Diagnosis Of Non-metastatic Breast Cancer Research Articles

Delays in receipt of neoadjuvant chemotherapy compared to upfront surgery in patients with operable breast cancer.

100 Background: Delays in time from breast cancer (BC) diagnosis to BC treatment initiation (BCTI) including upfront breast surgery (UBS) or neoadjuvant chemotherapy (NACT), can negatively impact BC survival. We evaluated odds of delay in BCTI among patients (pts) who received NACT compared to pts who received UBS. Methods: We conducted a retrospective cohort study using the National Cancer Database. Eligibility included age ≥18 years, diagnosis of non-metastatic BC between 1/1/2010 – 12/31/2020, who were treated with NACT followed by surgery or UBS followed by adjuvant chemotherapy (AC). Pts who did not receive NACT or UBS within 180 days of diagnosis were excluded. The cohort was stratified by first BC treatment (NACT or UBS), and time to NACT (TTNACT) or time to surgery (TTS) was recorded for each patient in days. Pts were categorized into sub-cohorts by receptor status and clinical stage: 1) Hormone Receptor positive/HER-2 negative (HR+/HER2-) lymph node (LN)+; 2) HER-2 positive (HER2+) cT2+ or LN+; and 3) triple negative BC (TNBC) cT2+ or LN+. Logistic regression adjusted for demographic, socioeconomic, and tumor characteristics was used to identify delays in BCTI > 60 days. Multiple imputation was used for missing data. Inverse probability treatment weighting (IPTW) was done as a sensitivity analysis. Results: We identified 218,049 eligible pts, 75% were White, 18% were Black, and 8.6% were Hispanic. Median age was 53 years (range 18-90). There were 145,697 (67%) pts who received NACT with median TTNACT of 32days (range 0-180), and 9.8% had a delay > 60 days (Table). There were 72,353 (33.0%) pts who received UBS followed by AC, with a median TTS of 33 days (range 0-180), and 13% with a delay > 60 days. In multivariable analysis, pts who received UBS had higher odds of BCTI delays compared to NACT, with OR 1.50 (95%CI 1.42-1.57) [HR+/HER2-], OR 1.49 (95%CI 1.41-1.58) [HER2+], and OR 1.26 (95%CI 1.18-1.34) [TNBC]. Results from IPTW analysis were similar, groups were well balanced, and pts who received UBS had higher odds of BCTI OR 1.50 (95%CI 1.44-1.57) [HR+/HER2-], OR 1.75 (95%CI 1.67-1.83) [HER2+], and OR 1.46 (95%CI 1.38-1.53) [TNBC]. Conclusions: Among high clinical risk BC patients who received surgery and chemotherapy, those who underwent NACT were less likely to experience delays in BCTI compared to pts who received UBS first. Among eligible pts, use of NACT may reduce delays in BCTI. Patients who received NACT and UBS and associated delays by sub-cohort (n = 218,050). Neoadjuvant Chemotherapy Upfront Surgery N (%) Median TTNACT in Days N (%) Delayed >60 Days N (%) Median TTS in Days N (%) Delayed >60 days Total Cohort 145,697 (67.0) 32 14,221 (9.8) 72,353 (33.0) 33 9,725 (13) HR+/HER2 40,345 (27.7) 34 4,773 (11.8) 29, 676 (41.0) 36 4,754 (16.0) HER+ 56,868 (39.0) 32 5,135 (9.0) 21,759 (30.1) 32 2,771 (12.7) TNBC 48,484 (33.3) 31 4,313 (8.9) 20,917 (28.9) 30 2,200 (10.5)

Factors associated with delays in receipt of neoadjuvant chemotherapy in patients with operable breast cancer.

126 Background: Delays in neoadjuvant chemotherapy initiation (NACTI) after breast cancer (BC) diagnosis have been associated with worse outcomes. We evaluated incidence and predictors of delays of NACTI among high clinical risk patients treated with NACT on a national level. Methods: We conducted a retrospective cohort study using the National Cancer Database. Eligibility included age ≥18 years, diagnosis of non-metastatic BC between 1/1/2010 – 12/31/2020, who were treated with NACT within 180 days of diagnosis. Patients who received neoadjuvant endocrine therapy were excluded. Time to chemotherapy (TTC) in days was recorded. Patients were categorized into sub-cohorts by receptor status and clinical stage: 1) Hormone Receptor positive/HER-2 negative (HR+/HER2-) and were lymph node (LN) LN+; 2) HER-2 positive (HER2+) cT2+ or LN+; and 3) triple negative BC (TNBC) cT2+ or LN+. Multivariable logistic regression, adjusted for demographic, socioeconomic and tumor characteristics, was used to identify characteristics associated with delays > 60 days from diagnosis to NACTI. Multiple imputation was used for missing data. Results: We identified 145,697 eligible patients, 74% were White, 18% were Black, 3.3% were Asian, and 4.6% were Other/Unknown. Across all racial categories, 9.2% were Hispanic. Median age at diagnosis was 52 years (range 18-90), median TTC was 32 days (range 0-180), and 10% had a delay > 60 days. There were 40,345 patients in the HR+/HER2- cohort, 56,868 in the HER2+ cohort, and 48,484 in the TNBC cohort; 12%, 9.0%, and 8.9% (p < 0.001) had a delay in NACTI, respectively. In multivariable analysis among the HR+/HER2- sub-cohort, characteristics associated with delays in NACTI included Black race (OR 1.71, 95%CI 1.57-1.86) and Hispanic ethnicity (OR 1.76, 95%CI 1.60-1.94) compared to White and non-Hispanic patients. Patients with Medicare, Medicaid, or who were uninsured were more likely to be delayed (OR 1.44 95%CI 1.30-1.58, 2.10, 95%CI 1.92-2.29, 2.28, 95%CI 1.99-2.61) compared to those with commercial insurance. Results were similar in the HER2+and TNBC cohorts, as seen (Table). Conclusions: Among patients with operable BC who received NACT, patients who were Black, Hispanic, had Medicaid or no insurance had as high as a twofold increase in odds of a delay in NACTI. Targeted interventions to address these racial and socioeconomic disparities are necessary to ensure equitable care. Multivariable logistic regression adjusted for demographic, socioeconomic, and tumor characteristics variables (n = 145,697). HR+/HER2-N= 40,345 HER2+N= 56,868 TNBCN= 48,484 OR 95%CI OR 95%CI OR 95%CI Black Race 1.71 1.57-1.86 1.89 1.74-2.04 1.90 1.76-2.06 Hispanic Ethnicity 1.76 1.60-1.94 2.18 2.00-2.36 2.00 1.80-2.21 Medicare 1.44 1.30-1.58 1.46 1.34-1.61 1.45 1.32-1.61 Medicaid 2.10 1.92-2.29 2.13 1.96-2.31 2.14 1.96-2.34 No Insurance 2.28 1.99-2.61 2.36 2.07-2.70 2.25 1.96-2.59

Delays in receipt of neoadjuvant chemotherapy compared to upfront surgery in patients with operable breast cancer.

e13561 Background: Delays in time from breast cancer (BC) diagnosis to BC treatment initiation (BCTI) including upfront breast surgery (UBS) or neoadjuvant chemotherapy (NACT), can negatively impact BC survival. We evaluated odds of delay in BCTI among patients (pts) who received NACT compared to pts who received UBS. Methods: We conducted a retrospective cohort study using the National Cancer Database. Eligibility included age ≥18 years, diagnosis of non-metastatic BC between 1/1/2010 – 12/31/2020, who were treated with NACT followed by surgery or UBS followed by adjuvant chemotherapy (AC). Pts who did not receive NACT or UBS within 180 days of diagnosis were excluded. The cohort was stratified by first BC treatment (NACT or UBS), and time to NACT (TTNACT) or time to surgery (TTS) was recorded for each patient in days. Pts were categorized into sub-cohorts by receptor status and clinical stage: 1) Hormone Receptor positive/HER-2 negative (HR+/HER2-) lymph node (LN)+; 2) HER-2 positive (HER2+) cT2+ or LN+; and 3) triple negative BC (TNBC) cT2+ or LN+. Logistic regression adjusted for demographic, socioeconomic, and tumor characteristics was used to identify delays in BCTI > 60 days. Multiple imputation was used for missing data. Inverse probability treatment weighting (IPTW) was done as a sensitivity analysis. Results: We identified 218,049 eligible pts, 75% were White, 18% were Black, and 8.6% were Hispanic. Median age was 53 years (range 18-90). There were 145,697 (67%) pts who received NACT with median TTNACT of 32 days (range 0-180), and 9.8% had a delay > 60 days (Table). There were 72,353 (33.0%) pts who received UBS followed by AC, with a median TTS of 33 days (range 0-180), and 13% with a delay > 60 days. In multivariable analysis, pts who received UBS had higher odds of BCTI delays compared to NACT, with OR 1.50 (95%CI 1.42-1.57) [HR+/HER2-], OR 1.49 (95%CI 1.41-1.58) [HER2+], and OR 1.26 (95%CI 1.18-1.34) [TNBC]. Results from IPTW analysis were similar, groups were well balanced, and pts who received UBS had higher odds of BCTI OR 1.50 (95%CI 1.44-1.57) [HR+/HER2-], OR 1.75 (95%CI 1.67-1.83) [HER2+], and OR 1.46 (95%CI 1.38-1.53) [TNBC]. Conclusions: Among high clinical risk BC patients who received surgery and chemotherapy, those who underwent NACT were less likely to experience delays in BCTI compared to pts who received UBS first. Among eligible pts, use of NACT may reduce delays in BCTI. [Table: see text]

Factors associated with delays in receipt of neoadjuvant chemotherapy in patients with operable breast cancer.

e13541 Background: Delays in neoadjuvant chemotherapy initiation (NACTI) after breast cancer (BC) diagnosis have been associated with worse outcomes. We evaluated incidence and predictors of delays of NACTI among high clinical risk patients treated with NACT on a national level. Methods: We conducted a retrospective cohort study using the National Cancer Database. Eligibility included age ≥18 years, diagnosis of non-metastatic BC between 1/1/2010 – 12/31/2020, who were treated with NACT within 180 days of diagnosis. Patients who received neoadjuvant endocrine therapy were excluded. Time to chemotherapy (TTC) in days was recorded. Patients were categorized into sub-cohorts by receptor status and clinical stage: 1) Hormone Receptor positive/HER-2 negative (HR+/HER2-) and were lymph node (LN) LN+; 2) HER-2 positive (HER2+) cT2+ or LN+; and 3) triple negative BC (TNBC) cT2+ or LN+. Multivariable logistic regression, adjusted for demographic, socioeconomic and tumor characteristics, was used to identify characteristics associated with delays > 60 days from diagnosis to NACTI. Multiple imputation was used for missing data. Results: We identified 145,697 eligible patients, 74% were White, 18% were Black, 3.3% were Asian, and 4.6% were Other/Unknown. Across all racial categories, 9.2% were Hispanic. Median age at diagnosis was 52 years (range 18-90), median TTC was 32 days (range 0-180), and 10% had a delay > 60 days. There were 40,345 patients in the HR+/HER2- cohort, 56,868 in the HER2+ cohort, and 48,484 in the TNBC cohort; 12%, 9.0%, and 8.9% (p <0.001) had a delay in NACTI, respectively. In multivariable analysis among the HR+/HER2- sub-cohort, characteristics associated with delays in NACTI included Black race (OR 1.71, 95%CI 1.57-1.86) and Hispanic ethnicity (OR 1.76, 95%CI 1.60-1.94) compared to White and non-Hispanic patients. Patients with Medicare, Medicaid, or who were uninsured were more likely to be delayed (OR 1.44 95%CI 1.30-1.58, 2.10, 95%CI 1.92-2.29, 2.28, 95%CI 1.99-2.61) compared to those with commercial insurance. Results were similar in the HER2+ and TNBC cohorts, as seen in Table. Conclusions: Among patients with operable BC who received NACT, patients who were Black, Hispanic, had Medicaid or no insurance had as high as a twofold increase in odds of a delay in NACTI. Targeted interventions to address these racial and socioeconomic disparities are necessary to ensure equitable care. Multivariable logistic regression adjusted for demographic, socioeconomic and tumor characteristics variables (n= 145,697). [Table: see text]

Abstract PO4-16-06: From Real-World Data to Improved Outcomes: Examining the Impact of Trastuzumab Disparities on Pathological Complete Response and Long-Term Survival in HER-2 Positive Breast Cancer Patients within the Brazilian Public Health System

Abstract Introduction: Equitable access to healthcare is a fundamental principle of public health, aiming to ensure that all individuals have the opportunity to receive effective treatments. However, disparities in access to healthcare still persist in many countries, including Brazil. These disparities can have significant impacts on the health and well-being of patients, particularly in the case of breast cancer treatment. Neoadjuvant chemotherapy (NAC) has been increasingly used for the treatment of breast cancer, encompassing conditions ranging from locally advanced tumors to early-stage triple-negative and HER-2 positive tumors. Objectives: The aim of this study is to evaluate the impact of disparities in the use of trastuzumab (Herceptin) within the Brazilian public health system on pathological complete response (pCR), overall survival (OS), and disease-free survival (DFS). We aim to investigate whether variations in access to trastuzumab treatment influence the achievement of pCR and impact long-term survival outcomes in breast cancer patients. Methods: This retrospective, multicenter cohort study included female patients over 18 years of age with a diagnosis of non-metastatic breast cancer undergoing NAC. pCR was defined as the absence of residual invasive or in situ tumor in the breast and axilla. As an exploratory real-world data study, no confirmatory hypothesis was established, thus no corrections for multiple comparisons were necessary. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method, calculated at five years. The study was approved by the Research Ethics Committee with registration number CAAE 64633422.4.0000.5463. Results: Between 2011 and 2020, a total of 1,891 patients were included in the study, of whom 454 (22.9%) were HER-2 positive. The pCR rate was 25.7%. Trastuzumab was accessed by 291 (64.1%) patients (p < 0.001). Among those who received trastuzumab, pCR was observed in 105 (36.1%) patients, compared to 12 (7.6%) in those who did not have access to trastuzumab (p < 0.001). OS in HER-2 positive patients was 90.1% with pCR and 64.5% without pCR (log-rank p < 0.001), while DFS was 89.2% with pCR and 68.2% without pCR (log-rank p = 0.003). Evaluating OS and DFS in patients who received trastuzumab versus those who did not, OS with trastuzumab and pCR was 94.3% and without pCR was 89.5% (log-rank p < 0.001); OS without trastuzumab and pCR was 83.3% and without pCR was 58.2% (log-rank p < 0.001). DFS in patients who received trastuzumab and achieved pCR was 94.5% and without pCR was 90.5% (log-rank p = 0.05), whereas without trastuzumab and pCR was 79.9% and without pCR was 62.1% (log-rank p = 0.001). Conclusion: These findings underscore the significant impact of disparities in trastuzumab utilization within the Brazilian public health system on pCR rates and long-term survival outcomes in HER-2 positive breast cancer patients. Access to trastuzumab was associated with higher pCR rates and improved overall and disease-free survival rates. Ensuring equitable access to targeted therapies is crucial for improving treatment response and long-term outcomes in breast cancer patients. Table 1 Clinicopathological characteristics of patients Legend: AJCC, American Joint Committee on Cancer; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; HR hormonal receptor. Table 2 - NAC schemas and correlation with pCR. AC-T, doxorubicin + cyclophosphamide – taxane; AC-TH, doxorubicin + cyclophosphamide – taxane+herceptin. Citation Format: Marcelo Antonini, Andre Mattar, Gabriel Pannain, Fernanda Grace Bauk Richter, Andressa Amorim, Marina Diogenes, Odair Ferraro, Luiz Gebrim, Reginaldo Coelho Lopes, Juliana Real. From Real-World Data to Improved Outcomes: Examining the Impact of Trastuzumab Disparities on Pathological Complete Response and Long-Term Survival in HER-2 Positive Breast Cancer Patients within the Brazilian Public Health System [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-16-06.

Abstract PO3-14-10: A single-center prospective cohort study to evaluate circulating tumor cells as a monitoring tool in women with breast cancer treated with neoadjuvant chemotherapy: final results of baseline data

Abstract Background: The presence of liquid biomarkers such as circulating tumor cells (CTCs) among women undergoing neoadjuvant chemotherapy (NAC) for breast cancer may be associated with treatment response and/or an increased risk of recurrence, but limited data is available. Objectives: To detect and enumerate CTCs in blood samples from women with a new diagnosis of non-metastatic breast cancer of any subtype both i) at baseline (prior to commencing NAC), and ii) after completion of NAC and surgery using the Epic Sciences platform. Methods: Women with non-metastatic breast cancer of any subtype who have not yet commenced NAC were included, irrespective of age. Those with a prior history of another invasive cancer (apart from non-melanoma skin cancer identified 5+ years prior to enrollment) were excluded. Blood samples were obtained to measure CTCs prior to commencing NAC, and after completion of NAC and surgery (at least 4 weeks post-operatively). As previously described, CTC identification was based on immunofluorescence analysis using the Epic Sciences platform (Ueno et al 2017). Clinical/pathological data and clinical outcomes were abstracted from patients’ medical records. Associations between CTC detection and clinical/pathologic characteristics were evaluated using Fisher’s exact test for categorical variables and t-test or Wilcoxon rank sum tests for numerical variables. All analyses were performed using the R software package. Results: 50 participants who met eligibility criteria were included; a baseline blood sample was evaluable for CTC detection and enumeration for 47 patients. The median age at breast cancer diagnosis was 52 (29-75). Among them, 18 (38.3%) had HER2+ breast cancer, 17 (36.1%) had hormone receptor (HR)+/HER2- breast cancer and 12 (25.5%) had triple negative breast cancer (TNBC). The majority of patients (91%) received anthracycline and taxane-based NAC. A total of 68 samples were tested for CTC enumeration (5 mL equivalent per sample) including 47 pre-treatment and 21 post-treatment samples. CTCs were detected in 37 (79%) of patients for whom a baseline (pre-NAC) sample was available with a mean of 4.2 (SD 17.0) CTCs/mL and a range of 0 - 115.4 CTCs/mL. Detection of CTCs at baseline was highest among patients with TNBC (n=10/12, 83%), followed by those with HER2+ (n=14/18, 78%) and HR+/HER2- (n=13/17, 76%) breast cancer. CTCs were detected in 43% (n=9/21) of post-treatment samples, with a mean of 1.2 (SD 3.6) CTCs/mL and range of 0 – 16.4 CTCs/mL. Among the 20 patients for whom matched pre- and post-treatment CTC results were available, 16 (80%) had detectable CTCs pre-treatment and 8 (40%) had detectable levels post-NAC and surgery; of the 8 patients with post-treatment CTCs, 4 (50%) had HR+/HER2- breast cancer, 2 had HER2+ (25%) and 2 (25%) had TNBC. Three patients had numerically higher CTC levels after completion of NAC and surgery compared to baseline levels, 2 of whom had HR+/HER2- breast cancer and one of whom had TNBC. To-date, only 8 patients (19% of 43 who have undergone surgery) have achieved a pathological complete response (PCR) to NAC, among whom 3 had matched pre- and post-treatment CTC results available. None of these 3 patients had detectable CTCs post treatment. Conclusions: Approximately 4 in 5 women with non-metastatic breast cancer who undergo NAC have detectable CTCs at baseline (pre-treatment) using the Epic Sciences Platform. Given that CTCs remain detectable in a high proportion (40%) of patients after NAC and surgery, evaluation of CTCs as a potential measure of minimal residual disease warrants further evaluation in this patient population. Citation Format: Rania Chehade, Arushi Jain, Veronika Moravan, Giuseppe Di Caro, Megan Slade, Nadine Hartmann, Rick Wenstrup, Ana Elisa Lohmann, William Tran, Katarzyna Jerzak. A single-center prospective cohort study to evaluate circulating tumor cells as a monitoring tool in women with breast cancer treated with neoadjuvant chemotherapy: final results of baseline data [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-14-10.

Abstract PO2-16-12: Real world evidence of neoadjuvant chemotherapy for breast cancer treatment in a Brazilian multicenter cohort: correlation of pathological complete response and overall survival

Abstract Introduction: Breast cancer is the most common malignancy among women in Brazil and worldwide. Neoadjuvant chemotherapy (NAC) has been increasingly used for the treatment of breast cancer conditions ranging from locally advanced tumors to early-stage triple-negative and HER-2 positive tumors. Nowadays only 5% of breast cancer patients are enrolled in clinical trials. Real-world data is important to evaluate how clinical trial treatments behave in the real world with all the heterogeneous patient characteristics of those treated differently from the homogeneity of clinical trials. Objectives: To evaluate the rates of pathological complete response (pCR) in patients undergoing neoadjuvant chemotherapy (NAC) for the treatment of breast cancer (BC) To examine the differences in pathological complete response (pCR) rates between HER-2 positive breast cancer patients with and without trastuzumab treatment, and between triple-negative breast cancer (TNBC) patients with and without platinum-based treatment, Additionally, we aim to assess the impact of pCR on overall survival (OS) and disease-free survival (DFS) using real-world data (RWD). Methods: This was a retrospective, multicentric cohort study, that included female patients over 18 years of age, with a diagnosis of non-metastatic breast cancer undergoing NAC. As an exploratory real-world data study, no confirmatory hypothesis was established, so no corrections for multiple comparisons were necessary. Overall survival (OS) and disease-free survival (DFS) were estimated by the Kaplan-Meier method calculated at five years. Additionally, we conducted a multivariate analysis to identify significant associations with pathologic complete response (pCR) and overall survival (OS). We employed a forest plot to visually represent these associations Results: From 2011 to 2020, 1,891 patients were included in the study, and 421 (22,3%) achieved pCR (ypT0 ypN0) and considering the presence of residual in situ carcinoma (DCIS) the pCR was seen in 467 patients (23,5) without significant difference (p=0,567) . The pCR rate varied between the subtypes: luminal A 17,0%, luminal B 21,3%, luminal HER2 23,0%, TNBC 22,5% and HER2 28,5% (p = 0,057). The type of neoadjuvant chemotherapy (NAC) regimen was correlated with pathological complete response (pCR). Among HER2-positive patients, those who received Trastuzumab had a significantly higher rate of pCR compared to those who did not receive it (p < 0.0001). Similarly, in patients with TNBC, those who underwent treatment with platinum-based regimens also showed higher rates of pCR (p < 0.0001). There were 694 deaths, and the 5-year OS rate was 62.9%. OS was also grouped according to pCR status, and pCR OS rate was 88,3% and non-pCR 58.1% significant difference observed (p < 0.0001). Five-year DFS of pCR was 92.2% and non-pCR 64.3% (p < 0.0001). Conclusion: this real-world data study evaluated the rates of pathological complete response (pCR) in breast cancer patients undergoing neoadjuvant chemotherapy (NAC). The results revealed varying pCR rates among different breast cancer subtypes, with HER2-positive and triple-negative subtypes showing higher rates. The use of Trastuzumab in HER2-positive patients and platinum-based regimens in triple-negative patients correlated with significantly higher pCR rates. Furthermore, achieving pCR was associated with improved overall survival (OS) and disease-free survival (DFS). These findings emphasize the importance of considering individual tumor characteristics and tailoring treatment strategies for breast cancer patients to optimize outcomes. Clinicopathological characteristics of patients AJCC, American Joint Committee on Cancer; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; TNBC triple negative breast cancer. NAC schemas and correlation with pCR. AC-T, doxorubicin + cyclophosphamide – taxane; AC-TPlatinum, doxorubicin + cyclophosphamide – taxane+carboplatin; AC-TH, doxorubicin + cyclophosphamide – taxane+herceptin. Citation Format: Marcelo Antonini, Andre Mattar, Fernanda Grace Bauk Richter, Gabriel Pannain, Andressa Amorim, Marina Diogenes, Odair Ferraro, Luiz Gebrim, Reginaldo Coelho Lopes, Juliana Real. Real world evidence of neoadjuvant chemotherapy for breast cancer treatment in a Brazilian multicenter cohort: correlation of pathological complete response and overall survival [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-16-12.

Hsp70-A Universal Biomarker for Predicting Therapeutic Failure in Human Female Cancers and a Target for CTC Isolation in Advanced Cancers.

Heat shock protein 70 (Hsp70) is frequently overexpressed in many different tumor types. However, Hsp70 has also been shown to be selectively presented on the plasma membrane of tumor cells, but not normal cells, and this membrane form of Hsp70 (mHsp70) could be considered a universal tumor biomarker. Since viable, mHsp70-positive tumor cells actively release Hsp70 in lipid micro-vesicles, we investigated the utility of Hsp70 in circulation as a universal tumor biomarker and its potential as an early predictive marker of therapeutic failure. We have also evaluated mHsp70 as a target for the isolation and enumeration of circulating tumor cells (CTCs) in patients with different tumor entities. Circulating vesicular Hsp70 levels were measured in the peripheral blood of tumor patients with the compHsp70 ELISA. CTCs were isolated using cmHsp70.1 and EpCAM monoclonal antibody (mAb)-based bead approaches and characterized by immunohistochemistry using cytokeratin and CD45-specific antibodies. In two out of 35 patients exhibiting therapeutic failure two years after initial diagnosis of non-metastatic breast cancer, progressively increasing levels of circulating Hsp70 had already been observed during therapy, whereas levels in patients without subsequent recurrence remained unaltered. With regards to CTC isolation from patients with different tumors, an Hsp70 mAb-based selection system appears superior to an EpCAM mAb-based approach. Extracellular and mHsp70 can therefore serve as a predictive biomarker for therapeutic failure in early-stage tumors and as a target for the isolation of CTCs in various tumor diseases.

Abstract 5758: Regular aspirin use, breast tumor characteristics and long-term breast cancer survival

Abstract Compelling epidemiologic data, supported by experimental evidence, suggest aspirin may improve survival in breast cancer patients. However, recent clinical trials showed a lack of protective effect, though length of intervention (18 months to 4.7 years) and follow-up (20 months to 4.7 years) were limited. We sought to examine the association between post-diagnostic aspirin use (frequency, dose, and duration), timing and age of initiation on breast cancer-specific mortality. Our study included 10,493 women diagnosed with stage I, II, or III invasive breast cancer. Participants were enrolled in the large, prospective Nurses’ Health Study (NHS) and NHSII in 1980 and 1989 prior to diagnosis and followed up through June 1, 2017. We collected information on frequency, dose and duration of aspirin use. Regular aspirin use was defined as using aspirin (standard- and low-dose) ≥2 days per week, and non-regular aspirin users were those who reported use of aspirin <2 days per week. We used Cox proportional hazard models to calculate multivariable adjusted hazard ratios (HRs) for breast cancer-specific mortality. After a median follow-up of 10 years, there were 2,506 total deaths and 1,221 breast cancer-specific deaths among 10,493 stage I to III breast cancer patients over 32 years of follow-up. In multivariable models, regular use of aspirin (n=3,523; 34%) was associated with a 38% lower risk of death from breast cancer compared with non-regular users (including nonusers) (HR=0.62, 95% CI: 0.54-0.71). The association was independent of pre-diagnostic aspirin use. Associations between aspirin use and breast cancer-specific mortality were stronger with longer time since diagnosis (HRs for <5 years since diagnosis: 0.73 (95% CI: 0.59-0.90), 5-<10 years: 0.63 (95% CI: 0.49-0.80), and ≥10 years: 0.53 (95% CI: 0.41-0.69)). The relations between aspirin use and breast cancer survival were similar across categories of dose (compared to non-users, HRs for 0.5-5 tablets per week: 0.59 (95% CI: 0.51-0.68); ≥6 tablets per week: 0.60 (95% CI: 0.48-0.74)) and appeared stronger with longer duration (compared to non-users, HRs for <5 years: 0.80 (95% CI: 0.57, 1.10); ≥5 years: 0.61 (95% CI: 0.51, 0.72)). For women who initiated regular aspirin use after age 70, regular aspirin use was associated with worse survival (HR=1.74, 95% CI: 1.16-2.63); on the other hand, initiation of regular aspirin use at age ≤60 (HR=0.72, 95% CI: 0.54-0.95) or 60-≤70 (HR=0.69, 95% CI: 0.50-0.95) was associated with improved survival (p-interaction=0.02). Regular aspirin use after diagnosis of nonmetastatic breast cancer was associated with improved long-term survival over 32 years. Although the associations between post-diagnostic regular aspirin use and improved survival did not differ by BMI, smoking or tumor characteristics, women who initiated regular aspirin use >70 years of age had increased risk of death due to breast cancer. Citation Format: Cheng Peng, Michelle D. Holmes, Wendy Y. Chen, Tengteng Wang, Kristen D. Brantley, Yujing Jan Heng, Pepper J. Schedin, Bernard A. Rosner, Walter C. Willett, Meir J. Stampfer, Rulla M. Tamimi, A. Heather Eliassen. Regular aspirin use, breast tumor characteristics and long-term breast cancer survival. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5758.

Abstract P6-01-17: A single-center prospective cohort study to evaluate circulating tumor cells as a monitoring tool in women with breast cancer treated with neoadjuvant chemotherapy

Abstract Background The presence of circulating tumor cells (CTCs) among women before and/or after completion of neoadjuvant chemotherapy (NAC) for breast cancer may be associated with an increased risk of recurrence, but limited data is available. Objectives To use the Epic Sciences platform to detect and enumerate CTCs in blood samples from women with a new diagnosis of non-metastatic breast cancer of any subtype both i) prior to commencing NAC, and ii) after completion of NAC and surgery. Methods Inclusion criteria included women of any age with non-metastatic breast cancer of any subtype who have not yet commenced NAC. Those diagnosed with prior invasive cancer at any site (apart from non-melanoma skin cancer diagnosed more than five years prior to enrollment) were excluded. Blood samples were obtained to measure CTCs prior to NAC and after NAC and surgery, respectively. CTC identification was based on immunofluorescence analysis using Epic Sciences platform as previously described (Ueno et al 2017). The presence of CTCs was correlated with clinical/pathological data and treatment response, which were abstracted from patients’ medical records. The association between the presence of CTCs and clinical/pathologic characteristics was tested using Fisher’s exact test for categorical variables and t-test or Wilcoxon rank sum tests for numerical variables. All analyses were performed using the R software package. An ad-hoc preliminary analysis was conducted among the first 34 of 50 participants. Results 41 patients (out of an intended 50) have been recruited to-date. 34 participants have a pre- and/or post-treatment CTC measurement available, but 1 was excluded because it was identified to have metastatic disease shortly after enrollment. Among 33 evaluable patients without metastatic disease, 6 (19%) had triple negative breast cancer (TNBC), 13 (39%) had HER2+ and 13 (39%) had hormone receptor (HR)+/HER2- breast cancer. Most (94%) received anthracycline and taxane-based NAC. The median age of breast cancer diagnosis was 50 (29-75). A total of 53 samples were tested for CTC enumeration (5 mL per sample) including 33 pre-treatment and 20 post-treatment samples. CTCs were detected in 32 samples (n=32/53, 60%), including 24 pre-NAC (n=24/33, 73%) with a median of 0.9 CTCs per mL (0.2-19) and 8 post-NAC and surgery (n= 8/20, 40%) with a median of 0.6 CTCs per mL (0.3-3.3). Among the 24 patients (73%) who had detectable CTCs pre-NAC, 10 had HR+/HER2- (41.7%), 9 had HER2+ (37.5%) and 4 (16.7%) had triple negative disease. Among the 20 patients for whom matched pre- and post-treatment CTC results were available, 16 (80%) had detectable CTCs pre-treatment and 8 (40%) had detectable levels post-NAC and surgery. Among the 8 patients (40%) for whom CTCs were detectable post NAC and surgery, 4 (50%) had HR+/HER2-, 2 had HER2+ (25%) and 2 (25%) had triple negative disease. 3 of these patients had numerically higher CTC levels after completion of NAC and surgery compared to pre-NAC levels, 2 of whom had HR+/HER2- breast cancer and one of whom had TNBC. A total of 7 of 33 patients achieved a pathological complete response (PCR) to NAC, among whom 3 had matched pre- and post-treatment CTC results available; none of these 3 patients had detectable CTCs post-treatment. Conclusions Approximately 3 in 4 women with non-metastatic breast cancer who undergo NAC have detectable CTCs pre-treatment using the Epic Sciences Platform. Of 20 patients with matched pre-/post-treatment results, a high proportion (40%) have persistently detectable CTCs. Hence, CTCs may represent an additional measure of minimal residual disease for patients undergoing NAC for breast cancer. Citation Format: Rania chehade, Arushi Jain, Veronika Moravan, Giuseppe Di Caro, Amanda Anderson, Megan M. Slade, Rick Wenstrup, Ana Elisa Lohmann, William Tran, Katarzyna Jerzak. A single-center prospective cohort study to evaluate circulating tumor cells as a monitoring tool in women with breast cancer treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-17.

Adipose tissue radiodensity and mortality among patients with nonmetastatic breast cancer

Computed tomography (CT) scans can measure quantity and distribution of adipose tissue, which are associated with breast cancer prognosis. As a novel prognostic marker, radiodensity of adipose tissue has been examined in multiple cancer types, but never in breast cancer. Lower density indicates larger adipocytes with greater lipid content, whereas higher density can reflect inflammation, fibrosis, vascularity, or even metabolic changes; and both may impact breast cancer prognosis. We included 2868 nonmetastatic patients with breast cancer diagnosed between January 2005 and December 2013at Kaiser Permanente Northern California, an integrated healthcare system. From CT scans at diagnosis, we assessed the radiodensity of subcutaneous (SAT) and visceral adipose tissue (VAT) at the third lumbar vertebra and categorized their radiodensity into three levels: low (<1 standard deviation [SD] below the mean), middle (mean±1 SD), and high (>1 SD above the mean). Using multivariable Cox proportional hazards regression with adjustment for clinicopathological characteristics including body mass index, we calculated hazard ratios (HRs [95% confidence intervals]) for the associations of adipose tissue radiodensity with overall mortality and breast-cancer-specific mortality. Median age at diagnosis of breast cancer was 56.0 years, most (63.3%) were non-Hispanic White and nearly half (45.6%) were stage II. Compared to middle SAT radiodensity, high SAT radiodensity was significantly associated with increased risk of overall mortality (HR: 1.45 [1.15-1.81]), non-significantly with breast-cancer-specific mortality (HR: 1.32 [0.95-1.84]). Neither low SAT radiodensity nor high or low VAT radiodensity was significantly associated with overall or breast-cancer-specific mortality. High radiodensity of SAT at diagnosis of nonmetastatic breast cancer was associated with increased risk of overall mortality, independent of adiposity and other prognostic factors. Considering both radiodensity and quantity of adipose tissue at different locations could deepen understanding of the role of adiposity in breast cancer survival.

Long term risk of distant metastasis in women with non-metastatic breast cancer and survival after metastasis detection: a population-based linked health records study.

To estimate the long term risk of distant metastases (DM) for women with initial diagnoses of non-metastatic breast cancer; to estimate breast cancer-specific and overall survival for women with DM. Population-based health record linkage study. Women diagnosed with localised or regional primary breast cancer recorded in the NSW Cancer Registry, 2001-2002. Time from breast cancer diagnosis to first DM, time from first DM to death from breast cancer. time to death from any cause. 6338 women were diagnosed with non-metastatic breast cancer (localised, 3885; regional, 2453; median age, 59 years [IQR, 49-69 years]). DM were recorded (to 30 September 2016) for 1432 women (23%; median age, 62 years [IQR, 51-73 years]). The 14-year cumulative DM incidence was 22.2% (95% CI, 21.1-23.2%; localised disease: 14.3% [95% CI, 13.2-15.4%]; regional disease: 34.7% [95% CI, 32.8-36.6%]). Annual hazard of DM was highest during the second year after breast cancer diagnosis (localised disease: 2.8%; 95% CI, 2.3-3.3%; regional disease: 9.1%; 95% CI, 7.8-10.3%); from year five it was about 1% for those with localised disease, from year seven about 2% for women with regional disease at diagnosis. Five years after diagnosis, the 5-year conditional probability of DM was 4.4% (95% CI, 3.7-5.1%) for women with localised and 10.4% (95% CI, 9.1-12.0%) for those with regional disease at diagnosis. Median breast cancer-specific survival from first DM record date was 28 months (95% CI, 25-31 months); the annual hazard of breast cancer death after the first DM record declined from 36% (95% CI, 33-40%) during the first year to 14% (95% CI, 11-18%) during the fourth year since detection. DM risk declines with time from diagnosis of non-metastatic breast cancer, and the annual risk of dying from breast cancer declines with time from initial DM detection. These findings can be used to inform patients at follow-up about changes in risk over time since diagnosis and for planning health services.

Surgery Refusal Among Black and Hispanic Women with Non-Metastatic Breast Cancer.

Studies have shown a lower receipt of treatment among minority women with non-metastatic breast cancer. Those who refuse surgery have increased disease-specific mortality, contributing to disproportionately higher breast cancer mortality in non-Hispanic black (NHB) and Hispanic women. This study aimed to assess surgery refusal in these groups, identify factors associated with surgery refusal, and characterize the association between surgery refusal and survival. Surveillance, Epidemiology, and End Results (SEER) Program data from 2005 to 2015 for NHB and Hispanic women with a diagnosis of non-metastatic breast cancer (n = 113,987) was divided into data of those who underwent surgery and data of those who refused surgery. Sociodemographic and tumor clinical/pathologic differences were analyzed by multivariate logistic regression of predictors of surgery refusal and Cox-proportional hazard model of disease-specific mortality. Of 799 patients who refused surgery, 562 were NHB and 237 were Hispanic. The percentage of patients refusing surgery increased from 0.6% in 2005 to 0.9% in 2015. The women who refused surgery were more likely to be older than 81 years, less likely to be married, and more likely to be uninsured or have Medicaid. The refusers presented with more advanced disease and more frequent estrogen receptor-positivity (ER+) and progesterone receptor-positivity (PR+) subtype on histology. Breast cancer-specific mortality increased significantly with surgery omission. Surgery refusal was independently associated with NHB race. Surgery refusal among NHB and Hispanic women with potentially curable non-metastatic breast cancer is rising, especially among NHB women, women older than 60 years, single women, and women with a later stage of disease at diagnosis. Additional studies are needed to analyze qualitative data in these populations and their underlying health beliefs, communication needs, and possible use of alternative medicine.

Anxiety and depression in patients with breast cancer undergoing radiotherapy: the role of intelligence, life history, and social support\u2014preliminary results from a\xa0monocentric analysis

PurposeIt is known that the diagnosis of breast cancer often causes anxiety and depression. Radiotherapy of the breast as an obligatory part of a breast-conserving treatment concept can markedly increase these psychological symptoms in many, but not all patients. In this clinical observational study, we aimed at identifying cognitive, health-related and social factors that may either enhance or reduce the emergence of anxiety and depression.MethodsUsing a longitudinal study design with 25 women (mean age: 52.9 years; SD = 10.6; age range 29–70 years) with a first diagnosis of nonmetastatic breast cancer, measures of anxiety, depression, situational emotional states, intelligence, and aspects of social frameworks were assessed before, during, and after radiotherapy of the breast. At 4 time-points, standard and self-constructed questionnaires were used to assess the course of anxiety and depressive symptoms across the radiotherapy intervention.ResultsWe found that anxiety is highest immediately before the start of radiation therapy, while the anxiety level was lowest on the day that therapy was completed. Anxiety and depression were enhanced in women with a lifetime history of chronic diseases at all time points of measurement. Moreover, women with high intelligence and low social support had stronger symptoms of depression than women with low intelligence and a stable family background at some time points of measurement. The degree of anxiety was neither related to intelligence nor to social support.ConclusionFor the first time, we demonstrate empirical pilot data on cognitive and social modulators of anxiety and depression in women with breast cancer over the course of radiotherapy. Our results may help to optimize clinical procedures and thereby reduce symptoms of anxiety and depression in these patients.

P–455 Breast cancer recurrence in women with and without controlled ovarian stimulation for fertility preservation. Cohort study

Abstract Study question Do patients diagnosed with breast cancer who undergo ovarian stimulation for fertility preservation prior to chemotherapy have a higher risk of recurrence of the disease? Summary answer There was no statistically significant difference in the hazard ratio for breast cancer recurrence in fertility preservation-stimulated women compared to non-stimulated ones What is known already While many women with early breast cancer benefit from chemotherapy treatments in increasing disease-free survival, they are also at risk of permanent chemotherapy induced ovarian failure. Oocyte cryopreservation with an adapted protocol with letrozole may reduce the possible deleterious effect of the hyper estrogenic state during the controlled ovarian hyperstimulation (COH). Although fertility preservation in women diagnosed with breast cancer seems safe, the follow-up periods of most studies are short in time. In addition, follow-up data of COH before neoadjuvant chemotherapy in women with hormone negative tumor receptors is still scarce and briefly reported. Study design, size, duration It was a retrospective cohort study, where 208 women with non-metastatic breast cancer were included. The recruitment period was from 01/01/2009 to 01/12/2019. The minimum follow-up period was 6 months, and the maximum, 130 months. Participants were divided into two cohorts, those who received controlled ovarian hyperstimulation prior to their cancer treatment and those who did not. Patients were followed until disease recurrence, death, loss to follow-up, or end of the study Participants/materials, setting, methods Setting: university hospital in Buenos Aires, Argentina. We included women aged 18 to 45 years with a recent histological diagnosis of non-metastatic breast cancer who had to receive chemotherapy with gonadal toxicity. We excluded patients with a history of previous chemotherapy or radiotherapy for another cancer disease, or menopause. Follow-up was at least an annual clinical check-up and breast imaging. Cohorts were analysed using a Cox-proportional hazards model, adjusted for propensity score for receiving stimulation. Main results and the role of chance We included 208 women, 39 in the COH group and 169 in the non-stimulated group (NSG). The only statistically significant difference was in age: median years 33.7 (interquartile range -IQR- 30.9 to 36.9) and 40.0 years (IQR 36.8 to 44.0), respectively. The median size of cancer nodules was 19.0 millimetres (IQR 10.0–30.0) and 17.0 (IQR 11.0–25.0), p 0.547; percentage of positive lymph nodes: 41.0% vs 39.3%, p 0.841; positive hormonal receptors: 84.6% vs 85.2%, p 0.925; percentage of neoadjuvant chemotherapy: 20.5% vs 11.4%, p 0.128. There were also no statistically significant differences regarding tumour stage, high Ki–67 labelling index, positive breast cancer genes (BRCA 1 or 2), and radiotherapy. Overall, 18.0% of patients had cancer recurrence in the COH group and 20.7% in the NSG (p 0.699). Crude cancer recurrence rates were similar: 5.96 per 100 patients/year (95%CI 2.84–12.50), and 4.65 per 100 patients/year (95%CI 3.34–6.47), respectively. The crude hazard ratio (HR), comparing the COH group vs the NSG was 1.32 (95%CI 0.58–2.97; p 0.507). The adjusted HR using a propensity score for receiving ovarian stimulation treatment was 1.08 (95%CI 0.39–2.98; p 0.887). Results were similar if adjusted for age, neoadjuvant chemotherapy, and other confounders. Limitations, reasons for caution This was a single-center retrospective cohort study. There might be unknown or residual confounders that could influence results. Nevertheless, we accounted for treatment bias using a propensity score for ovarian stimulation. Results should be extrapolated with caution, especially in other non-university institutions and populations. Wider implications of the findings: This study provides new evidence on the safety of controlled ovarian stimulation in breast cancer patients prior to chemotherapy treatment, in a Latin American population. Letrozole continues to show safety and efficacy as an adapted protocol in breast cancer. Trial registration number Not applicable

The Diagnostic Value of Serum Exosomal Has_circ_0000615 for Breast Cancer Patients.

BackgroundTo explore the expression level of has_circ_0000615 in peripheral blood samples and evaluate its diagnostic value for breast cancer patients.MethodsThe peripheral blood samples of 95 breast cancer patients who underwent curative surgical resection and 95 age-matched healthy volunteers in our institutions from September 2019 to November 2020 were systematically collected. The expression level of has_circ_0000615 in the plasma was amplified and detected by qRT-PCR, and its correlation to clinicopathological characteristics of breast cancer patients were analyzed.ResultsBreast cancer patients had a significantly higher expression level of has_circ_0000615 in the plasma than healthy controls (P < 0.01), and its high expression was closely associated with advanced tumor stage (P=0.010), lymph node metastasis (P = 0.001) and high grade of recurrence risk (P=0.012). The receiver operator characteristic (ROC) curves showed that the area under curve (AUC) value, sensitivity and specificity of has_circ_0000615 for the diagnosis of non-metastatic breast cancer was 0.904 (95% CI: 0.863–0.944), 76.8% and 88.4%, respectively. Serum has_circ_0000615 expression had a better diagnostic efficiency than routine tumor biomarkers such as CA153, CA125 and CEA for distinguishing breast cancer patients from healthy individuals. TEM revealed that isolated exosomes from the culture medium of breast cancer cells had a disk-like appearance with a diameter of 80–200 nm vesicles, and the expression of exosome markers CD9 and CD81 was markedly increased. More importantly, the expression of has_circ_0000615 was detected in the exosomes and its expression level was markedly upregulated in breast cancer cell lines compared with normal ductal epithelial cells. The stability assay showed that there was no difference between RNA extraction at 0 hour and 24 hours in terms of the expression of has_circ_0000615 (P =0.327). Has_circ_0000615 might as exosomes be secreted into the circulating blood of breast cancer patients, resulting in a high expression level in plasma samples.ConclusionThe detection of has_circ_0000615 might be a promising diagnostic method for breast cancer.

Concomitant tamoxifen or letrozole for optimal oocyte yield during fertility preservation for breast cancer: the TAmoxifen or Letrozole in Estrogen Sensitive tumors (TALES) randomized clinical trial.

To determine whether concomitant tamoxifen 20 mg with gonadotropins (tamoxifen-gonadotropin) versus letrozole 5 mg with gonadotropins (letrozole-gonadotropin) affects mature oocyte yield. Open-label, single-institution, randomized trial. Inclusion criteria included the following: females, ages 18-44 years old, with new diagnosis of non-metastatic breast cancer, who were undergoing fertility preservation with either oocyte or embryo cryopreservation. Those with estrogen-receptor-positive (ER+) breast cancer were randomized to tamoxifen-gonadotropin or letrozole-gonadotropin. Another group with estrogen-receptor-negative (ER-) breast cancer was recruited, as a prospectively collected comparison arm who took neither letrozole nor tamoxifen (gonadotropin only). The primary outcome was the number of mature oocytes obtained from the cycle. The randomized groups were powered to detect a difference of three or more mature oocytes. Forty-five patients were randomized to tamoxifen-gonadotropin and fifty-one to letrozole-gonadotropin. Thirty-eight patients completed gonadotropin only. Age, antral follicle count, and body mass index were similar between the randomized groups. Our primary outcome of mature oocyte yield was similar between the tamoxifen-gonadotropin and letrozole-gonadotropin groups (12±8.6 vs. 11.6±7.5, p=0.81, 95%CI of difference =-2.9 to 3.7). In a pre-specified secondary comparison, mature oocyte yield was also similar with tamoxifen-gonadotropin or letrozole-gonadotropin versus gonadotropin only (12±8.6 vs. 11.6±7.5 vs. 12.4±7.2). There were no serious adverse events in any of the groups. Tamoxifen-gonadotropin and letrozole-gonadotropin produced a similar number of mature oocytes. Women who received either tamoxifen-gonadotropin or letrozole-gonadotropin had a similar number of oocytes to the gonadotropin-only group. NCT03011684 (retrospectively registered 1/5/2017, after 9% enrolled).

A Diagnostic Analysis Workflow to Optimal Multiple Tumor Markers to Predict the Nonmetastatic Breast Cancer from Breast Lumps.

Objective To assess the diagnostic performance of clinically common single markers and combinations to distinguish nonmetastatic breast cancer and benign breast tumor. A predictive model with a better diagnostic ability for nonmetastatic breast cancer was established by using the diagnostic process. Methods A total of 222 patients with nonmetastatic breast cancer and 265 patients with benign breast disease were enrolled in this study. CEA, Ca 15-3, Ca 125, Ca 72-4, CYFRA 21-1, FERR, AFP, and NSE were measured by an electrochemiluminescent immunoenzymometric assay on the Elecsys system. There are four key steps for our diagnostic workflow, that is, feature selection, algorithm selection, parameter optimization, and outer test data was used to validate the optimal algorithm and markers. Results CEA, Ca 15-3, CYFRA 21-1, AFP, and FERR were selected using the t-test in our inner development set. The optimal algorithm among logical regression, decision tree, support vector machine, random forest, and gradient boost machine was selected by 10-fold cross-validation, and we found that random forest and logistic regression are the better classification. The outer test data was used to validate the best markers and classification. The random forest with CEA, Ca 15-3, CYFRA 21-1, AFP, and FERR showed the optimal combination for distinguishing breast cancer and benign breast disease. The AUC value was 0.888, the cut-off point was 0.484, and sensitivity and specificity were 78.9% and 90.1%. Conclusions No single marker of these eight markers was good at identifying nonmetastatic breast cancer from benign tumors. But a diagnostic analysis workflow was established to develop a predictive model with better diagnostic capability for nonmetastatic breast cancer. This workflow is also applicable to the optimization of other disease markers and diagnostic models. The predictive model showed good diagnostic performance, and it could be gradually incorporated as a support method for the diagnosis of nonmetastatic breast cancer.

Association of Obesity With Breast Cancer Outcome in Relation to Cancer Subtypes: A Meta-Analysis.

BackgroundObesity at breast cancer (BC) diagnosis has been associated with poor outcome, although the magnitude of effect in different BC subtypes is uncertain. We report on the association of obesity or overweight at diagnosis of nonmetastatic BC with disease-free (DFS) and overall survival (OS) in the following defined subtypes: hormone receptor positive/HER2 negative (HR+HER2−), HER2 positive (HER2+), and triple negative (TNBC).MethodsWe searched MEDLINE, EMBASE, and COCHRANE databases up to January 1, 2019. Study eligibility was performed independently by 2 authors. Studies reporting hazard ratios (HRs) of OS and/or DFS for obesity or overweight in BC subtypes were included. The pooled hazard ratio was computed and weighted using generic inverse variance and random effects models.ResultsTwenty-seven studies were included. Obese compared with nonobese women had worse DFS in all subtypes: the hazard ratios were 1.26 (95% confidence interval [CI] = 1.13 to 1.41, P < .001) for HR+HER2− BC, 1.16 (95% CI = 1.06 to 1.26, P < .001) for HER2+ BC, and 1.17 (95% CI = 1.06 to 1.29, P = .001) for TNBC. OS was also worse in obese vs nonobese women (HR+HER2− BC HR = 1.39, 95% CI = 1.20 to 1.62, P < .001; HER2+ BC HR = 1.18, 95% CI = 1.05 to 1.33, P = .006; and TNBC HR = 1.32, 95% CI = 1.13 to 1.53, P < .001). As opposed to obesity, overweight was not associated with either DFS or OS in HER2+ BC (HR = 1.02, 95% CI = 0.81 to 1.28, P = .85; and HR = 0.96, 95% CI = 0.76 to 1.21, P = .99, respectively) or TNBC (HR = 1.04, 95% CI = 0.93 to 1.18, P = .49; and HR = 1.08, 95% CI = 0.81 to 1.44, P = .17), respectively. In HR+HER2− BC, being overweight was associated with worse OS (HR = 1.14, 95% CI = 1.07 to 1.22, P < .001).ConclusionsObesity was associated with modestly worse DFS and OS in all BC subtypes.

Elucidating therapeutic molecular targets in premenopausal Asian women with recurrent breast cancers

Breast cancer is an increasing problem in Asia, with a higher proportion of premenopausal patients who are at higher risk of recurrence. Targeted sequencing was performed on DNA extracted from primary tumor specimens of 63 premenopausal Asian patients who relapsed after initial diagnosis of non-metastatic breast cancer. The most prevalent alterations included: TP53 (65%); PIK3CA (32%); GATA3 (29%); ERBB2 (27%); MYC (25%); KMT2C (21%); MCL1 (17%); PRKDC, TPR, BRIP1 (14%); MDM4, PCDH15, PRKAR1A, CDKN1B (13%); CCND1, KMT2D, STK11, and MLH1 (11%). Sixty of the 63 patients (95%) had at least one genetic alteration in a signaling pathway related to cell cycle or p53 signaling. The presence of MCL1 amplification, HIF-1-alpha transcription factor network pathway alterations, and direct p53 effectors pathway alterations were independent predictors of inferior overall survival from initial diagnosis. Comparison with non-Asian premenopausal tumors in The Cancer Genome Atlas (TCGA) revealed a higher prevalence of TP53 mutations among HER2-positive cancers, and more frequent TP53, TET2, and CDK12 mutations among hormone receptor-positive HER2-negative cancers in our cohort. Given the limited number of non-Asian premenopausal breast cancers that had relapsed in TCGA, we compared the frequency of mutations in our cohort with 43 premenopausal specimens from both TCGA and International Cancer Genome Consortium that had relapsed. There was a trend toward higher prevalence of TP53 mutations in our cohort. Certain genomic aberrations may be enriched in tumors of poor-prognosis premenopausal Asian breast cancers. The development of novel therapies targeting these aberrations merit further research.