Distant Breast Cancer Research Articles

Abstract PD2-11: Breast cancer index is a molecular signature of endocrine responsiveness that determines extended endocrine benefit independent of prognostic risk

Abstract Background: For patients with early stage, hormone receptor positive (HR+) breast cancer, extension of endocrine therapy beyond 5 years reduces the ongoing risk of late distant recurrence and new primary breast cancer but is associated with potentially serious toxicities and side effects that can impair quality of life. While risk stratification by clinicopathological factors and prognostic biomarkers is recommended to guide patient selection, predictive biomarkers that are directly informative of therapeutic response are critical for clinical utility. Breast Cancer Index (BCI) is a gene expression-based signature that reports: 1) BCI Prognostic (BCI Score), which combines the Molecular Grade Index (MGI) with the HOXB13/IL17BR (H/I) ratio to provide individualized risk of late (post-5y) distant recurrence, and 2) BCI Predictive (BCI H/I), which predicts benefit from extended endocrine therapy. In this study, BCI and endocrine benefit from 5 vs 2.5y of extended letrozole were examined by comparing the deterministic effects of prognostic risk vs endocrine response in patients treated in the IDEAL trial.Methods: 908 patients with available tumor tissue were included in this pre-specified and blinded analysis, with recurrence-free interval (RFI) as the primary endpoint. Kaplan-Meier and Cox proportional hazards regression were performed using pre-defined assay cut-points. Clinically high prognostic risk was defined as pN+ and ≥pT2; low prognostic risk was defined as pN0 or pN1 and pT1 or G1. Genomic risk was defined by BCI prognostic categories (High vs Low risk). Results: Patients classified with endocrine responsive disease by BCI (H/I)-High status showed a statistically significant benefit from 5 vs 2.5y of letrozole irrespective of clinical risk, whereas those classified as BCI (H/I)-Low did not show benefit in either clinical risk category. Both clinically High and Low risk patients derived a similar magnitude of benefit when stratified as BCI (H/I)-High (12.5% and 15.1%, respectively). Evaluation of BCI (H/I) predictive performance in the context of BCI prognostic risk categories showed similar results. In particular, patients with High Risk/High Likelihood to benefit showed significantly improved outcomes with extended therapy (HR 0.42 [0.20-0.89]; absolute benefit 10.7%; P=0.020), whereas those with High Risk but Low Likelihood to benefit did not show response to extended endocrine therapy (HR 1.05 [0.58-1.88]; absolute benefit -0.7%; P=0.880), despite considerable risk of late distant recurrence (~20%). Conclusion: Results from this study highlight distinct tumor biology underlying recurrence risk vs endocrine responsiveness in HR+ early stage breast cancer. BCI (H/I) as a molecular signature to identify patients with endocrine responsive disease is a key determinant of benefit and improved outcome with extended endocrine therapy. Prediction of endocrine benefit with BCI (H/I) is a more actionable approach vs risk assessment to individualize discontinuation of or continued treatment with prolonged durations of endocrine therapy. Prognostic RiskBCI Predictive NHR (95% CI)P valueClinical RiskHigh Risk: N+/ T2+ (N=353)High BCI(H/I)1620.32 (0.10-0.98)0.035Low BCI(H/I)1911.13 (0.55-2.31)0.742Low Risk: N0 or N1 & T1 or grade 1 (N=404)High BCI(H/I)1910.15 (0.03-0.66)0.004Low BCI(H/I)2130.75 (0.33-1.70)0.484Genomic RiskHigh BCI Score(N=621)High BCI(H/I)3410.42 (0.20-0.89)0.020Low BCI(H/I)2801.05 (0.58-1.88)0.880Low BCI Score(N=227)High BCI(H/I)600.35 (0.04-3.38)0.344Low BCI(H/I)1670.64 (0.22-1.92)0.425 Citation Format: Gerrit-Jan Liefers, Iris Noordhoek, Kai Treuner, Hein Putter, Yi Zhang, Jenna Wong, Elma Meershoek-Klein Kranenbarg, Marjolijn Duijm-de Carpentier, Cornelis JH Van De Velde, Catherine A Schnabel. Breast cancer index is a molecular signature of endocrine responsiveness that determines extended endocrine benefit independent of prognostic risk [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD2-11.

Abstract PD2-08: Endocrine therapy non-persistence and recurrence in young women with early stage breast cancer

Abstract Background: Young age at diagnosis is an independent risk factor for recurrence and death from breast cancer (BC), with the greatest impact of young age demonstrated in hormone receptor positive (HR+) disease. Younger women are less likely to be adherent to endocrine therapy (ET), which may contribute to disparate outcomes. Methods: As part of a prospective cohort that enrolled women with BC diagnosed at age ≤40 between 2006-2016, we identified women with HR+, Stage I-III BC. Serial surveys with items assessing socio-demographic and treatment information including medication use are administered 1-2 times per year. Medical record review was used to ascertain stage and HR status and to confirm recurrent disease (locoregional, distant, or new primary breast cancer). Women who initiated ET but discontinued it <5-years post-diagnosis without resumption were classified as non-persistent. Univariable and multivariable regression models were fit to identify predictors of non-persistence and recurrence.Results: Among 607 women who initiated ET (median age at diagnosis: 36, range:17-40; 38%, 45%, 17% were Stage 1, 2, and 3, respectively).16% (99/607) were non-persistent, of whom 30% (30/99) discontinued ET ≤2 years post-diagnosis and over half had discontinued (54%, 54/99) by 3 years. In multivariable regression, those who were younger at diagnosis (age ≤30 vs. 36-40: OR: 3.39, 95% CI: 1.84-6.24; age 31-36 vs. 36-40: OR: 2.81 95% CI: 1.70-4.64) were more likely to discontinue ET while those with a higher stage at diagnosis were less likely to discontinue ET (Stage 2 vs. 1: OR: 0.46, 95% CI: 0.29-0.74; Stage 3 vs 1: OR: 0.32, 95% CI: 0.15-0.68). At a median follow-up time from diagnosis of 7.8 years (range 1-13 years), 15% of women (88/607) recurred or developed a new primary BC at a median time from diagnosis of 3.5 years (range 1-12 years). Of these, 66% (58/88) were distant recurrences, 32% (28/88) loco-regional, and 2% (2/88) new primary BCs. Rates of recurrence were higher among women who were persistent (81/508, 16%) vs. non-persistent (7/99, 7%, p=0.02). In multivariable regression, those who were non-persistent were less likely to recur (OR: 0.43, 95% CI: 0.19-0.98) while those with a higher stage were more likely to recur (Stage 3 vs. 1: OR: 2.36, 95% CI: 1.03-5.41). Sociodemographic, patient, and other treatment factors did not predict recurrence. Conclusions: Approximately 16% of young women with HR+ BC stop ET earlier than indicated, however non-persistence was not a risk factor for BC recurrence a median of 8 years following diagnosis in our cohort. Importantly, women with higher risk disease who are likely to benefit most from adherence to ET were less likely to discontinue treatment. Extended follow-up will further inform the impact of non-persistence on the incidence of late recurrences for which women with HR+ BC are at increased risk. Citation Format: Shoshana M Rosenberg, Yue Zheng, Philip Poorvu, Kathryn Ruddy, Rachel Gaither, Rulla Tamimi, Lidia Schapira, Jeffrey Peppercorn, Steven Come, Virginia Borges, Ann Partridge. Endocrine therapy non-persistence and recurrence in young women with early stage breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD2-08.

Abstract PS1-57: Mastectomy versus breast conserving surgery for the management of locally advanced breast cancer

Abstract Background: Breast conserving surgery (BCS) has become increasingly employed as a surgical option for patients with locally advanced breast cancer (LABC). However, guidelines on selecting appropriate LABC patients for BCS remain vague. Methods: Our Local Integrated Health Network (LHIN) conducted a multidisciplinary conference, known as the LHIN4 day, during which consensus criteria on which LABC patients may be safely offered BCS were established. These criteria included: clinical T3 or smaller, clinical and/or radiographic response to neoadjuvant therapy, patient seen by radiation oncology and deemed a candidate for post-operative radiation, and surgeon confident that negative margins could be achieved. A retrospective chart review was then performed of patients treated with neoadjuvant systemic therapy for LABC in the one year before, and three years after the LHIN4 day, which was between June 2015 and June 2019. Objectives: The primary objective of this study was to determine the rates of local and distant breast cancer recurrence in LABC patients treated with BCS using our consensus guidelines. The secondary objectives were: (1) to determine if there was an increase in BCS being performed following the LHIN4 educational day as compared to before this day, (2) to determine the rates of mastectomy followed by reconstruction among the patients treated within the past 3 years, and (3) to determine the rates of pathologic complete response (PCR). Results: A total of 391 patients were included in this study. Among the 26 patients who underwent BCS, the rate of local recurrence was 0% (0/26), and the rate of distant recurrence was 12% (3/26). Rates of BCS were 1.9% (2/108) before the LHIN4 day, and 8.5% (24/283) after the LHIN4 day. Rates of mastectomy followed by reconstruction were 12% (21/181) in the last 3 years. PCR was achieved in 15% (58/391) of all patients, of which 57% (33/58) were Her2 positive and 24% (14/58) were triple negative. Conclusion: We propose specific criteria for appropriately selecting LABC patients for BCS. Our results indicate that these criteria can be feasibly applied with low rates of local and distant breast cancer recurrence. A minority of patients with LABC who do not undergo BCS, either due to ineligibility or personal preference, are opting for mastectomy with reconstruction. Citation Format: Roochi Arora, Ghazaleh Kazemi, Graydon Lucas. Mastectomy versus breast conserving surgery for the management of locally advanced breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS1-57.

Abstract PS6-06: The 70-gene signature (MammaPrint) accurately predicts distant breast cancer recurrence risk in patients aged ≥70 years from the population-based observational FOCUS cohort

Abstract Background Predicting breast cancer recurrence in patients aged ≥70 years is challenging, as they generally have more indolent tumors and a higher chance of dying of competing causes than younger patients. The 70-gene signature test (MammaPrint) has been shown to accurately predict recurrence in women with early breast cancer and up to 3 positive lymph nodes. Aim To study outcome related to MammaPrint result in patients aged ≥70 years with breast cancer using a population-based cohort. Methods The population-based FOCUS cohort included all 2095 consecutive patients with any stage breast cancer, diagnosed between 1997 and 2004, aged ≥65 years, in the Comprehensive Cancer Center region West, the Netherlands. In the present exploratory sub-study, patients from FOCUS with the following criteria were included: ≥70 years old, T1-2N0-3M0, hormone receptor positive, HER2 negative, no neo-adjuvant treatment and available tumor specimens. MammaPrint is a genomic risk profile based on microarray gene expression analysis, classifying patients as ultralow risk (M-ULR), low (not UL) risk (M-LR) or high risk (M-HR) of developing a recurrence. Patients were considered clinically low risk (C-LR) with T1-2N0 grade 1-2 tumors and clinically high risk (C-HR) with N+ or T2/grade 3 tumors. Primary endpoint was 10-year distant recurrence free interval (DRFi) in relation to genomic risk, estimated from cumulative incidence and Fine and Gray analyses to take competing mortality into account. Results In this study, 422 patients were included. Median age was 78 years, 238 patients (56%) had node negative disease, 235 patients (56%) had T2 tumors and 227 patients (54%) were C-LR. Most patients were treated with endocrine therapy (ET), and 22 patients (5%) were treated with chemotherapy (CT; table 1). Overall, 50 (12%) patients were M-ULR, 226 (53%) were M-LR and 146 (35%) were M-HR. Discrepancies were found between C and M risk groups in 18/50 M-ULR patients with C-HR, and 56/146 M-HR patients with C-LR. Of the 59 patients that experienced a recurrence during 10 years of follow-up, 44 (75%) were distant recurrences. In the M-ULR group, DRFi was 2% (95%CI 0-6) after 10 years of follow-up, this was 8% (95%CI 5-12) in the M-LR group and 17% (95%CI 11-23) in the M-HR group (p<0.001). In the C-HR subgroup, none of the 18 M-ULR patients developed a recurrence, and DRFi was 10% (95%CI 3-16) in M-LR patients and 20% (95%CI 12-28) in M-HR patients (p=0.015). C risk alone was not able to predict distant recurrence risk (C-LR 8%, C-HR 14%, sHR 1.8 [95%CI 0.9-3.2); p=0.060; table 2). Conclusion MammaPrint accurately predicts 10-year DRFi in older patients with breast cancer. Patients classified as ultralow risk by MammaPrint had a very low chance of developing metastatic disease. Even in clinically high-risk patients who were M-ULR, recurrent disease did not occur 10 years after diagnosis. These findings are in line with published results of the STO-3 trial (JAMA Oncol, 2017) and provide foundation for de-escalation of treatment in older patients guided by genomic testing. Table 1: Baseline characteristics. BCS = breast conserving surgery. RT = radiotherapyM-ULRM-LRM-HRTotal patientsN (%)50 (11.8)226 (53.6)146 (34.6)AgeMedian (IQR)79 (74-85)79 (74-84)77 (74-84)Histological grade [N (%)]I11 (22.0)39 (17.3)5 (3.4)II21 (42.0)92 (40.7)42 (28.8)III1 (2.0)31 (13.7)54 (37.0)Missing17 (34.0)64 (28.3)45 (30.8)T-stage [N (%)]Tis0 (0.0)2 (0.9)0 (0.0)T117 (34.0)111 (49.1)54 (37.0)T233 (66.0)113 (50.0)89 (61.0)Missing0 (0.0)0 (0.0)3 (2.0)N-stage [N (%)]N032 (64.0)140 (61.9)66 (45.2)N117 (34.0)72 (31.9)67 (45.9)N20 (0.0)6 (2.7)6 (4.1)N30 (0.0)2 (0.9)3 (2.1)Missing1 (2.0)6 (2.7)4 (2.7)Clinical risk [N (%)]Low32 (64.0)139 (61.5)56 (38.4)High18 (36.0)87 (38.5)90 (61.6)Local treatment [N (%)]None4 (8.0)5 (2.2)6 (4.1)BCS only3 (6.0)16 (7.1)13 (8.9)BCS + RT9 (18.0)62 (27.4)29 (19.9)Mastectomy34 (68.0)143 (63.3)98 (67.1)Adjuvant ET [N (%)]None24 (48.0)103 (45.6)40 (27.4)Tamoxifen17 (34.0)87 (38.5)80 (54.8)Aromatase inhibitor3 (6.0)11 (4.9)9 (6.2)Unspecified ET6 (12.0)25 (11.1)17 (11.6)Adjuvant CT [N (%)]No46 (92.0)217 (96.0)137 (93.8)Yes4 (8.0)9 (4.0)9 (6.2) Table 2: Primary endpoint stratified by genomic and clinical risk. sHR=subdistribution hazard ratio.M-ULRM-LRM-HRTotalC-LRN=32 (14%). DRFi=3% (95%CI 0-9). sHR=1 (reference).N=139 (61%). DRFi=7% (95%CI 3-12). sHR=2.1 (95%CI 0.3-16.5).N=56 (25%). DRFi=13% (95%CI 4-21). sHR=4.3 (95%CI 0.5-34.7).N=227. DRFi=8% (95%CI 4-12).C-HRN=18 (9%).DRFi=0% (95%CI 0-0). sHR=N/A (n events=0).N=87 (45%). DRFi=10% (95%CI 3-16). sHR=1 (reference).N=90 (46%). DRFi=20% (95%CI 12-28). sHR=3.0 (95%CI 1.3-6.9).N=195. DRFi=14% (95%CI 9-19).TotalN=50 (12%). DRFi=2% (95%CI 0-6). sHR=1 (reference).N=226 (53%). DRFi=8% (95%CI 5-12). sHR=3.8 (95%CI 0.5-28.2).N=146 (35%). DRFi=17% (95%CI 11-23). sHR=9.8 (95%CI 1.3-72.6).N=422. Citation Format: Iris Noordhoek, Esther Bastiaannet, Ersan Lujinovic, Laura Esserman, Jelle Wesseling, Astrid Scholten, Carolien P Schröder, Sjoerd Elias, Nienke A de Glas, Judith R Kroep, Johanneke EA Portielje, Miranda Kleijn, Gerrit-Jan J Liefers. The 70-gene signature (MammaPrint) accurately predicts distant breast cancer recurrence risk in patients aged ≥70 years from the population-based observational FOCUS cohort [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-06.

Breast cancer recurrence risk after hormonal contraceptive use in survivors of reproductive age

ObjectiveTo assess the risk of recurrence with hormonal contraceptive use in breast cancer survivors of reproductive age. Study designIn this retrospective study, women ages 18–51 years who were diagnosed with primary stage 0–3 breast cancer between 2006–2016 and subsequently entered remission were included. Patients with missing information within the cancer registry or electronic medical record and those with a history of hysterectomy and/or sterilization procedure prior to diagnosis were excluded. Hormonal contraception use was defined as being prescribed an oral contraceptive pill (OCP), patch, vaginal ring, medroxyprogesterone injection, etonogestrel implant, or levonorgestrel-releasing intrauterine device (IUD). Women were separated into two groups, hormonal contraceptive users and non-users. Basic descriptive and inferential statistics were used to compare groups as appropriate. The primary outcome reviewed was local or distant breast cancer recurrence. Secondary outcomes included all-cause mortality and pregnancy. ResultsFollowing exclusions, 1370 women remained in the cohort. Ninety-seven women (7.08 %) received a prescription for a form of hormonal contraception. When comparing groups, hormonal contraceptive users were more likely to be between 18−40 years of age (46.39 % vs. 17.99 % non-users;P < 0.01) and never smokers (68.04 % vs. 38.57 % non-users; P < 0.01). Patients did not differ between groups based on any other demographic or cancer-related characteristic, including tumor hormone receptor expression. Overall, 92 patients (6.72 %) experienced local or distant recurrence during the study period. Recurrence did not differ between groups (6.19 % users vs. 6.76 % non-users; P = 0.83). All-cause mortality and pregnancy rates also did not differ between hormonal contraceptive users and non-users. ConclusionThe study shows no increased risk of recurrence associated with hormonal contraceptive use after breast cancer diagnosis and remission.

Prediction of breast cancer distant recurrence using natural language processing and knowledge-guided convolutional neural network

Distant recurrence of breast cancer results in high lifetime risks and low 5-year survival rates. Early prediction of distant recurrent breast cancer could facilitate intervention and improve patients’ life quality. In this study, we designed an EHR-based predictive model to estimate the distant recurrent probability of breast cancer patients. We studied the pathology reports and progress notes of 6,447 patients who were diagnosed with breast cancer at Northwestern Memorial Hospital between 2001 and 2015. Clinical notes were mapped to Concept unified identifiers (CUI) using natural language processing tools. Bag-of-words and pre-trained embedding were employed to vectorize words and CUI sequences. These features integrated with clinical features from structured data were downstreamed to conventional machine learning classifiers and Knowledge-guided Convolutional Neural Network (K-CNN). The best configuration of our model yielded an AUC of 0.888 and an F1-score of 0.5. Our work provides an automated method to predict breast cancer distant recurrence using natural language processing and deep learning approaches. We expect that through advanced feature engineering, better predictive performance could be achieved.

Polycyclic organic matter and invasive breast cancer

p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 12.0px 'Helvetica Neue'} Background: Emerging evidence suggests that environmental endocrine disrupting chemicals, such as polycyclic aromatic hydrocarbons (PAHs), increase breast cancer risk. Polycyclic organic matter (PAHPOM) is a USEPA Environmental Quality Index (EQI) air domain factor, which includes PAHs and PAH-derivatives present in the atmosphere in particulate form. Sources include tobacco smoke, vehicle exhaust, residential heating, coal and tar burning, and grilling meat. Methods: Herein, we investigated associations between polycyclic organic matter exposure and invasive breast cancer. Breast cancer diagnoses were obtained from the North Carolina Central Cancer Registry (2009-2014), and county of residence at diagnosis was linked with the quartiled PAHPOM variable. We first constructed generalized linear models to assess county-level breast cancer incidence by stage in counties of high versus low PAHPOM exposure, adjusted for mammography screening rates, %African American, and %Smokers. Next, we constructed generalized estimating equations to evaluate the odds of individual patients having localized, regional, or distant invasive breast cancer versus non-invasive carcinoma in situ in counties of high versus low PAHPOM exposure, adjusted for age, BMI, smoking status, and race. We further evaluated the odds of patients having hormone receptor positive versus hormone receptor negative invasive breast cancer. All models were stratified by urbanicity. Results: High PAHPOM exposure was associated with increased total and localized breast cancer incidence (total estimate 22.36, 95% CI 6.77-37.95, p=0.006; localized estimate 12.43, 95% CI 3.36-21.5, p=0.008), as well as increased odds of having hormone receptor positive versus hormone receptor negative invasive breast cancer (OR 1.04; 95% CI: 1.00, 1.08, p=0.0187) in urban counties. Conclusions: Our results suggest that high polycyclic aromatic compound exposure is associated not only with increased breast cancer incidence, but also increased odds of having hormone receptor positive invasive breast cancer, especially in urban areas.

S100A14 serum level and its correlation with prognostic factors in breast cancer

BackgroundBreast cancer is the most commonly occurring cancer in women worldwide. S100A14 is a novel important member of S100 proteins family. Its importance is due to its role in tumorigenesis and metastasis process. In this study, we aimed to determine serum levels of S100A14 protein in breast cancer patients and healthy individuals to know if it can be suggested as a new biomarker for breast cancer and to reveal whether it is correlated with cancer pathological features.MethodsThis cross-sectional study was performed in two groups: study group contains 46 breast cancer patients (29 metastatic and 17 non-metastatic) and control group contains 22 healthy women. Enzyme-linked immunoabsorbent assay was performed to determine S100A14 protein levels in samples. Pathological data were obtained for each patient. The data were statistically analyzed using Kruskal-Wallis H, Mann-Whitney U, and Spearman correlation tests.ResultsS100A14 serum levels were elevated in study group compared with control group (P < 0.05). S100A14 serum levels were significantly increased in distant breast cancer patients compared with regional breast cancer patients (P = 0.001). There was a strong positive correlation between serum S100A14 level and tumor grade (rs = 0.713, P < 0.001).ConclusionOur study indicated that S100A14 serum levels are elevated in breast cancer patients compared with control individuals. High S100A14 serum levels were correlated with poor tumor differentiation so it might have a prognostic significance for breast cancer tumors. The elevation of S100A14 levels in distant breast cancer patients suggests the ability of using serum S100A14 as a biomarker for detection of breast cancer metastasis.

Prognostic associations of plasma hepcidin in women with early breast cancer.

Iron is essential to energy metabolism, cell proliferation and DNA synthesis, and sufficient iron availability may be required for tumor growth. The hormone hepcidin is a systemic regulator of iron concentration in plasma. Intra-tumor RNA expression of hepcidin has been linked to shorter metastasis-free survival in women with early breast cancer, but the prognostic implications of this inflammatory marker and iron-regulating plasma peptide in the blood are unknown. Using an ELISA assay, hepcidin was measured in the banked blood of 518 women who were recruited from 1989 to 1996 for a prospective cohort study of diet and lifestyle factors in breast cancer. Blood samples were obtained 4-12weeks post-operatively, prior to treatment with chemotherapy or tamoxifen. Hepcidin was not associated with time to distant breast cancer recurrence (primary outcome) nor time to death from any cause. However, a pre-planned interaction test of body mass index (BMI) was statistically significant (p < 0.01). Among obese women (BMI > 30kg/m2), higher hepcidin was associated with a shorter time to distant breast cancer recurrence in both uni- and multivariable analyses (adjusted HR 1.84; 95% CI 1.04-3.25). For overall survival, a similar pattern was seen in the univariable model but the effect was diminished in a multivariable analysis. Plasma hepcidin was not associated with high-sensitivity C-reactive protein, but it was significantly associated (r ≥ 0.32) with iron indices, including total iron (p < 0.01), transferrin (p < 0.01) and soluble transferrin receptor (p < 0.01). Hepcidin may be associated with poor breast cancer outcome in obese women, however, replication is required. The biologic basis for this prognostic association requires further research.

Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial.

ObjectiveTo determine whether risk adapted intraoperative radiotherapy, delivered as a single dose during lumpectomy, can effectively replace postoperative whole breast external beam radiotherapy for early breast cancer.DesignProspective, open label, randomised controlled clinical trial.Setting32 centres in 10 countries in the United Kingdom, Europe, Australia, the United States, and Canada.Participants2298 women aged 45 years and older with invasive ductal carcinoma up to 3.5 cm in size, cN0-N1, eligible for breast conservation and randomised before lumpectomy (1:1 ratio, blocks stratified by centre) to either risk adapted targeted intraoperative radiotherapy (TARGIT-IORT) or external beam radiotherapy (EBRT).InterventionsRandom allocation was to the EBRT arm, which consisted of a standard daily fractionated course (three to six weeks) of whole breast radiotherapy, or the TARGIT-IORT arm. TARGIT-IORT was given immediately after lumpectomy under the same anaesthetic and was the only radiotherapy for most patients (around 80%). TARGIT-IORT was supplemented by EBRT when postoperative histopathology found unsuspected higher risk factors (around 20% of patients).Main outcome measuresNon-inferiority with a margin of 2.5% for the absolute difference between the five year local recurrence rates of the two arms, and long term survival outcomes.ResultsBetween 24 March 2000 and 25 June 2012, 1140 patients were randomised to TARGIT-IORT and 1158 to EBRT. TARGIT-IORT was non-inferior to EBRT: the local recurrence risk at five year complete follow-up was 2.11% for TARGIT-IORT compared with 0.95% for EBRT (difference 1.16%, 90% confidence interval 0.32 to 1.99). In the first five years, 13 additional local recurrences were reported (24/1140 v 11/1158) but 14 fewer deaths (42/1140 v 56/1158) for TARGIT-IORT compared with EBRT. With long term follow-up (median 8.6 years, maximum 18.90 years, interquartile range 7.0-10.6) no statistically significant difference was found for local recurrence-free survival (hazard ratio 1.13, 95% confidence interval 0.91 to 1.41, P=0.28), mastectomy-free survival (0.96, 0.78 to 1.19, P=0.82), distant disease-free survival (0.88, 0.69 to 1.12, P=0.30), overall survival (0.82, 0.63 to 1.05, P=0.13), and breast cancer mortality (1.12, 0.63 to 1.28, P=0.54). Mortality from other causes was significantly lower (0.59, 0.40 to 0.86, P=0.005).ConclusionFor patients with early breast cancer who met our trial selection criteria, risk adapted immediate single dose TARGIT-IORT during lumpectomy was an effective alternative to EBRT, with comparable long term efficacy for cancer control and lower non-breast cancer mortality. TARGIT-IORT should be discussed with eligible patients when breast conserving surgery is planned.Trial registrationISRCTN34086741, NCT00983684.

Primary 21-Gene Recurrence Score and Disease Outcome in Loco-Regional and Distant Recurrent Breast Cancer Patients.

Background: The 21-gene recurrence score (RS) assay has been proven prognostic and predictive for hormone receptor-positive/HER2-negative, node-negative early breast cancer patients. However, whether primary 21-gene RS can predict prognosis in recurrent breast cancer patients remained unknown.Patients and Methods: Consecutive breast cancer patients operated in Comprehensive Breast Health Center, Shanghai Ruijin Hospital between January 2009 and December 2018 were retrospectively analyzed. Patients with available 21-gene RS result for the primary tumor and reporting disease recurrence during follow-up were included. Association of 21-gene RS and overall survival (OS), post-recurrence overall survival (PR-OS), post-recurrence progression-free survival (PR-PFS), and first-line systemic treatment after recurrence were compared among different groups.Results: A total of 74 recurrent patients were included, with 10, 27, 37 patients in the RS <18, 18–30, and ≥ 31 groups, respectively. Recurrent patients with RS ≥ 31 were more likely to receive chemotherapy as their first-line treatment compared to those with RS <31 (P = 0.025). Compared to those with RS <31, patients with RS ≥ 31 had significantly worse OS (P = 0.025), worse PR-OS (P = 0.026), and a trend of inferior PR-PFS (P = 0.106). Multivariate analysis demonstrated that primary ER expression level (OS: P = 0.009; PR-OS: P = 0.017) and histological grade (OS: P = 0.003; PR-OS: P = 0.009), but not primary 21-gene RS (OS: P = 0.706; PR-OS: P = 0.120), were independently associated with worse OS and PR-OS.Conclusions: High primary 21-gene RS tended to be associated with worse disease outcome in loco-regional and distant recurrent breast cancer patients, which could influence the first-line systemic treatment after relapse, warranting further clinical evaluation.

How Useful Are Tumor Markers in Detecting Metastases with FDG-PET/CT during Breast Cancer Surveillance?

Background: To assess the clinical usefulness of serum tumor markers for early detection of distant breast cancer recurrence using FDG-PET/CT. Methods: We retrospectively analyzed 561 consecutive patients who underwent surgery for invasive primary breast cancer and had increased tumor markers (CA 15-3 and CEA) after completion of locoregional therapy. FDG-PET/CT data were reviewed for all cases. CA 15-3 and CEA were evaluated both in a continuous and in a quartile (Q) distribution. The Wilcoxon rank-sum test and logistic regression models were used to evaluate the association between increased tumor marker values and the presence (and type) of distant metastases. Results: The median value of CA 15-3 was 35.0 U/mL (IQR, 29.5–43.0) in cases where no distant metastases were detected, and it was 58.9 U/mL (IQR, 40.0–108.0) in cases where metastases were detected (p < 0.001). The median value of CEA was 6.6 U/mL (IQR, 4.4–10.0) in cases of no metastases and 12.4 U/mL (IQR, 6.9–30.0) in cases of metastases (p < 0.001). Increased levels of both tumor markers (Q3 and Q4) were strongly associated with the presence of distant metastases. The association between CA 15-3 and bone/liver metastases was stronger compared with other types of metastases (p heterogeneity between odds ratios [ORs] = 0.03 for Q3 and <0.001 for Q4), while no relevant heterogeneity between ORs emerged for CEA. Conclusion: Increased tumor marker levels detected in asymptomatic breast cancer patients during adjuvant therapies and follow-up are significantly predictive of distant metastases identified on FDG-PET/CT.

Stage-specific survival has improved for young breast cancer patients since 2000: but not equally

PurposeThe stage-specific survival of young breast cancer patients has improved, likely due to diagnostic and treatment advances. We addressed whether survival improvements have reached all socioeconomic groups in a country with universal health care and national treatment guidelines.MethodsUsing Norwegian registry data, we assessed stage-specific breast cancer survival by education and income level of 7501 patients (2317 localized, 4457 regional, 233 distant and 494 unknown stage) aged 30–48 years at diagnosis during 2000–2015. Using flexible parametric models and national life tables, we compared excess mortality up to 12 years from diagnosis and 5-year relative survival trends, by education and income as measures of socioeconomic status (SES).ResultsThroughout 2000–2015, regional and distant stage 5-year relative survival improved steadily for patients with high education and high income (high SES), but not for patients with low education and low income (low SES). Regional stage 5-year relative survival improved from 85 to 94% for high SES patients (9% change; 95% confidence interval: 6, 13%), but remained at 84% for low SES patients (0% change; − 12, 12%). Distant stage 5-year relative survival improved from 22 to 58% for high SES patients (36% change; 24, 49%), but remained at 11% for low SES patients (0% change; − 19, 19%).ConclusionsRegional and distant stage breast cancer survival has improved markedly for high SES patients, but there has been little survival gain for low SES patients. Socioeconomic status matters for the stage-specific survival of young breast cancer patients, even with universal health care.

Abstract B122: Spatial analysis of ductal carcinoma in situ, locoregional, and distant metastatic breast cancer in North Carolina: Evidence for rural-urban disparities

Abstract Introduction: A projected 8870 women will be diagnosed with breast cancer in North Carolina (NC) in 2019, with 1390 estimated deaths. However, breast cancer is a heterogenous disease, and investigating total incidence may hide differences in how sociodemographic factors impact the development of different subtypes of breast cancer, in particular early vs late stage aggressive phenotypes. The objective of this study was to investigate geographical variation of breast cancer in NC by stage, and to determine stage-specific associations with race and urbanicity. Methods: Breast cancer patient data were obtained from the NC Central Cancer Registry (NC CCR 2009-14) and stratified by stage and comprised of patients diagnosed with ductal carcinoma in situ (7975; DCIS), locoregional (38,200; combined localized, regional, and regional with direct extensions), or distant metastatic breast cancer (2073) based on derived summary staging defined by the Surveillance, Epidemiology, and End Results (SEER) program. Spatial distribution maps were generated in ArcMap 10.5.1 software for age-standardized incidence ratios (SIRs) by county using the NCCCR patient dataset described and age distributions from 2014 U.S. Census population estimates. Additionally, we stratified patients by rural-urban continuum code (RUCC), condensed for our purposes into three rural-urban categories: metropolitan urbanized, non-metro urbanized, and less populated. Results: DCIS, locoregional, and distant metastatic breast cancers all exhibited patterns of significantly different SIRs than expected based on state incidence rates in the northeastern region of NC, while DCIS and total breast cancer also had significantly different SIRs in the western region. Approximately 70% of patients inhabited metropolitan urbanized areas regardless of breast cancer stage, however, the highest incidence rates for all stages were consistently observed in less populated counties. Mean age at diagnosis for all stages was slightly higher in less populated areas, for example 61.4yrs DCIS and 62.8yrs distant metastatic breast cancer, than metropolitan areas, at 60.0yrs DCIS and 60.1yrs distant metastatic breast cancer. A higher percentage of distant metastatic breast cancer patients (29%) versus locoregional or DCIS patients (both 20%) in the dataset self-identified as Black, a pattern consistent across rural-urban categories. The percentage of current smokers was also higher for distant metastatic breast cancer cases (10%) than locoregional (6%) or DCIS cases (5%) across all rural-urban categories. Conclusions: Our results indicate that breast cancer incidence in NC varies geospatially by stage with incidence often higher in less populated areas. There were also age, race, and smoking status disparities across rural-urban stratifications and in patients with late stage breast cancer, which have the potential to contribute to poor survival outcomes in high risk patients. Citation Format: Larisa M Gearhart-Serna, Kate Hoffman, Gayathri R Devi. Spatial analysis of ductal carcinoma in situ, locoregional, and distant metastatic breast cancer in North Carolina: Evidence for rural-urban disparities [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B122.

Identification of TUBB2A by quantitative proteomic analysis as a novel biomarker for the prediction of distant metastatic breast cancer

BackgroundMetastasis of breast cancer to distal organs is fatal. However, few studies have identified biomarkers that are associated with distant metastatic breast cancer. Furthermore, the inability of current biomarkers, such as HER2, ER, and PR, to differentiate between distant and nondistant metastatic breast cancers accurately has necessitated the development of novel biomarker candidates.MethodsAn integrated proteomics approach that combined filter-aided sample preparation, tandem mass tag labeling (TMT), high pH fractionation, and high-resolution MS was applied to acquire in-depth proteomic data from FFPE distant metastatic breast cancer tissues. A bioinformatics analysis was performed with regard to gene ontology and signaling pathways using differentially expressed proteins (DEPs) to examine the molecular characteristics of distant metastatic breast cancer. In addition, real-time polymerase chain reaction (RT-PCR) and invasion/migration assays were performed to validate the differential regulation and function of our protein targets.ResultsA total of 9441 and 8746 proteins were identified from the pooled and individual sample sets, respectively. Based on our criteria, TUBB2A was selected as a novel biomarker candidate. The metastatic activities of TUBB2A were subsequently validated. In our bioinformatics analysis using DEPs, we characterized the overall molecular features of distant metastasis and measured differences in the molecular functions of distant metastatic breast cancer between breast cancer subtypes.ConclusionsOur report is the first study to examine the distant metastatic breast cancer proteome using FFPE tissues. The depth of our dataset allowed us to discover a novel biomarker candidate and a proteomic characteristics of distant metastatic breast cancer. Distinct molecular features of various breast cancer subtypes were also established. Our proteomic data constitute a valuable resource for research on distant metastatic breast cancer.

Development and validation of natural language processing (NLP) algorithm for detection of distant versus local breast cancer recurrence and metastatic site.

2043 Background: Electronic health records (EHR) are used for retrospective cancer outcomes analysis. Sites and timing of recurrence are not captured in structured EHR data. Novel computerized methods are necessary to use unstructured longitudinal EHR data for large scale studies. Methods: We previously developed a neural network-based NLP algorithm to identify no recurrence vs. metastatic recurrence cases by analyzing physician notes, pathology and radiology reports in Stanford’s breast cancer database, Oncoshare (Cohort A). To validate this algorithm for local vs. distant recurrence, we identified a distinct Oncoshare cohort (Cohort B). Cases were manually curated for longitudinal development of local or distant recurrence and metastatic sites. A two-sided t-test was used to compare mean probabilities between local and distant recurrence cases. Next, we combined cases in Cohorts A and B to train and validate a novel NLP classifier that identifies metastatic site. The combined cohort was randomly divided into training and validation sets. Sensitivity and specificity were calculated for the NLP algorithm’s ability to detect metastatic sites compared to manual curation. Results: In Cohort B: 350 metastatic cases were identified. Mean probability for local and distant recurrence was 0.43 and 0.79, respectively and differed significantly for patients with local vs. distant recurrence (p&lt;0.01). In Cohorts A and B: 632 metastatic cases were used for determination of sites. Sensitivity and specificity were highest for detection of peritoneal metastasis followed by liver, lung, skin, bone and central nervous system (table). Conclusions: This NLP algorithm is a scalable tool that uses unstructured EHR data to capture breast cancer recurrence, distinguishing local from distant recurrence and identifying metastatic site. This method may facilitate analysis of large datasets and correlation of outcomes with metastatic site. [Table: see text]

Local and Systemic Antitumor Effects of Photo-activatable Paclitaxel Prodrug on Rat Breast Tumor Models.

We demonstrated that a large primary and a small untreated distant breast cancer could be controlled by local treatment with our light-activatable paclitaxel (PTX) prodrug. We hypothesized that the treated tumor would be damaged by the combinational effects of photodynamic therapy (PDT) and locally released PTX and that the distant tumor would be suppressed by systemic antitumor effects. Syngeneic rat breast cancer models (single- and two-tumor models) were established on Fischer 344 rats by subcutaneous injection of MAT B III cells. The rats were injected with PTX prodrug (dose: 1umolekg-1 , i.v.), and tumors were treated with illumination using a 690-nm laser (75 or 140mWcm-1 for 30min, cylindrical light diffuser, drug-light interval [DLI] 9h). Larger tumors (~16mm) were effectively ablated (100%) without recurrence for >90days. All cured rats rejected rechallenged tumor for up to 12months. In the two-tumor model, the treatment of the local large tumor (~16mm) also cured the untreated tumor (4-6mm) through adaptive immune activation. This is our first demonstration that local treatment with our PTX prodrug produces systemic antitumor effects. Further investigations are warranted to understand mechanisms and optimal conditions to achieve clinically translatable systemic antitumor effects.

Spotlight in Plastic Surgery: April 2020

Spotlight in Plastic Surgery: April 2020

Breast Cancer Population Screening Program Results in Early Detection and Reduced Treatment and Health Care Costs for Medicaid.

The National Breast and Cervical Cancer Early Detection Program has increased access to screening services for low-income females since 1991; however, evaluation information from states implementing the program is sparse. This study evaluates the impact of the Missouri program, Show Me Healthy Women (SMHW), on early detection and treatment cost. To estimate breast cancer treatment and health care services costs by stage at diagnosis among Missouri's Medicaid beneficiaries and assess the SMHW program impact. Analyzed Missouri Medicaid claims linked with Missouri Cancer Registry data for cases diagnosed 2008-2012 (N = 1388) to obtain unadjusted and incremental costs of female breast cancer treatment and follow-up care at 6, 12, and 24 months following diagnosis. Noncancer controls (N = 3840) were matched on age, race, and disability to determine usual health care cost. Regression analyses estimated the impact of stage at diagnosis on expenditures and incremental cost. Show Me Healthy Women participants were compared with other breast cancer patients on stage at diagnosis. A comparison of SMHW participants to themselves had they not been enrolled in the program was analyzed to determine cost savings. Expenditures increased by stage at diagnosis from in situ to distant with unadjusted cost at 24 months ranging from $50 245 for in situ cancers to $152 431 for distant cancers. Incremental costs increased by stage at diagnosis from 6 months at $7346, $11 859, $21 501, and $20 235 for in situ, localized, regional, and distant breast cancers, respectively, to $9728, $17 056, $38 840, and $44 409 at 24 months. A significantly higher proportion of SMHW participants were diagnosed at an early stage resulting in lower unadjusted expenditures and cost savings. Although breast cancer treatment costs increased by stage at diagnosis, the population screening program's significant impact on early diagnosis resulted in important cost savings over time for Medicaid.

Impact of Older Age and Comorbidity on Locoregional and Distant Breast Cancer Recurrence: A Large Population-Based Study.

Studies have demonstrated worse breast cancer-specific mortality with older age, despite an increasing risk of dying from other causes due to comorbidity (competing mortality). However, findings on the association between older age and recurrence risk are inconsistent. The aim of this study was to assess incidences of locoregional and distant recurrence by age, taking competing mortality into account. Patients surgically treated for nonmetastasized breast cancer between 2003 and 2009 were selected from The Netherlands Cancer Registry. Cumulative incidences of recurrence were calculated considering death without distant recurrence as competing event. Fine and Gray analyses were performed to characterize the impact of age (70-74 [reference group], 75-79, and ≥80 years) on recurrence risk. A total of 18,419 patients were included. Nine-year cumulative incidences of locoregional recurrence were 2.5%, 3.1%, and 2.9% in patients aged 70-74, 75-79, and ≥80 years, and 9-year cumulative incidences of distant recurrence were 10.9%, 15.9%, and 12.7%, respectively. After adjustment for tumor and treatment characteristics, age was not associated with locoregional recurrence risk. For distant recurrence, patients aged 75-79 years remained at higher risk after adjustment for tumor and treatment characteristics (75-79 years subdistribution hazard ratio [sHR], 1.25; 95% confidence interval [CI], 1.11-1.41; ≥80 years sHR, 1.03; 95% CI, 0.91-1.17). Patients aged 75-79 years had a higher risk of distant recurrence than patients aged 70-74 years, despite the higher competing mortality. Individualizing treatment by using prediction tools that include competing mortality could improve outcome for older patients with breast cancer. In this population-based study of 18,419 surgically treated patients aged 70 years or older, patients aged 75-79 years were at higher risk of distant recurrence than were patients aged 70-74 years. This finding suggests that patients in this age category are undertreated. In contrast, it was also demonstrated that the risk of dying without a recurrence strongly increases with age, and patients with a high competing mortality risk are easily overtreated. To identify older patients who may benefit from more treatment, clinicians should therefore take competing mortality risk into account. Prediction tools could facilitate this and thereby improve treatment strategy.