Comment on Clinical Outcomes in Early-Stage Metaplastic Breast Cancer.

Early-onset diagnosis, defined by age <40 years, has historically been associated with inferior outcomes in breast cancer. Recent evidence suggests that this association is modified by molecular subtype. We performed a systematic review and meta-analysis of the literature to synthesize evidence on the association between early-onset diagnosis and clinical outcomes in triple-negative breast cancer (TNBC). Studies comparing the risk of clinical outcomes in non-metastatic TNBC between early-onset patients and later-onset patients (≥40 years) were queried in Medline and EMBASE from inception to February 2023. Separate meta-analyses were performed for breast cancer specific survival (BCSS), overall survival (OS), and disease-free survival (DFS), locoregional recurrence-free survival (LRRFS), distant recurrence-free survival (DRFS), and pathological complete response (pCR). In total, 7581 unique records were identified, and 36 studies satisfied inclusion criteria. The pooled risk of any recurrence was significantly greater in early-onset patients compared to later-onset patients. Better BCSS and OS were observed in early-onset patients relative to later-onset patients aged >60 years. The pooled odds of achieving pCR were significantly higher in early-onset patients. Future studies should evaluate the role of locoregional management of TNBC and the implementation of novel therapies such as PARP inhibitors in real-world settings, and whether they improve outcomes.

BACKGROUND Anthracycline(A)-containing regimens (AReg) became an established standard (neo)adj CTx for ESBC following fairly consistent demonstration of a modest superiority over older anti-metabolite/alkylating CTx. However, substantial translational data and a recently presented pooled analysis [Blum, 2016] suggest that this superiority could be largely driven by greater benefits in specific ESBC subgroups, i.e. HER2-altered BrCa (due to co-amplification of topoisomerase 2 and HER2), and triple-negative BrCa (TNBC). A are cardiotoxic (including late onset of cardiomyopathic congestive heart failure) and potentially leukaemogenic. In late 2006, following the results of the first USONC randomized clinical trial that showed superior outcomes of the non-AReg TC (docetaxel/cyclo­phosphamide) over AC, we established a routine, uniform policy of TC for all Pts receiving (neo)adj CTx for HER2-normal ESBC. We report the mature follow up of this single-institution unselected experience. METHODS We performed a retrospective outcome analysis of all Pts who received at least 1 cycle of (neo)adj TC (docetaxel 75 mg/m2 + cyclophosphamide 600 mg/m2 IV every 3 weeks) at our Department for HER2-normal ESBC and with at least 5 years of follow up (FU). Pts were identified by systematic analysis of the dataset of the Oncology Pharmacy Unit. Information on tumour characteristics [e.g. axillary lymph nodes (N) metastases, hormonal receptors (HR) and HER2 status] and Pts FU were retrieved and collected into an ad hoc designed database. Pts with node-positive (N+) ESBC received TC×6 cycles, and Pts with high-risk node-negative (N−) [e.g. primary tumour (T) &amp;gt;2 cm, or HRneg, or T &amp;gt;3 cm] ESBC received TC×4 cycles. Pts received adjuvant hormone therapy and radiotherapy as per standard of care. From 2008 on, many lower risk HR+/N− Pts were not given CTx due to OncotypeDx availability. RESULTS Between September 2006 and December 2015, 810 female HER2-normal ESBC Pts were treated with (neo)adj TC. In the final outcome analysis we included 464 Pts treated before June 2011 thus having a minimum FU of 5 years. Pts characteristics are: median age 53 yrs (range 30-77), N− 246 (53%), N+ 218 (47%), hormone receptors positive (HR+) 391 (84%), TNBC 73 (16%). The database was locked as of June 1st 2016. Median FU from first cycle of TC is 7.5 yrs (range 5.3-10). 63 BrCa-specific relapse events (defined as time to local, regional or distant recurrence, invasive contralateral breast cancer, excluding non-breast second primaries) have been observed, accounting for an overall Relapse-Free Survival (RFS) rate of 86.4%. 42 deaths have occurred, 36 (86%) due to BrCa, accounting for an Overall Survival (OS) rate of 91%. RFS and OS rates for the different Pts subgroups are reported in Table 1 Table 1 - Outcome parameters RFS (%)OS (%)All Pts8691HR+/N-9396HR+/N+8190TN/N-9191TN/N+5858 CONCLUSIONS These mature data with long FU suggest that the outcome for a large cohort of unselected Pts with HER2-normal HR+ ESBC (regardless of nodal status) and for TN/N− ESBrCa treated with nonAReg TC is excellent. However, N+TN ESBrCa in this setting remains a significant clinical challenge. Citation Format: Losurdo A, Gullo G, Buckley C, Lowry C, Ballot J, Silva N, Hammond L, Crown J. Long-term outcome of HER2-normal early stage breast cancer (ESBC) patients (Pts) treated with docetaxel-cyclophosphamide (TC) chemotherapy (CTx): Mature results of a single-institution experience [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-14-12.

Purpose: Disparities in breast cancer outcomes have been a long-standing and persistent challenge. Earlier onset, advanced stage at diagnosis, aggressive tumor subtypes [triple negative breast cancer (TNBC)], and worse overall survival (OS) are some of the characteristic features of breast cancer in non-Hispanic Black (NHB) women compared to their non-Hispanic White (NHW) counterparts, denoting one of the most significant examples of racial/ethnic differences in oncology. Given our location in South Florida, gateway to Latin America and the Caribbean, we discovered that these disparities in tumor characteristics and outcomes among NHB and NHW also extend to Hispanic Blacks (HB) compared to Hispanic Whites (HW). Since Hispanics are the second largest ethnic group in the US and have a rich genetic architecture with contributions from European (EU), West African (WA), and Native American (NA) populations, we sought to investigate genomic associations between observed inter and intra-racial/ethnic differences and breast cancer characteristics and outcomes. Methods: Patients with stage I-IV breast cancer were included. Patient socioeconomnic status (SES), tumor and treatment characteristics, and follow-up data were collected for each patient. Genomic analysis was performed on the peripheral blood from a cohort of 309 patients with breast cancer. This breast cancer cohort was comprised of 192 self-reported HW, 12 HB, 46 NHW, 47 NHB, and 12 unknown (declined to report) patients. Leukocyte DNA from each patient was genotyped, generating whole genome single nucleotide polymorphism (SNP) profiles. Global ancestral estimates, using &amp;gt;100,000 SNPs, were calculated against reference samples from EU, WA, NA, and East Asian (EA) ancestral populations. A genomic diversity space was generated via principal component analysis and ADMIXTURE was used to estimate the ancestral proportions among the patients. Results: The genetic structure of individual patient sample revealed a diverse ancestral admixture where average EU, WA, NA, and EA ancestries were 64.5%, 21.8%, 11.2%, and 2.5%, respectively. Multinomial logistic regression revealed a significant association between increasing WA ancestry and aggressive tumor subtypes (ER-/HER2+ and TNBC), p=0.009 and p=0.031, respectively. These findings remained significant when correcting for patient age and tumor stage; however, when adjusting for income, the association between WA ancestry and ER-/HER2+ and TNBC was no longer significant. Kaplan Meier survival curves showed a significant difference in 5-year OS for patients with &amp;gt;70% WA ancestry compared to those with &amp;lt;70% WA ancestry, p=0.023. Conclusions: In this first integrative approach studying genetic ancestry and SES on breast cancer characteristics and outcomes, we found a significant association between increasing WA ancestry and aggressive breast cancer subtypes, even after adjusting for known covariates. More striking, this association was negated when adjusting for income, suggesting potential gene-environment interactions not accounted for by genetic race. We also discovered that Hispanics have a more complex genetic architecture than non-Hispanic patients, which may in-turn drive genetically-associated survival patterns of resiliency with improved survival in HW compared to NHB patients. Furthermore, the OS differences based on quantitative genetic ancestry cut-offs may serve as a future tool in patient prognosis. Collectively, our results show that genetic ancestry and SES influence breast cancer subtypes and survival. This lays a foundation for future studies to investigate complex genomic relationships between race/ethnicity, SES, and breast cancer characteristics and outcomes through the lens of gene-environment interactions. Citation Format: Daniel A Rodriguez, Sina Yadegarynia, J. William Harbour, Nipun B. Merchant, Erin N. Kobetz, Neha Goel. Comprehensive analysis of global genetic ancestry and socioeconomic status on breast cancer outcomes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-13-05.

Tumor-associated macrophages (TAMs) and abnormalities in cancer cells affect cancer progression and response to therapy. TAMs are a major component of the tumor microenvironment (TME) in breast cancer, with their invasion affecting clinical outcomes. Programmed death-ligand 1 (PD-L1), a target of immune checkpoint inhibitors, acts as a suppressive signal for the surrounding immune system; however, its expression and effect on TAMs and the clinical outcome in breast cancer are unknown. In this study, we used high-throughput multiple immunohistochemistry to spatially and quantitatively analyze TAMs. We subjected 81 breast cancer specimens to immunostaining for CD68, CD163, PD-1, PD-L1, CD20, and pan-CK. In both stromal and intratumoral areas, the triple-negative subtype had significantly more CD68/CD163, CD68/PD-L1, and CD163/PD-L1 double-positive cells than the estrogen receptor (ER)/progesterone receptor (PR) subtype. Interestingly, a higher number of CD68+/PD-L1+/CK-/CD163- TAMs in the intratumoral area was correlated with a favorable recurrence rate (p = 0.048). These findings indicated that the specific subpopulation and localization of TAMs in the TME affect clinical outcomes in breast cancer.

BackgroundEvidence of the association between dietary pattern and outcomes of breast cancer was limited in Asian women, including Chinese.Patients and MethodsA prospective cohort study was initiated among Chinese breast cancer patients to investigate lifestyle habits and outcomes of breast cancer. At each follow-up, validated food frequency questionnaires (FFQ) were used to assess patients’ dietary intake. This study included 1226 patients with invasive early-stage breast cancer with detailed data at 18-month follow-up after cancer diagnosis. Factor analysis was used to derive dietary patterns, whereby two dietary patterns were identified. Cox proportional hazards models were used to investigate associations between dietary patterns and time to outcome, including breast cancer recurrence, overall mortality and breast cancer-specific mortality.ResultsWith a median follow-up time of 54.1 months, 165 patients had breast cancer recurrence and 98 deaths occurred. Two dietary patterns were identified: “Western dietary pattern” characterized by high intake of refined grains and cakes, red and processed meat and oil; “healthy dietary pattern” characterized by high consumption of vegetables and fruits. Participants in the highest tertile of “Western dietary pattern” did not have a higher risk of breast cancer recurrence (Ptrend = 0.89), overall mortality (Ptrend = 0.48) and breast cancer-specific mortality (Ptrend = 0.75). Similarly, a null association existed between “healthy dietary pattern” and outcomes of breast cancer.ConclusionNeither dietary pattern was associated with risk of breast cancer recurrence, all-causes death or death from breast cancer. Prospective follow-up is still needed to further confirm the association between specific dietary pattern and outcomes of breast cancer.

Fasting insulin is related to outcome in early breast cancer. We evaluated the expression of insulin receptor (IR) and its prognostic significance in patients with early stage breast cancer. Tumors from 191 patients with T1-3, N0-1, M0 breast cancer who were enrolled at a single center of a multicenter cohort study were used to construct microarrays with subsequent immunohistochemical evaluation of IR, IGF-IR, ER, PgR and HER2/neu. Correlation of biomarker expression with traditional prognostic factors, serum biochemistry (notably insulin) and clinical outcome was assessed. IR was strongly positive (Allred score = 8) in 54% of tumors. High IR expression significantly correlated with favorable prognostic markers (low tumor grade, lymph node negativity and progesterone receptor positivity) but not with fasting levels of circulating insulin. At a median follow-up of 9.1 years, high vs. low IR expression (an Allred score of 8 vs. 0-7) was associated with statistically significant improved distant disease-free survival (multivariate hazard ratio (HR) = 0.4; P = 0.027) and overall survival (multivariate HR = 0.26; P = 0.005). IR is highly expressed in the majority of early stage breast cancers but this expression is not clearly down-regulated in the presence of high insulin levels. Furthermore, high expression of IR is independently and significantly associated with more favorable clinical outcomes. Follow-up intervention research is recommended.

BackgroundYoung women with breast cancer are determined to present poorer survival compare with elderly patients. Therefore, identifying the clinical prognostic factors in young women with early-stage (T1-2N0-1M0) breast cancer is pivotal for surgeons to make better postoperative management.MethodsThe clinicopathological characteristics of female patients with early-stage breast cancer from the Surveillance, Epidemiology, and End Results program between Jan 2010 and Dec 2015 were retrospectively reviewed and analyzed. Univariate and multivariate Cox regression analyses were used to determine the potential risk factors of cancer-specific survival in young women with early-stage breast cancer. The nomogram was constructed and further evaluated by an internal validation cohort. The Kaplan-Meier survival curves were used to estimate cancer-specific survival probability and the cumulative incidence.ResultsSix variables including race, tumor location, grade, regional lymph node status, tumor subtype, and size were identified to be significantly associated with the prognosis of young women with early-stage breast cancer during the postoperative follow-up. A nomogram for predicting the 3-, 5- year cancer-specific survival probability in this subpopulation group was established with a favorable concordance index of 0.783, supported by an internal validation cohort with the AUC of 0.722 and 0.696 in 3-, 5- year cancer-specific survival probability, respectively.ConclusionsThe first predictive nomogram containing favorable discrimination is successfully established and validated for predicting the 3-, 5- year cancer-specific survival probability in young women with early-stage breast cancer during the postoperative follow-up. This model would help clinicians to make accurate treatment decisions in different clinical risk population.

Background: Observational studies suggest that physical activity following a diagnosis of breast cancer may be associated with a lower risk of recurrence and death. Some studies also suggest possible effect modification by disease stage, body mass index, and receptor status. To date, however, there are no randomized trials examining the effects of exercise on disease outcomes in any cancer patient group. Here, we report an exploratory follow-up of disease outcomes from the Supervised Trial of Aerobic versus Resistance Training (START). Patients and Methods: The START Trial was a Canadian multicenter trial that randomized 242 breast cancer patients starting adjuvant chemotherapy to either usual care (n = 82) or supervised aerobic (n = 78) or resistance (n = 82) exercise for the duration of their chemotherapy. The primary efficacy endpoint for this exploratory analysis was disease-free survival (DFS). Secondary endpoints were overall survival (OS), distant disease-free survival (DDFS), and recurrence-free interval (RFI). The two exercise arms were combined for the analysis (n = 160) and selected subgroups were explored. Results: After a median follow-up of 89 months (IQR 81 to 96), there were 25/160 (15.6%) DFS events in the exercise groups and 18/82 (22.0%) in the control group (log-rank p = 0.21). Eight-year DFS was 82.7% for the exercise groups compared with 75.6% for the control group (Hazard ratio [HR] = 0.68, 95% CI = 0.37-1.24). There were 13/160 (8.1%) deaths in the exercise groups and 11/82 (13.4%) in the control group (log-rank p = 0.21). Eight-year OS was 91.2% in the exercise groups compared with 82.7% in the control group (HR = 0.60, 95% CI = 0.27 to 1.33. There were 20/160 (12.5%) DDFS events in the exercise groups and 16/82 (19.5%) in the control group (log-rank p = 0.15). Eight-year DDFS was 86.7% in the exercise groups compared with 78.3% in the control group (HR = 0.62, 95% CI = 0.32 to 1.19). Finally, there were 20/160 (12.5%) RFI events in the exercise groups and 17/82 (20.7%) in the control group (Gray's p = 0.095). Eight-year cumulative incidence of RFI was 12.6% in the exercise groups compared with 21.6% in the control group (HR = 0.58, 95% CI = 0.30 to 1.11). Subgroup analyses for DFS and RFI suggested stronger effects for women who were overweight/obese, had stage II/III cancer, receptor positive tumors, HER2 positive tumors, received taxane-based chemotherapies, and received at least 85% of their intended chemotherapy dose-intensity. The most notable subgroup effect was for patients who received optimal chemotherapy dosing with a borderline significant effect for DFS (HR = 0.50, 95% CI = 0.25 to 1.01) and a significant effect for RFI (HR = 0.38, 95% CI = 0.18 to 0.81). Conclusions: In this exploratory follow-up of the START Trial, there was a suggestion that exercise during adjuvant chemotherapy may improve several efficacy endpoints although none achieved statistical significance. Nevertheless, the magnitude of the effects appear to be meaningful with absolute 8-year survival differences between 7% and 9% and relative rate reductions between 30% and 40%. The START Trial provides the first randomized data to suggest that adding exercise to standard chemotherapy for breast cancer may improve outcomes. A definitive phase III trial is warranted. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-08-01.

ctDNA dynamics during neoadjuvant chemotherapy can predict clinical outcomes in breast cancer.

Background: Murine tumor models show that cold stress increases tumor growth rate by norepinephrine release, altering the tumor microenvironment (TME). Tumor-bearing mice when housed at standard temperature of 22°Celsius (°C) exhibited a pro-tumorigenic TME (with fewer CD8+ T Cells and an increase in immunosuppressive cells) than mice housed at 30°C. The incidence of cancer has been shown to be higher in colder climates. Achievement of pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC) for early stage breast cancer (BC) is associated with improved overall survival (OS) and disease specific survival (DSS). Based on these findings, we hypothesized that pCR would be increased while mortality would be decreased in BC patients (pts) living in warmer climates. Methods: A retrospective, population-based analysis was conducted utilizing the Surveillance, Epidemiology and End Results (SEER) from 1996-2017 and National Cancer Database (NCDB) from 2004-2018, and average annual temperature (AAT) data from the National Centers for Environmental Information. Cut-offs for AAT were obtained using the Youden’s index (for pCR) and maximum log-rank (for OS and DSS) methods. Associations between AAT and both pCR and OS/DSS were evaluated using logistic and Cox regression models, respectively, adjusting for confounders (age, race, education, insurance, BC subtype, treatment). Results: A total of 1,209,332 and 270,496 stage I-III BC pts in the US were analyzed using NCDB and SEER, respectively. In NCDB, 52.1% were hormone receptor (HR)+/HER2-, 8.6% triple negative (TNBC), 7.2% HR+/HER2+ and 3.1% HR-/HER2+ and 29% unknown. 37.7% received chemotherapy, 62.6% radiation and 94.3% surgery. 10.2% pts received NAC and 19.5% (19,021/97,669) achieved pCR. The AAT ranged from 44.7°Fahrenheit (°F) to 62.3°F with median 50.9°F. When adjusting for covariates, pts in regions with AAT &amp;gt; 60.9°F, had a greater chance of achieving pCR compared to AAT &amp;lt; 60.9°F with odds ratio (OR) 1.12 (95% CI 1.07-1.18), p &amp;lt;0.001. This was consistent in the TNBC and HR-/HER2+ subgroups with OR 1.14 (95% CI 1.07-1.23) and 1.15 (95% CI 1.04-1.27), respectively. There was a 2% improvement in OS with every 5°F increment, HR 0.98 (95% CI 0.97-0.99), p &amp;lt; 0.001. In SEER, 22.4% were HR+/HER2-, 4.4% TNBC, 4.0% HR+/HER2+, 1.8% HR-/HER2+ and 68.5% unknown. 43.4% received chemotherapy, 49.7% radiation and 94.2% surgery. The AAT ranged from 33.6°F to 67.3°F with median 57.4°F. There was a 3% improvement in OS [HR 0.97 (95% CI 0.968-0.977), p &amp;lt; 0.001] and 2.5% improvement in DSS [HR 0.98 (95% CI 0.968-0.982), p&amp;lt;0.001] with every 5°F increment. Conclusions: Higher environmental temperatures are associated with significant improvements in rate of pCR, OS and DSS in Stage I-III BC pts. Research focusing on underlying mechanisms and therapeutic strategies to abrogate this disparity is warranted. Citation Format: Ashish Gupta, Kristopher Attwood, Kush Gupta, Asha Gandhi, Stephen Edge, Kazuaki Takabe, Elizabeth Repasky, Shipra Gandhi. Favorable impact of higher environmental temperature on clinical outcomes in breast cancer - Does residence matter? A NCDB and SEER population-based study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 31.

Introduction: Stromal tumor-infiltrating lymphocytes (sTILs) have established prognostic and predictive significance in triple-negative breast cancer (TNBC). However, the roles of other immune cells in TNBC are less well-established. We performed high-plex quantitative spatial profiling in a cohort of early-stage TNBC to 1) apply spatial context to tumoral immune landscapes and 2) identify immune proteins associated with clinical outcomes, independently of TILs and other established prognostic clinicopathologic variables, in patients (pts) treated with or without adjuvant chemotherapy (CTX). Methods: The Mayo TNBC cohort comprises pts with centrally-verified, CTX-naive tumors resected from 1985-2012. Using a cohort-based TMA, with Nanostring GeoMX DSP, we quantitated 58 proteins within spatially-distinct intra-epithelial, cytokeratin-positive tumor segments and adjacent cytokeratin-negative/nuclei-positive stromal segments. Differentially-expressed (DE) proteins were identified using a negative binomial generalized linear model (SNR&amp;gt;2, p&amp;lt; 0.05) and a target DE protein set was dichotomized (80th percentile). After adjusting for prognostic clinicopathologic variables, proteins associated with recurrence-free survival (RFS, defined as time from surgery to either local, regional, and distant recurrence, or death by any cause) were identified by performing variable selection using the Akaike Information Criterion (AIC) obtained from fitting all possible Cox proportional hazards regression models (performed separately for intra-epithelial/stromal segments, and in groups +/- adjuvant CTX. Results: From the TNBC TMA, DSP data (N=250 tumors) included 169 pts who received adjuvant CTX+ and 81 who did not (CTX-). Overall, 85/250 developed recurrent disease. In the CTX+ group, intra-epithelial tumor segments from pts without recurrent disease were enriched in 10 immune proteins, including CD8, markers involved in antigen presentation/dendritic cells (CD11c, CD40, HLA-DR) or NK cells (CD56) (FC: 1.4-2.1, p&amp;lt;0.05); CD14 was increased in stroma (FC: 1.5, p&amp;lt;0.05). In contrast, in the CTX- group, both the intra-epithelial tumor and stromal segments from pts without recurrences were enriched in immune proteins (N= 12 and 15 respectively; FC 1.6-5.5, p&amp;lt; 0.05) most markedly CD40, IDO1 and HLA-DR (FC: 3.2-5.5, p&amp;lt; 0.05). Overall, CD3, CD4, CD27, CD44, and ICOS among others were enriched only in the CTX- group; CD14 and CD56 were enriched only in the CTX+ group. Based on these spatial data, biologic function and DSP data from another set of TNBC (FinXX trial), CD11c, CD14, CD27, CD40, CD56, and IDO1 were selected for RFS analysis. After applying our model selection criterion and adjusting for pt age at surgery, tumor size, lymph node status, and sTILs, intra-epithelial CD56 was independently associated with improved RFS in the CTX+ group (HR: 0.31[0.12, 0.81]). In the CTX- group, intra-epithelial CD11c was independently associated with improved RFS (0.10 [0.01, 0.81]). Conclusion: In this early-stage TNBC cohort, spatially-distinct tumor immune landscapes were associated with RFS but differed according to receipt of CTX after surgical resection. In the patients who received CTX, the intra-epithelial compartment, rather than stromal compartment, was immune-enriched in pts without recurrences. Among a targeted protein set, intra-epithelial CD56 remained associated with improved outcomes, independent of sTILs and other clinicopathologic features. In the CTX- group, spatial landscapes were more balanced, and intra-epithelial CD11c was independently associated with improved outcomes. These data provide insight into the spatial context of intrinsic immune landscapes in TNBC, and identify candidate prognostic immune biomarkers which may inform therapeutic strategies. Citation Format: Jodi M Carter, Saranya Chumsri, David W Hillman, David M Zahrieh, Yaohua Ma, Xue Wang, Jennifer M Kachergus, Judy C Boughey, Minetta C Liu, Krishna R Kalari, JC Villasboas, Roberto A Leon Ferre, Fergus J Couch, Matthew P Goetz, E. Aubrey Thompson. Intra-epithelial tumor immune landscapes are associated with clinical outcomes in early-stage triple-negative 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 PS16-01.

Background: CTCs are associated with clinical outcomes in metastatic breast cancer irrespective of ER/PR/HER2 status. Some data support the prognostic relevance of serial CTC enumeration relative to adjuvant chemotherapy in early stage breast cancer. However, data from a large scale study focused on HER2 directed therapy for HER2+ disease have been lacking. We therefore sought to prospectively evaluate the effect of trastuzumab +/- lapatinib on CTCs and assess the prognostic/predictive value of CTC monitoring in HER2+ early stage breast cancer patients (pts). Methods: The Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO; NCT00490139) Trial is an international, randomized, open-label phase III study of two targeted agents for HER2+ breast cancer. From June 2007 to July 2011, 8381 pts were randomised from 946 sites in 44 countries to 1 of 4 arms with sequential or concurrent chemotherapy: (i) 52 wks of trastuzumab (T); (ii) 52 wks of oral lapatinib (L); (iii) 12 or 18 wks of T followed by a washout and then 34 or 38 wks of L; or (iv) 52 wks of L+T. 540 (6%) pts provided optional informed consent and up to 30 mL peripheral blood suitable for CTC analyses at baseline with additional collections at 13 or 19 wks, 52 wks, 18 mos, 24 mos, and recurrence. CTC analyses are being conducted in three laboratories (Mayo Clinic Rochester, n=431; Institut Jules Bordet and University of Munich, n=109). 2-3 x 10 mL CellSave™ samples are pooled and processed at each time point for CTC enumeration and HER2 expression using the immunomagnetic/immunofluorescence assay (CellSearch™). A round-robin concordance project was done between Mayo Clinic Rochester and Institut Jules Bordet before embarking on the primary correlative work. Results: At baseline, 20% pts had detectable (i.e., ≥1) EpCAM+/CK+/DAPI+/CD45- CTCs, and 16% pts had detectable EpCAM+/CK+/DAPI+/CD45-/HER2+ CTCs. Correlative analyses with clinical outcome are ongoing with plans for completion by Fall 2014. Conclusions: CTCs were detected in 20% of pts with HER2+ early stage breast cancer. This is similar to the frequency of detection in mixed early stage breast cancer populations relative to ER/PR and HER2 status. Concordance of enumeration and HER2 assessments between the two experienced laboratories, and correlation between disease free survival and CTC findings (from serial samples collected at baseline, during the course of HER2 directed therapy, and at set intervals of follow-up) will be reported. Citation Format: Minetta C Liu, Brigitte Rack, Amylou C Dueck, David W Hillman, Michael B Campion, Monica M Reinholz, Kevin C Halling, Christos Sotiriou, Françoise Rothé, Marion Maetens, Ghizlane Rouas, Wolfgang Janni, Antonio C Wolff, Lyndsay N Harris, Julie R Gralow, Kathleen I Pritchard, Susan Ellard, Nguyet A Le-Lindqwister, Frances Boyle, Evandro De Azambuja, Martine J Piccart-Gebhart, Michail Ignatiadis, Edith A Perez. Circulating tumor cell (CTC) enumeration and HER2 assessment as predictors of breast cancer outcomes in the ALTTO (BIG 2-06, Alliance N063D) Trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-01-01.

BACKGROUND:While long-term outcomes have improved for patients with breast cancer, 20% to 30% will still develop recurrence, and identifying these patients remains a challenge. MicroRNAs (miRNAs) are small, noncoding molecules that modulate genetic expression and affect oncogenesis.STUDY DESIGN:This prospective, multicenter trial (ICORG10/11-NCT01722851) recruited patients undergoing neoadjuvant chemotherapy across 8 Irish centers. Predetermined miRNAs were quantified from patient whole blood using quantitative reverse transcriptase polymerase chain reaction. Venous sampling was performed at diagnosis (timepoint 1) and midway during neoadjuvant chemotherapy (timepoint 2 [T2]). miRNA expression profiles were correlated with recurrence-free survival (RFS), disease-free survival (DFS), and overall survival. Data analysis was performed using R v3.2.3.RESULTS:A total of 124 patients were recruited with a median age of 55.0 years. The median follow-up was 103.1 months. Increased miR-145 expression at T2 was associated with improved RFS (hazard ratio 0.00; 95% confidence interval [CI] 0.00 to 0.99; p = 0.050). Using survival regression tree analysis, a relative cutoff of increased miR-145 expression greater than 0.222 was associated with improved RFS (p = 0.041). Increased miR-145 expression at T2 trended towards significance in predicting improved DFS (hazard ratio 0.00; 95% CI 0.00 to 1.42; p = 0.067). Using survival regression tree analysis, a relative cutoff of increased miR-145 expression greater than 0.222 was associated with improved DFS (p = 0.012). No miRNAs correlated with overall survival.CONCLUSIONs:ICORG10/11 is the first Irish multicenter, translational research trial evaluating circulatory miRNAs as biomarkers predictive of long-term survival and correlated increased miR-145 expression with enhanced outcomes in early-stage breast cancer. Validation of these findings is required in the next generation of translational research trials.

BackgroundThe role of vitamin E in breast cancer prevention and treatment has been widely investigated, and the different tocopherols that comprise this nutrient have been shown to have divergent associations with cancer outcome. Our previous studies have shown that α-Tocopherol-associated protein (TAP), a vitamin E binding protein, may function as a tumor suppressor-like factor in breast carcinogenesis. The current study addresses the association of TAP expression with breast cancer clinical outcomes.MethodsImmunohistochemical stain for TAP was applied to a tissue microarray from a breast cancer cohort consisting of 271 patients with a median follow-up time of 5.2 years. The expression of TAP in tumor cells was compared with patient’s clinical outcome at 5 years after diagnosis. The potential role of TAP in predicting outcome was also assessed in clinically relevant subsets of the cohort. In addition, we compared TAP expression and Oncotype DX scores in an independent breast cancer cohort consisting of 71 cases.ResultsWe demonstrate that the expression of TAP was differentially expressed within the breast cancer cohort, and that ER+/PR ± tumors were more likely to exhibit TAP expression. TAP expression was associated with an overall lower recurrence rate and a better 5-year survival rate. This association was primarily in patients with ER+ tumors; exploratory analysis showed that this association was strongest in patients with node-positive tumors and was independent of stage and treatment with chemotherapy. TAP expression in ER/PR negative or triple negative tumors had no association with clinical outcome. In addition, we did not observe an association between TAP expression and Oncotype DX recurrence score.ConclusionsThe significant positive association we found for α-Tocopherol-associated protein with outcome in breast cancer may help to better define and explain studies addressing α-tocopherol’s association with cancer risk and outcome. Additionally, further studies to validate and extend these findings may allow TAP to serve as a breast-specific prognostic marker in breast cancer patients, especially in those patients with ER+ tumors.

Angiogenesis and cell cycle control play critical roles in breast cancer susceptibility and clinical outcome and are mainly controlled by vascular endothelial growth factor (VEGF) and cyclin-dependent kinases, respectively. Functional germline polymorphisms in these genes alter the function, thereby causing inter-individual differences in breast cancer risk and clinical outcome. In this study, we investigated the influence of the functional polymorphisms VEGF-A rs3025039 C > T and CCND1 rs9344 G > A on risk and clinical outcome in early-stage breast cancer. DNA of 539 female patients with histologically confirmed early-stage breast cancer and 804 control subjects was genotyped for these polymorphisms. Genotypes were tested for associations with breast cancer risk and clinical outcome. There was no significant association between the polymorphisms and breast cancer risk. However, the minor allele of VEGF-A rs3025039 C > T was significantly associated with decreased recurrence-free survival (HR 1.845; 95% confidence interval [CI] 1.035-3.290; P = 0.038) and remained significant in multivariate analysis (HR 1.880; 95% CI 1.020-3.465; P = 0.043). Patients carrying at least one A-allele in CCND1 rs9344 G > A showed a trend towards decreased recurrence-free survival in univariate analysis (HR 2.379; 95% CI 0.841-6.728; P = 0.068). This study provides evidence that the functional VEGF-A rs3025039 C > T polymorphism influences recurrence-free survival in early-stage breast cancer.