Asymptomatic distant recurrence detection and survival in early stage breast cancer: A nationally representative study.

6520 Background: Breast cancer follow-up guidelines recommend imaging for distant metastases only in the presence of signs/symptoms. However, data supporting this recommendation predates the current era of improved imaging and targeted therapies based on molecular subtype. The objective was to assess the relationship between mode of distant recurrence detection and survival. Methods: A stage-stratified random sample of Stage II-III breast cancer patients diagnosed in 2006-7 was selected from NCDB records from 1,217 CoC-accredited facilities (10/hospital n = 10,853). Women were categorized by subtype: 1) ER or PR+/HER2-; 2) ER and PR-/Her2- (triple negative); 3) HER2+. Medical records abstracted for 5-years post-surgery supplemented NCDB data and assessed distant recurrence and mode of detection (prompted by signs/symptoms or surveillance imaging), imaging (chest CT, abdomen/pelvis CT/MRI, head CT/MRI, bone scan, PET/CT), death date. The relationship between mode of recurrence detection and days from initial cancer diagnosis to death was assessed using propensity-weighted multivariable Cox proportional hazards regression stratified by subtype. Propensity weights, based on receipt of surveillance systemic imaging, accounted for sociodemographic and tumor/treatment factors. Results: 5-year distant recurrence was 22.3% for triple negative, 14.8% HER2+, and 11.2% for ER or PR+/ HER2- patients. Asymptomatic imaging detected recurrence in 22.9% and signs/symptoms in 77.1%. Patients with asymptomatic as compared to sign/symptom detected recurrences had reduced risk of death in 5 years if triple negative (HR = 0.68, 95% CI = 0.50-0.93) or HER2+ (HR = 0.40, 95% CI = 0.24-0.65) with no significant association for ER or PR+/HER2- (HR = 1.2, 95% CI = 0.88-1.51). This translated to a between-group difference in weighted median survival of 5 months for triple negative and 13 months for HER2+ patients. Conclusions: This is the first nationally representative study to show a survival advantage with asymptomatic detection of distant metastases for patients, with the benefit limited to triple negative and HER2+ disease. Further research to confirm observational findings is warranted.

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Prognostic Value of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancers From Two Phase III Randomized Adjuvant Breast Cancer Trials: ECOG 2197 and ECOG 1199

Journal of Clinical Oncology ◽

10.1200/jco.2013.55.0491 ◽

2014 ◽

Vol 32 (27) ◽

pp. 2959-2966 ◽

Cited By ~ 602

Author(s):

Sylvia Adams ◽

Robert J. Gray ◽

Sandra Demaria ◽

Lori Goldstein ◽

Edith A. Perez ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative ◽

Eastern Cooperative Oncology Group ◽

Multivariable Analysis ◽

Tumor Infiltrating Lymphocytes ◽

Distant Recurrence ◽

Phase Iii ◽

Prognostic Impact ◽

Risk Of Death ◽

Infiltrating Lymphocytes

Purpose Recent studies suggest that tumor-infiltrating lymphocytes (TILs) are associated with disease-free (DFS) and overall survival (OS) in operable triple-negative breast cancer (TNBC). We seek to validate the prognostic impact of TILs in primary TNBCs in two adjuvant phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG). Patients and Methods Full-face hematoxylin and eosin–stained sections of 506 tumors from ECOG trials E2197 and E1199 were evaluated for density of TILs in intraepithelial (iTILs) and stromal compartments (sTILs). Patient cases of TNBC from E2197 and E1199 were randomly selected based on availability of sections. For the primary end point of DFS, association with TIL scores was determined by fitting proportional hazards models stratified on study. Secondary end points were OS and distant recurrence–free interval (DRFI). Reporting recommendations for tumor marker prognostic studies criteria were followed, and all analyses were prespecified. Results The majority of 481 evaluable cancers had TILs (sTILs, 80%; iTILs, 15%). With a median follow-up of 10.6 years, higher sTIL scores were associated with better prognosis; for every 10% increase in sTILs, a 14% reduction of risk of recurrence or death (P = .02), 18% reduction of risk of distant recurrence (P = .04), and 19% reduction of risk of death (P = .01) were observed. Multivariable analysis confirmed sTILs to be an independent prognostic marker of DFS, DRFI, and OS. Conclusion In two national randomized clinical trials using contemporary adjuvant chemotherapy, we confirm that stromal lymphocytic infiltration constitutes a robust prognostic factor in TNBCs. Studies assessing outcomes and therapeutic efficacies should consider stratification for this parameter.

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Pathological characteristics, distant recurrence rates, and survival outcomes of breast cancer with triple-negative phenotype

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e11554 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e11554-e11554

Author(s):

C. K. Lee ◽

E. Choo ◽

C. R. Lewis

Keyword(s):

Breast Cancer ◽

Triple Negative ◽

Histological Grade ◽

Survival Rates ◽

Distant Metastases ◽

Distant Recurrence ◽

Screening Mammography ◽

Survival Outcomes ◽

Recurrence Rates ◽

Time To Recurrence

e11554 Background: Breast cancer is a heterogeneous disease encompassing entities with distinct biological characteristics and clinical course. Triple-negative disease (TND) is clinically aggressive disease with limited effective therapy. We compare the clinico- pathologic characteristics, recurrence and survival rates of patients with TND and non-TND. Methods: The POWH Cancer Centre breast cancer database was retrospectively reviewed from January 1995 to December 2005. 1254 eligible women with breast cancer undergoing definitive primary breast surgery were identified. TND was defined as ER-, PR- and HER2 0 or 1+ by IHC and / or florescent in- situ hybridization (FISH) negative. Non-TND was defined as either ER+ and / or PR+ and/or HER2+. Further comparisons of survival outcomes were analyzed in a subgroup of 785 patients subdivided into three groups: ER+ and/or PR+ and HER2-, HER2+ and TND. Results: There were 135 patients (10.8%) with TND. TND tumours were characterized by larger size (p=0.02), histological grade 3 (p<0.001), presence of lymphovascular invasion (p=0.03), and less likely to be diagnosed by screening mammography (p<0.001) when compared with non-TND. Amongst those developing distant metastases, the median time to recurrence was 16 months for TND compared to 35 months in non-TND. There was a trend in visceral metastases for TND as compared to non-TND (OR=1.86, p=0.06). The adjusted rates for distant recurrence (HR=3.55, p=0.006), and death (HR=3.48, p=0.01) were significantly higher for TND when compared with non-TND only for first two years after diagnosis. Beyond the two years, there was no difference in distant recurrence and overall survival. Majority of the patients did not receive adjuvant anti-HER2 therapy during the study period. When compared to ER+ and/or PR+ and HER2- cohort, the survival rate was significantly poorer for TND (HR=2.66, p<0.001) but non-significant for HER2+ (1.61, p=0.1). Conclusions: Poorer histopathological phenotypes are observed in TND. Patients with TND have higher rates of developing distant metastases. Survival rates are also poorer in TND patients. The risks of distant recurrence and death are not proportional across time and these risks are strongly time-dependent. No significant financial relationships to disclose.

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Adjuvant therapy for early stage breast cancer (EBC): Distant disease-free survival (DDFS) as a predictor of overall survival (OS)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.583 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 583-583 ◽

Cited By ~ 4

Author(s):

M. Melisko ◽

A. Lin ◽

H. Rugo

Keyword(s):

Breast Cancer ◽

Early Stage ◽

Disease Free Survival ◽

Distant Metastases ◽

Cancer Therapies ◽

Risk Of Death ◽

Hormone Receptor Positive ◽

Post Surgery ◽

Estrogen Receptor Positive ◽

The Impact

583 Background: OS advantages are often difficult to demonstrate in trials evaluating treatment for EBC, as this requires long follow-up (FU) and large trials. Results are also confounded by factors such as further treatment. DFS, the primary endpoint in many adjuvant trials, is not a consistent predictor of OS and lack of standard definitions renders its interpretation difficult. A better, quicker endpoint is needed as a surrogate for OS. Distant metastases (DM), the most common type of recurrence, are responsible for the initial peak of relapse seen at 2 years post surgery and are associated with the highest risk of death compared to locoregional and contralateral events. DDFS may be a better short-term OS predictor. Methods: The impact of common adjuvant therapies (chemotherapy [CT], tamoxifen [TAM], and aromatase inhibitors [AIs]) on DM risk and OS was examined. Results: CT trials show that improvements in DDFS often precede subsequent improvements in OS. In NSABP B14, TAM significantly improved DDFS at 4 years and OS at 10 years. In ATAC and BIG 1–98, over half of EBC recurrences are DM, but OS differences are limited by short FU. BIG 1–98 showed a significant reduction in DM risk with letrozole versus TAM, but ATAC showed no significant reduction in DM risk with anastrozole in hormone receptor-positive patients. The reason for this difference is unclear. IES initially showed a significant reduction in DM risk, which was later followed by a borderline significant OS benefit in estrogen receptor-positive/unknown patients, favoring exemestane. Conclusion: Data from several adjuvant trials show that improvements in DDFS often precede significant improvements in OS. AIs show superiority over TAM in reducing DM risk (IES, BIG 1–98). DDFS may be a better, more achievable endpoint than OS for women with EBC and could quicken the development of future adjuvant breast cancer therapies. [Table: see text] No significant financial relationships to disclose.

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Topographic distribution of lymphocyte infiltrate in triple negative tumors and its impact on the survival of the patient with breast cancer

Mastology ◽

10.29289/259453942020v30s1060 ◽

2020 ◽

Vol 30 (Suppl 1) ◽

Author(s):

Jose Peixoto ◽

Marcos Duarte Guimarães ◽

Maria Aparecida Seabra ◽

Olávio Campos ◽

Ana Carolina Ferraz Pascoal

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Molecular Subtype ◽

Early Stage ◽

Target Therapy ◽

Intraclass Correlation ◽

Cross Sectional ◽

Risk Of Death ◽

Lymphocyte Infiltrate

Introduction: Tumor infiltrating lymphocytes (TIL) are generally measured using subjective methods unable to differentiate subpopulations and to locate immune cells in the tumor microenvironment. The identification and location of these cells is of great importance as they present different responses to immune stimuli. Objective: to analyze the presence of TIL in early-stage breast cancer of the triple negative molecular subtype, and to evaluate the association of TIL with the overall survival time (OS). Methods: a cross-sectional study was carried out at the Hospital de Câncer de Pernambuco (HCP), where patients diagnosed with triple negative breast cancer were selected between 2009 and 2013. TIL evaluation was performed by two methods: on slides stained with hematoxylin and eosin (H&E), by two pathologists blindly and independently, and on slides submitted to immunohistochemistry, with CD3 and CD8 lymphocyte marking. In this case, the sample was then subjected to computerized histophotometry and morphometric analysis. Results: 87 patients were included, of which 22 patients had an event in the follow-up period. The evaluation of TIL, by two pathologists, showed regular agreement between the evaluators, with an intraclass correlation coefficient of 0.574 and p=0.001. CD3+ and CD8+ lymphocytes were in greater quantity in the intra tumor area compared to those outside the tumor margin (extra tumor). When the association between the presence of lymphocytes and the patient’s OS was analyzed, a directly proportional relationship with this survival was observed, that is, the greater the amount of lymphocytes, the lower the risk of death. Conclusion: results suggest that there is a correlation between the tumor lymphocyte infiltrate of triple negative breast cancer and OS. As this tumor subtype has a poor prognosis and does not have specific target therapy, TIL analysis can be explored as a prognostic marker for the treatment of breast cancer.

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Highly metastatic claudin-low mammary cancers can originate from luminal epithelial cells

Nature Communications ◽

10.1038/s41467-021-23957-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Patrick D. Rädler ◽

Barbara L. Wehde ◽

Aleata A. Triplett ◽

Hridaya Shrestha ◽

Jonathan H. Shepherd ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cell ◽

Epithelial Cells ◽

Triple Negative ◽

Molecular Subtype ◽

Ras Signaling ◽

Preneoplastic Lesions ◽

Independent Manner ◽

Oncogenic Ras ◽

Luminal Epithelial Cells

AbstractClaudin-low breast cancer represents an aggressive molecular subtype that is comprised of mostly triple-negative mammary tumor cells that possess stem cell-like and mesenchymal features. Little is known about the cellular origin and oncogenic drivers that promote claudin-low breast cancer. In this study, we show that persistent oncogenic RAS signaling causes highly metastatic triple-negative mammary tumors in mice. More importantly, the activation of endogenous mutant KRAS and expression of exogenous KRAS specifically in luminal epithelial cells in a continuous and differentiation stage-independent manner induces preneoplastic lesions that evolve into basal-like and claudin-low mammary cancers. Further investigations demonstrate that the continuous signaling of oncogenic RAS, as well as regulators of EMT, play a crucial role in the cellular plasticity and maintenance of the mesenchymal and stem cell characteristics of claudin-low mammary cancer cells.

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Expression of Phosphorylated BRD4 Is Markedly Associated with the Activation Status of the PP2A Pathway and Shows a Strong Prognostic Value in Triple Negative Breast Cancer Patients

Cancers ◽

10.3390/cancers13061246 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1246

Author(s):

Marta Sanz-Álvarez ◽

Ion Cristóbal ◽

Melani Luque ◽

Andrea Santos ◽

Sandra Zazo ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Molecular Subtype ◽

Molecular Target ◽

Prognostic Impact ◽

Breast Cancer Patients ◽

Bet Inhibitors ◽

Brd4 Inhibition ◽

Bet Protein

The bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal domain (BET) protein family, has emerged in the last years as a promising molecular target in many tumors including breast cancer. The triple negative breast cancer (TNBC) represents the molecular subtype with the worst prognosis and a current therapeutic challenge, and TNBC cells have been reported to show a preferential sensitivity to BET inhibitors. Interestingly, BRD4 phosphorylation (pBRD4) was found as an alteration that confers resistance to BET inhibition and PP2A proposed as the phosphatase responsible to regulate pBRD4 levels. However, the potential clinical significance of pBRD4, as well as its potential correlation with the PP2A pathway in TNBC, remains to be investigated. Here, we evaluated the expression levels of pBRD4 in a series of 132 TNBC patients. We found high pBRD4 levels in 34.1% of cases (45/132), and this alteration was found to be associated with the development of patient recurrences (p = 0.007). Interestingly, BRD4 hyperphosphorylation predicted significantly shorter overall (p < 0.001) and event-free survival (p < 0.001). Moreover, multivariate analyses were performed to confirm its independent prognostic impact in our cohort. In conclusion, our findings show that BRD4 hyperphosphorylation is an alteration associated with PP2A inhibition that defines a subgroup of TNBC patients with unfavorable prognosis, suggesting the potential clinical and therapeutic usefulness of the PP2A/BRD4 axis as a novel molecular target to overcome resistance to treatments based on BRD4 inhibition.

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Retrospective Study about the Prevalence of (TILs) Tumor Infiltrating Lymphocytes in Non-Metastatic Triple Negative Breast Cancer Patients and its Prognostic Value

QJM ◽

10.1093/qjmed/hcab103.003 ◽

2021 ◽

Vol 114 (Supplement_1) ◽

Author(s):

Hesham Ahmed ElGhazaly ◽

Manal Mohamed El-Mahdy ◽

Azza Mohamed Adel ◽

Nermeen Mostafa ◽

Aya Magdy Kamal Ali

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Retrospective Study ◽

Triple Negative Breast Cancer ◽

Prognostic Value ◽

Triple Negative ◽

Free Survival ◽

Female Patients ◽

Risk Of Death ◽

Reduced Risk

Abstract Background TNBC comprises a distinct disease entity with a unique microenvironment of TILs, the immunogenic potential of TNBC is derived from its genetic instability and high mutation rate. Tumors from patients with TNBC are more likely than tumors from patients with other subtypes to exhibit chromosomal instability and potential mutations. Objectives The study aims to evaluate the prevalence of CD8+ TILs biomarker by IHC in triple negative breast cancer and its prognostic value. TILs are an important prognostic value for the response of patient to chemotherapy the greater number of TILS is associated with higher probability of response to chemotherapy also decrease recurrence. TILS in triple negative breast cancer suggest a likely option for immunotherapy in this disease. Patients and Methods This is a retrospective study, which was carried on 30 female patients, Clinical data and paraffin wax block of female patients with triple negative breast cancer are to be collected from the breast cancer unit, department of clinical Oncology and Nuclear medicine Ain Shams university and Matarya teaching hospital. Results Several large systematic reviews and meta-analyses have confirmed that high levels of TILs are associated with better disease free survival and overall survival only in triple negative and HER2 positive subtypes, with no significant benefit seen in estrogen receptor positive breast carcinoma. In the Breast International Group (BIG) 02-98 trial shows that for every 10% increase in the intertumoral TILs there was a 17% reduced risk of relapse, and 27% reduced risk of death regardless of chemotherapy type. Also in eastern cooperative oncology group trial (ECOG) 2197, and 1199 showed that for every 10% increase in TILs, a 14% reduction of risk of recurrence, and 19% reduction in risk of death were observed. Conclusion Our study showed that All our patients (100%) were positive for CD8+, with a minimum range of 1% and a maximum range of 60%, most of the patients (20 patients) had CD8% between (10% to 20%). High levels of CD8 + TILs are good prognostic indicators in TNBC. our study showed that there were associations of CD8+ TILs infiltrate status with longer progression free survival and better overall survival in triple-negative breast cancer, but were not statistically significant probably due to our small sample size.

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VPS52 expression associates with survival in triple negative breast cancer.

10.31219/osf.io/tjzdh ◽

2021 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Molecular Subtype ◽

Breast Cancer Patients ◽

Primary Tumors ◽

Free Survival ◽

Significant Gene ◽

Vacuolar Protein

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival following treatment: dead or alive. We observed significant transcriptome-wide differential expression of vacuolar protein sorting 52, encoded by VPS52 when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, VPS52 expression was correlated with recurrence-free survival in basal subtype breast cancer, a molecular subtype sharing significant overlap with triple negative breast cancer. VPS52 may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.

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MAP4K2 expression associates with survival in triple negative breast cancer.

10.31219/osf.io/rx3jv ◽

2021 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Molecular Subtype ◽

Mitogen Activated Protein Kinase ◽

Breast Cancer Patients ◽

Primary Tumors ◽

Mitogen Activated Protein ◽

Significant Gene

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival following treatment: dead or alive. We observed significant transcriptome-wide differential expression of mitogen-activated protein kinase kinase kinase kinase 2, encoded by MAP4K2 when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, MAP4K2 expression was correlated with distant metastasis-free survival in basal subtype breast cancer, a molecular subtype sharing significant overlap with triple negative breast cancer. MAP4K2 may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.

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PAX5 expression associates with survival in triple negative breast cancer.

10.31219/osf.io/rh6xb ◽

2021 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cancer Patients ◽

Triple Negative Breast Cancer ◽

Microarray Data ◽

Triple Negative ◽

Molecular Subtype ◽

Breast Cancer Patients ◽

Primary Tumors ◽

Significant Gene

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival following treatment: dead or alive. We observed significant transcriptome-wide differential expression of paired box 5, encoded by PAX5 when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, PAX5 expression was significantly correlated with overall survival in basal subtype breast cancer, a molecular subtype sharing significant overlap with triple negative breast cancer. PAX5 may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.

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