SLN) and number of positive SLNs multiplied by tumor size. Indicating discrimination, AUC values for the training cohort and the validation cohort were 0.80 (95%CI 0.71-0.89) and 0.80 (95%CI 0.65-0.92) in the XGBoost model and 0.85 (95%CI 0.77-0.93) and 0.75 (95%CI 0.58-0.89) in the logistic regression model, respectively.Conclusions: This machine learning model was able to maintain its discrimination in the validation cohort better than the logistic regression model. This indicates advantages in employing modern artificial intelligence techniques into nomogram development. The nomogram could be used to help identify nodal stage N2-3 in early breast cancer and to select appropriate treatments for patients.

Synchronous small lymphocytic lymphoma and metastatic breast carcinoma in axillary lymph nodes: Preservation of follicular architecture only in the portions of affected lymph nodes involved by metastatic carcinoma.

We present a case of metastatic ductal carcinoma of breast with the incidental discovery of small lymphocytic lymphoma (SLL) in regional axillary nodes. The co-occurence of metastatic carcinoma and low-grade lymphoma in lymph nodes is rare but well recognized. However, in this case, in the lymph nodes in which sizeable metastatic carcinoma deposits were present, the follicular structures between the sinusoidal carcinomatous infiltrates were preserved, whereas the uninvolved portions of the nodes were overrun by SLL. This is the first description of this phenomenon. We suggest that further cases displaying this previously unpublished pattern are collated in order that we may begin to investigate the underlying etiological mediators.