bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P2-11-01: Effects of radiotherapy on breast cancer outcomes among stage I, low-Recurrence risk, hormone-Sensitive breast cancer: Pooled analysis of individual data from phase III trials
Authors: Jayasekera JC , Schechter C , Jagsi R , White J , Chapman J-AW , Whelan T , Sparano JA , Anderson SJ , Fyles A , Sauerbrei W , Zellars RC , Li Y , Song J , Julian T , Berry D , Feuer EJ , Luta G , Mandelblatt JS
Published: February 2018

Purpose: Radiotherapy after breast conservation has become the standard of care. Prior meta-analyses of radiotherapy benefits pre-dated availability of gene expression profiling (GEP) to assess recurrence risk and/or did not include all relevant outcomes. This analysis utilized GEP information with individual-level data from seven clinical trials to evaluate the impact of omitting radiotherapy on recurrence and mortality.

Patients and Methods: The pooled observational data included women who had undergone breast conservation surgery for stage I, ER+ and/or PR+/HER2- cancers with clinicopathologically estimated 21-Gene Recurrence Scores (RS) of ≤ 18, and did not receive chemotherapy (n= 1,684). The primary endpoint was 10-year invasive or DCIS recurrence free-interval (IRFI-DCIS), including breast cancer death and was estimated using adjusted Cox models. Secondary outcomes were breast-cancer specific and all-cause survival. Covariates included for all models were age, tumor size, grade, hormonal status, type of hormonal therapy, risk score, and trial.

Results: Ten-year IRFI-DCIS was high (96.6% with radiotherapy vs. 91.6% without), for an absolute difference of 5%. Omission of radiotherapy (vs. radiotherapy) was associated with an overall adjusted hazard ratio of 2.6 (95% confidence interval 1.5-4.5) for any first event. There was only a significant increase in risk of loco-regional; not, distant recurrence, breast cancer–specific or overall survival. The effect of radiotherapy varied across subgroups, with lower first event rates for those with estimated RS of <11 (vs. 11-18), and women ages 60+ (vs. <60 years).

Conclusion: Omission of radiotherapy in hormone-sensitive patients with low recurrence risk may lead to a modest absolute increase in loco-regional recurrence, but does not appear to increase risk of distant recurrence or death.

Citation Format: Jayasekera JC, Schechter C, Jagsi R, White J, Chapman J-AW, Whelan T, Sparano JA, Anderson SJ, Fyles A, Sauerbrei W, Zellars RC, Li Y, Song J, Julian T, Berry D, Feuer EJ, Luta G, Mandelblatt JS. Effects of radiotherapy on breast cancer outcomes among stage I, low-Recurrence risk, hormone-Sensitive breast cancer: Pooled analysis of individual data from phase III trials [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-11-01.
Abstract P2-11-23: Not presented
Authors: Xia W , Zheng Q , Wang S
Published: February 2018

This abstract was not presented at the symposium.
Abstract P2-12-09: histopathologic correlation of residual tumor in breast with residual mammographic microcalcification and magnetic resonance imaging after neoadjuvant systemic treatment
Authors: Um E
Published: February 2018

Introduction. In patients with advanced breast cancer, neoadjuvant chemo-therapy is performed to increase breast conserving surgery. Although MRI is known to be accurate in predicting residual cancer after treatment, if calcification remains, the issue of whether to perform surgery based on the residual tumor prediction range in mammography and MRI has not yet been solved. The objective of this study was to estimate the accuracy of residual mammographic (MMG) microcalcification and enhancing lesion in magnetic resonance imaging (MRI) in predicting residual tumor after neoadjuvant systemic treatment (NST).

Method. This is a single-center, retrospective study. We included patients with breast cancer who underwent NST and have microcalcifications in the post NST mammogram and had the surgery from January 2, 2013 to December 30, 2014. All the patients had post NST imaging exams of MMG and MRI. Final pathologic tumor size with histopathology and biomarker status was obtained after surgery. Analysis of correlation between image findings and pathology was evaluated.

Result. Of 151 patients that were included in this study, 125 patients (82.8%) had residual invasive tumor and 26 patients (17.2%) had pathologic complete response. In overall, MRI correlated better than MMG in predicting tumor size (intraclass correlation coefficient [ICC] = 0.769 vs 0.651), but for HR+/HER2- subtype, MMG had higher correlation than MRI (ICC = 0.747 vs 0.575). Specially in HR- subtype, MRI had strong correlation with pathology (ICC for HR-/HER2+ = 0.939 and TN = 0.75), while MMG tend to overestimate the tumor size (ICC for HR-/HER2+ = 0.543 and TN = 0.479).

Discussion. Overall post-NST residual microcalcifications on MMG have lower correlation with residual tumor size than MRI. In other than HR+/HER2- subtype, the extent of calcifications on pre-OP evaluation may not be accurate in evaluating the residual extent of the tumor after NST.

Citation Format: Um E. histopathologic correlation of residual tumor in breast with residual mammographic microcalcification and magnetic resonance imaging after neoadjuvant systemic treatment [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-12-09.
Abstract P2-12-11: Does conservative surgery treatment for locally advanced breast cancer safe after neoadjuvant treatment?
Authors: Boufelli G , Mota BS , Franca FC , Doria MT , Maesaka JY , Ricci MD , Piato JRM , Rocha FBC , Giribela AHG , Gonçalves R , Masili-Oku S , Mano MS , Chala LF , Thompson BM , Baracat EC , Filassi JR
Published: February 2018

BACKGROUND:

The aim of this study was to assess the oncological efficacy of breast conserving surgery (BCS) after neoadjuvant chemotherapy in patients with local advanced breast cancer.

PATIENTS AND METHODS:

A retrospective cohort study was conducted with locally advanced breast cancer invasive (Stage IIb to III) treated at ICESP, an oncologic referral center between 2008 and 2016. Endpoints were disease free survival (DFS), local disease free survival (LDFS) and overall survival (OS). Multivariable analyses were performed using Cox proportional hazards models.

RESULTS:

530 patients were included, 26% (138) were stage IIB, 41.9% (222) IIIA, 29.6% (157) IIIB and 2.5% (13) IIIA. 88.8% (470) were invasive ductal carcinoma. The mean age was 51.5(23-95). 95.5% and 4.5% were submitted Neoadjuvant Chemotherapy and Hormone therapy, respectively. The BCS were performed in 24.5% (130) patients versus 75.5% (400) of mastectomies. The mean follow up was 36.4(0.16-80.2) months. There were no differences in local disease free-survival 59 (95%CI 58-61) versus 60 (95%CI 57-60); p=0.4 and overall survival 56.2 (95%CI 52-60) versus 59.3(95%CI 53-65); p= 0.24 for mastectomy and BCS. The disease free survival was lower at mastectomy group 51.4 (95%CI 49-53) versus 56,8 (95%CI 53-59); p=0.01. Logistic regression models were significant only for cancer stage both patterns, although the results were better for masses, particularly when kinetic assessments were included (LR 12.8; p = 0.005)

CONCLUSION:

In our population, the BCS does not affect the overall and local disease-free survival rates, which seems to be safe to perform in patients who desire to conserve the breast after neoadjuvant treatment.

Citation Format: Boufelli G, Mota BS, Franca FC, Doria MT, Maesaka JY, Ricci MD, Piato JRM, Rocha FBC, Giribela AHG, Gonçalves R, Masili-Oku S, Mano MS, Chala LF, Thompson BM, Baracat EC, Filassi JR. Does conservative surgery treatment for locally advanced breast cancer safe after neoadjuvant treatment? [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-12-11.
Abstract P2-12-14: Not presented
Authors: Kuru B , Yuruker S , Sullu Y , Gursel B , Ozen N
Published: February 2018

This abstract was not presented at the symposium.
Abstract P2-13-04: Not presented
Authors: Kim J , Kwak MJ
Published: February 2018

This abstract was not presented at the symposium.
Abstract P3-03-02: ER dependent breast cancer phenotype in BRCA
1/2 carriers
Authors: Peretz TY , Zick A , Luna K , Grinshpun A , Sonneblick A , Iziely B , Hamburger TG , Cohen S , Granit AM , Dvir M , Rosenberg S
Published: February 2018

Background: Hereditary breast cancer (HBC) comprises more than 10% of all breast cancers (BC). Mutations in the BRCA1/2 genes are found in approximately half of HBC patients. The majority of BRCA1 associated tumors are ER, PR and HER2 negative with basal-like expression pattern. BRCA2 associated tumors are mostly ER positive (ER+). In the present study we aim to further explore clinical and molecular characteristics of BRCA associated BC in 3 different cohorts.

Methods: Three different BC databases (DB) were evaluated: (i) Hadassah oncogenetic BC DB (n=4429); (ii) Nick-Zainal et al. BC DB (n=560), and (iii) METABRIC BC DB (n= 1980). We tested for differences in age at diagnosis between BRCA positive (BRCA+) and BRCA negative (BRCA-) patients with either ER+ or ER negative (ER-) tumors. Point mutation analysis was performed in cohorts ii & iii and mRNA differential expression (DEA) and pathway analysis were performed in cohort iii, using Ingenuity Pathway Analysis (IPA).

Results: Age (years) at diagnosis for cohorts i, ii,&iii respectively, for ER+ PT:BRCA1-44, NA, 60; for BRCA2-49, 48, 64; for BN – 53, 56, 63. For ER-: BRCA1-42, 42, 47; for BRCA2-48, 52, 49; for BN-49, 54, 56. For cohorts ii&iii, higher frequencies of TP53 and PIK3Ca mutations were found among BRCA+&BRCA-, respectively. DEA was performed between BRCA+&BRCA- in ER- tumors: the major activated pathways involved cancer related processes and were highly significant (up to p=1e-7.5, FDR=1e-4.5). Surprisingly - the most significant pathway was Estrogen Mediated S-phase Entry and the most activated upstream regulator was ERBB2. Similar evaluation in ER+ showed mostly differences in immune related pathways (differences not statistically significant).

Conclusions: Younger age at presentation was observed in BRCA1 vs. BRCA2 patients. No age differences were observed between ER+&ER- PT in cohort i&ii, in cohort iii ER- BRCA+ Patients were younger than ER+ BRCA+ (similar age as ER+ BRCA-). BRCA+ show different mutational profile than BRCA-. ER+ BRCA+ and BRCA- show similar genomic characteristics. By contrast, for ER- BRCA+ differs markedly from BRCA-. This might imply that BRCA+ associated tumors consist of two genomically distinct subtypes: (i) ER-, and (ii) ER+. The results may shed light on possible somatic factors which affect the development of BC BRCA+ and carry preventive and therapeutic implications.

Citation Format: Peretz TY, Zick A, Luna K, Grinshpun A, Sonneblick A, Iziely B, Hamburger TG, Cohen S, Granit AM, Dvir M, Rosenberg S. ER dependent breast cancer phenotype in BRCA 1/2 carriers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-03-02.
Abstract P3-05-15: PD-1 expression and its correlation with tumour infiltrating lymphocytes and Ki67 in patients with breast cancer
Authors: Vos H , Lambein K , Floris G , Nevelsteen I , Smeets A
Published: February 2018

Introduction: Immunotherapy targeting the programmed death-1 (PD-1) checkpoint has resulted in good outcomes in patients with melanoma, non-small cell lung cancer and head and neck cancer. Recent data have showed that patients with ER/PR negative breast cancer might benefit from immunotherapy as well. We investigated PD-1 expression on tumour infiltrating lymphocytes (TILs), the presence of TILs and Ki67. Furthermore, the association of PD-1, TILs and Ki67 with time to metastasis was statistically determined.

Methods: Resection specimens of 284 patients with an ER/PR negative invasive ductal adenocarcinoma of at least 2 cm were analysed. Haematoxylin-eosin staining was performed to determine the percentage of TILs. Subsequently these percentages were divided into three groups: less than 10%, 10%-30% and more than 30% which matches with respectively 30%, 50% and 20% of the patients. PD-1 expression on the TILs of 116 patients and Ki67 expression of 185 patients were assessed using immunohistochemistry.

Results: An increase in the fraction of TILs was significantly associated with a lower risk of metastasis (hazard ratio [HR] = 0.7, 95% CI = 0.6-0.9). PD-1 expression on TILs was observed in 97% of the patients. Three patients had no expression of PD-1, this lack of PD-1 expression significantly increased the risk of metastasis (HR = 5.541, 95% CI = 1.2-25.0). No association could be noted between PD-1 expression and the amount of TILs or Ki67 (p-values of respectively 0.272 and 0.637). Similarly, no association could be noted between Ki67 and the amount of TILs (p-value = 0.1954)

Conclusion: PD-1 was expressed on TILs in patients with breast cancer. Surprisingly, no correlation was found between PD-1 expression and TILs or Ki67. However, an increased amount of TILs was significantly associated with a lower risk of metastasis.

Citation Format: Vos H, Lambein K, Floris G, Nevelsteen I, Smeets A. PD-1 expression and its correlation with tumour infiltrating lymphocytes and Ki67 in patients with breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-05-15.
Abstract P3-07-01: IRS1 expression is required for estrogen stimulated growth in breast cancer cells
Authors: Zhang X , Varma S , Yee D
Published: February 2018

Insulin receptor substrate (IRS) proteins are adaptor proteins phosphorylated by activated type I insulin-like growth factor receptor (IGF-1R) and insulin receptor (IR). In addition to their roles in normal cell physiology, we have shown IRS expression is required for breast cancer cell growth and motility. IRS1 plays a more important role in mitogenesis and survival while IRS2 in cancer cell metastasis. Moreover, this family of adaptor proteins is also involved in the signal transduction of many other transmembrane receptors. Thus, IRS proteins could be potential cancer therapeutic targets. We have previously shown that reduced IRS1 impairs IGF and insuliln stimulated cancer cell growth and tumorigenicity even when signaling is not affected due to possible compensation of IRS2 and other adaptor proteins. To further study the role of IRS-1 function in breast cancer, we created doxycycline inducible IRS-1 shRNA cells. We also found that IRS1 knockdown significantly reduced estradiol stimulated growth. To investigate if reduced IRS1 regulated E2 stimulated binding of ERa ChIP assay was performed using the pS2 promoter. Compared to parental MCF-7L cells, inducible IRS1 knock down clone 3G5 demonstrated significantly reduced promoter binding. Degradation of IRS-1 with a pharmacologic antagonist (NT-157) also diminished ERa binding to pS2 promoter. Further qRT-PCR analysis for mRNA levels of estrogen regulated genes, such as PGR, TFF1, etc. showed those genes were significantly down regulated. To evaluate effects of IRS-1 levels on estrogen stimulated growth, we evaluated 3G5-B12 (a subclone of 3G5) cell growth in a xenograft model. 3G5-B12 cells have similar levels of IGFIR and ERa expression compared to their parent cells. Estrogen dependent xenograft growth was similar to those of parent MCF-7L cells. After doxycycline was administered in the diet, 3G5-B12 tumor growth was significantly inhibited compared to those fed with normal mouse diet, and this inhibition was prolonged at least 2 and a half months. Parental MCF-7L tumor growth was not affected by the doxycycline diet. Doxycycline inducible IRS1 knock down significantly prolonged the time before tumors reached 1000mm3 compared with those tumors on a normal diet. In conclusion, IRS-1 is required for optimal estrogen receptor function as measured by promoter binding and xenograft growth. Our data suggested suppression of IRS-1 function may target several growth pathways in breast cancer cells and represents a new drug target.

Citation Format: Zhang X, Varma S, Yee D. IRS1 expression is required for estrogen stimulated growth in breast cancer cells [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-07-01.
Abstract P3-08-11: The prognostic impact of retinoic acid-induced 2 (RAI2) expression in ERα-positive breast cancer patients
Authors: Nishikawa S , Kondo N , Endo Y , Hato Y , Hisada T , Nishimoto M , Dong Y , Okuda K , Kato H , Takahashi S , Nakanishi R , Toyama T
Published: February 2018

Background: Breast cancer cells disseminate to the bone marrow and form bone metastases in a large majority of late-stage patients. Retinoic Acid-Induced 2 (RAI2) was reported as a putative suppressor of early hematogenous dissemination of tumor cells to the bone marrow in breast cancer, particularly in estrogen receptor α (ERα)-positive breast cancer. Here, we investigated mRNA expression of RAI-2 in breast cancer patients during long-term follow-up.

Materials and methods: A total of 451 invasive breast cancer tissues was available for analysis of RAI2 mRNA using a TaqMan PCR system. We also sought correlations between clinicopathological factors and levels of RAI2 expression in these samples. The expression of markers associated with tumor-initiating capacity, such as SNAI1, SNAI2 and VIM was also analyzed. The median follow-up period was 9.0 years. Survival curves were analyzed using the Kaplan-Meier method. Cox proportional hazards regression analysis was used for univariate and multivariate analyses of prognostic values.

Results: We found positive correlations between low expression of RAI2 mRNA and shorter disease-free survival and overall survival in breast cancer patients (P=0.003, P<0.0001, respectively), which was limited to ERα-positive patients (P=0.04, P=0.0009, respectively), and not seen in ERα-negative patients (P=0.52, P=0.27, respectively). Low RAI2 mRNA levels were positively correlated with high grade, ERα-negativity and PgR negativity. Multivariate analysis indicated that low level RAI2 mRNA expression was an independent factor for survival both overall in breast cancer and in ERα-positive breast cancer patients

Multivariate analysis (ERα-positive breast cancer patients)  OS  Multivariate patientsp valueHR(95%CI)Tumor size≤2cm1390.83691 (Reference) >2cm207 1.08(0.54-2.28)Node statusNegative176<0.00011 (Reference) Positive144 4.72(2.33-10.34)Grade11240.95921 (Reference) 2•3218 0.98(0.50-2.14)RAI2 mRNA expressionhigh140<0.00011 (Reference) middle•low206 4.79(2.14-12.78)

.

Conclusion:We show that low expression of RAI2 is an independent factor predictive of a poor prognosis in ERα-positive breast cancer patients. RAI2 could be a promising candidate biomarker and therapeutic target in ERα-positive breast cancer to prevent dissemination to the bone marrow.

Citation Format: Nishikawa S, Kondo N, Endo Y, Hato Y, Hisada T, Nishimoto M, Dong Y, Okuda K, Kato H, Takahashi S, Nakanishi R, Toyama T. The prognostic impact of retinoic acid-induced 2 (RAI2) expression in ERα-positive breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-08-11.
Abstract P3-09-04: Withdrawn
Authors: Li YR , Steel L , Carrigan E , Nguyen J , Williams A , So A , Mamtani R , Tchou JC
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P3-09-10: Withdrawn
Authors: Pollán M , Lope V , Pérez-Gómez B , Molina AJ , Tardón A , Díaz-Santos M , Ardanaz E , O'Callhagan C , Altzibar JM , Gómez-Acebo I , Moreno V , Peiró R , Marcos-Grajera R , Kogevinas M , Aragonés N , López-Abente G , García-Pérez J
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P3-10-04: Obesity and adipose inflammation in men with breast cancer
Authors: Williams S , Parrish JC , Zhou XK , Wang H , Dierickx A , Gucalp A , Dannenberg AJ , Iyengar NM
Published: February 2018

Background: Elevated body mass index (BMI) is associated with increased risk of hormone receptor (HR)-positive breast cancer in postmenopausal women and worsened outcomes after breast cancer diagnosis. These observations may be partly attributable to adipose inflammation, which is prevalent in the breasts of obese women and is associated with worsened breast cancer survival. In men, some studies have reported obesity to be a risk factor for breast cancer, however the biologic links are not well characterized. Whether adipose inflammation occurs in male breast tissue has not been previously reported. Here we examined the relationships among pre-diagnosis BMI, adipose inflammation, and breast cancer features in men.

Methods: Males diagnosed with stage 0 – III breast cancer who underwent mastectomy at Memorial Sloan Kettering (MSK) between August 1991 – November 2011 were included in this retrospective cohort study. Pre-operative BMI was categorized as normal or underweight (<25), overweight (25 – 29.9), obese (≥30), or morbidly obese (≥40 or ≥35 + co-morbidity). Archived breast tissue was subjected to CD68 immunohistochemistry to detect adipose inflammation, defined by the presence of dead or dying adipocytes surrounded by macrophages – known as crown-like structures of the breast (CLS-B). Clinicopathologic associations with BMI and CLS-B were analyzed by logistic regression and Fisher's exact test.

Results: A total of 141 men were included; median age 63 (range 23 – 96). By BMI category, 25 were normal or underweight, 65 overweight, and 51 obese – of which 19 were morbidly obese. Only 11 men had known BRCA1/2 mutations. Median age at diagnosis was 69 in normal/underweight men versus 63 in obese men and 51 in morbidly obese men (P≤0.05). Among those with invasive tumors, average tumor size was 1.50 cm (± 0.84) in normal/underweight men versus 2.04 (±0.81) in morbidly obese men (P≤0.05). Archived breast tissue was available from 92 (65%) men. Breast adipose inflammation was present in 55 (60%) men, and average BMI was 31 (±8) versus 28 (±5) in men with versus without inflammation, respectively (P=0.07).

Conclusions: Obesity is associated with early onset breast cancer in men. Morbidly obese men were diagnosed with breast cancer at an even younger age and had larger tumors than normal weight individuals. These findings support further studies to investigate mechanisms, such as adipose inflammation, through which obesity may promote breast cancer in men.

Citation Format: Williams S, Parrish JC, Zhou XK, Wang H, Dierickx A, Gucalp A, Dannenberg AJ, Iyengar NM. Obesity and adipose inflammation in men with breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-10-04.
Abstract P3-10-15: Stellate cells and mesenchymal stem cells in benign mammary stroma are associated with risk factors for breast cancer
Authors: Olsson HL , Isfoss BL , Holmqvist B , Jernstrom H
Published: February 2018

Background: It is not known whether stromal cells in benign breast tissue can mediate risk of breast cancer. We recently described aldehyde dehydrogenase 1 A1 (ALDH1) positive (+) cells in morphologically normal breast stroma of premenopausal women, and the data indicated that their distribution is associated with clinical risk factors for breast cancer. The aim of the present study was to define the identities of these cells using histological and immunohistological methods, and to investigate associations between those cells and hormonal and genetic risk factors in pre- and postmenopausal women.

Methods: Stroma of morphologically normal tissue was analyzed in samples from 101 well-characterized women whose breasts had been operated. Morphology and immunolabeling were applied to determine cell identities based on the putative stem cell markers ALDH1 and stage-specific embryonic antigen-3 (SSEA3), and immunophenotypes indicating mast cells or stellate cells. The results were compared with the patients' risk factors using regression analysis (two-tailed).

Results: ALDH1+ round/oval cells were associated with low parity in BRCA1/2 carriers (p = 0.022), while in non-BRCA1/2-carriers they were negatively associated with nulliparity (p = 0.057). In premenopausal women ALDH1+ round/oval cells were associated with family history (p = 0.058). SSEA3+ round/oval cells were morphologically and immunohistologically consistent with multilineage stress-enduring (Muse) cells, and these cells were independently associated with the breast cancer risk factors low parity (p = 0.015), family history (p = 0.021), and hormone use after menopause (p = 0.032). ALDH1+ spindle-shaped/polygonal cells were immunohistologically consistent with stellate cells, and were negatively associated with family history of breast cancer (p = 0.001).

Conclusion: This study identified novel stromal cell types in benign breast tissue that have a potential for stratifying women for breast cancer risk.

Citation Format: Olsson HL, Isfoss BL, Holmqvist B, Jernstrom H. Stellate cells and mesenchymal stem cells in benign mammary stroma are associated with risk factors for breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-10-15.
Abstract P3-12-12: Serum estrogen-levels in women 48-56yrs with hormone receptor-positive breast cancer. Cross-Sectional study using an ultra-sensitive LC-MS/MS-method
Authors: Van Houdt M , Neven P , Anneleen L , Ivo J , Dirk V , Jaak B , Annouschka L , Hans W
Published: February 2018

Background and Purpose: Randomized clinical trials in early stage hormone receptor positive breast cancer (HR+BC), have shown that total estrogen suppression (TES) for 5 yrs or after 2-3 yrs of tamoxifen treatment improved outcome over 5 yrs of TAM monotherapy. This relative improvement is in absolute figures most visible in patients with a high relapse risk. To achieve TES, women need to be (rendered) menopausal and treated with an oral aromatase inhibitor (AI). We measured serum estrogens in women of peri-menopausal age with HR+BC starting or on anti-hormonal agents.

Methods: Serum estradiol (E2) and estrone (E1) were quantified using a sensitive liquid chromatography-tandem mass spectrometry method (LC-MS/MS; Pauwels et al. JCO 2013) in women 48-56 yrs old with HR+BC starting or on anti-hormonal therapy in a cross sectional observational monocentric study. We report the frequency that (and explore why) AI-users had estrogens above the lower limit of quantification (LLOQ). We measured estrogen levels in TAM users with > 3 months' amenorrhea by previous use of (neo)adjuvant chemotherapy. Finally, we studied the frequency of both estrogens or either alone were < LLOQ in non-users. Statistics are descriptive; biomarkers for estrogen levels were analyzed using linear mixed models. [amendment on study NCT01223833]

Results: Estrogen levels were assessed in 566 samples from 401 women; 96 (126 samples) were on AI, 128 (182 samples) on TAM and 217 (258 samples) non-users. Some patients had more than one blood sample in different groups. 13,5% of AI users were above LLOQ for E2 and E1; 7,5% for E1 alone. Some were due to ovarian reactivation. An important proportion (18%) of 83 non-hysterectomized TAM users with amenorrhea had E2 levels >40ng/L; 9,1% and 28.2% respectively in patients who had and didn't have (neo)adjuvant chemotherapy. None of non-users were below LLOQ for E1, while 20.7% were below LLOQ for E2.

Conclusions:TES is not always achieved in AI-users; reasons why were multiple. Amenorrhea is no guarantee for TES in TAM users, as a significant proportion had high E2 levels even when previously exposed to (neo)adjuvant chemotherapy. Using LC-MS/MS, undetectable levels for E1 better reflect TES than below LLOQ for E2.

Citation Format: Van Houdt M, Neven P, Anneleen L, Ivo J, Dirk V, Jaak B, Annouschka L, Hans W. Serum estrogen-levels in women 48-56yrs with hormone receptor-positive breast cancer. Cross-Sectional study using an ultra-sensitive LC-MS/MS-method [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-12-12.
Abstract P3-14-08: The impact of a structured surveillance protocol using bioimpedance spectroscopy (BIS) on preventing breast cancer related lymphedema (BCRL) in high-Risk patients
Authors: Whitworth P , Cooper A , Shah C , Vicini F
Published: February 2018

Background: We evaluated the impact of structured surveillance using bioimpedance spectroscopy (BIS) to prevent clinical BCRL in a group of high-risk (axillary lymph node dissection) patients.

Methods: From April 2010 through November 2016, 93 patients who were treated with axillary lymph node dissection (ALND) were prospectively monitored with BIS using L-Dex (Impedimed). Patients received a pre-operative baseline L-Dex measurement followed by post-operative assessments at regular intervals. An elevated L-Dex score was defined as an increase of ≥10 points above baseline (considered subclinical BCRL). Intervention consisted of applying an over the counter (OTC) sleeve for 4 weeks followed by re-evaluation. The need for complete decongestive physiotherapy (CDP) represented a surrogate for the development of clinically significant, chronic BCRL.

Results: Median follow-up was 24 months (range: 0.3-206.4 months). The median number of nodes removed was 19 (range: 5-41) and the median number of positive nodes was 3. Median age was 53 years old. Eighty five percent of patients underwent mastectomy and the remainder breast conserving therapy. 55% of patients received taxane based chemotherapy, 24% received some form of axillary RT (15% high tangents and 9% comprehensive regional nodal RT) and 74% had an elevated body mass index (BMI, > 25). Overall, 75% of these patients had at least one additional high-risk feature, 48% had at least two, and 6% had 3 (either taxane chemotherapy, axillary RT or elevated BMI). Thirty-three patients (35.4%) developed an elevated L-Dex score at some point during follow up. Overall, 10 patients (11%) required CDP at any point after treatment.

Conclusions: The results of this analysis support previously published data on the efficacy of prospective BCRL surveillance and early intervention using BIS. Of the 93 high-risk patients prospectively followed and managed in this structured BCRL protocol, 11% required CDP. These results compare favorably to all contemporary studies reporting BCRL rates in high-risk patients.

Citation Format: Whitworth P, Cooper A, Shah C, Vicini F. The impact of a structured surveillance protocol using bioimpedance spectroscopy (BIS) on preventing breast cancer related lymphedema (BCRL) in high-Risk patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-14-08.
Abstract P4-04-01: Loss of mismatch repair predicts resistance to endocrine therapy and sensitivity to CDK4/6 inhibitors in ER+ breast cancer
Authors: Haricharan S , Punturi N , Singh P , Holloway KR , Anurag M , Schmelz J , Schmidt C , Lei JT , Suman V , Hunt K , Olson JA , Hoog J , Li S , Huang S , Edwards DP , Kavuri SM , Bainbridge MN , Ma CX , Ellis MJ
Published: February 2018

Estrogen receptor positive (ER+) breast cancer is treated with endocrine therapy but intrinsic resistance occurs in ˜1/3 of patients and acquired resistance in ˜1/5 of the remainder. While many resistance mechanisms have been explored, clinical trials testing associated therapeutics have had mixed outcomes. Understanding mechanisms of resistance and finding therapeutic strategies to target them, therefore, remain important challenges.

In this study we discover an intriguing link between mismatch repair (MMR) deficiency, specifically of the MutL complex (MLH1/3, PMS1/2), and endocrine therapy resistance in ER+ disease. We find a direct role for MutL loss in inducing endocrine therapy resistance in vitro and in vivo by knocking down multiple MutL genes using CRISPR and stable shRNA approaches validated using standard rescue experiments. We identify the underlying mechanism: MutL deficiency in ER+ breast cancer abrogates Chk2-mediated feedback inhibition of CDK4/6 that appears necessary for endocrine therapy responsiveness. Consequently, pharmacological targeting of CDK4/6 in vitro and in vivo significantly inhibits growth of endocrine therapy resistant MutL-deficient ER+ breast cancer cells. These results are corroborated by data from a neoadjuvant clinical trial demonstrating that cell cycle regulation of MutL-mutant tumors is estrogen-independent but CDK4/6 dependent.

The results of this study provide important biological and clinically relevant insights. 1) a novel role for MMR in endocrine therapy resistance 2) A mechanism underlying the effectiveness of CDK4/6 inhibitors in some de novo endocrine therapy resistant tumors. While there are currently no biomarkers to guide the use of CDK4/6 inhibitors for ER+ breast cancer, markers of MMR dysregulation could identify patients in whom CDK4/6 inhibition may, most effectively, prevent disease recurrence.

Citation Format: Haricharan S, Punturi N, Singh P, Holloway KR, Anurag M, Schmelz J, Schmidt C, Lei JT, Suman V, Hunt K, Olson Jr JA, Hoog J, Li S, Huang S, Edwards DP, Kavuri SM, Bainbridge MN, Ma CX, Ellis MJ. Loss of mismatch repair predicts resistance to endocrine therapy and sensitivity to CDK4/6 inhibitors in ER+ breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-04-01.
Abstract P4-04-17: Elacestrant (RAD1901) demonstrates anti-tumor activity in a fulvestrant-resistant PDX model
Authors: Arlt H , Garner F , Bihani T
Published: February 2018

Background: Breast cancer is subdivided into categories based on tumor receptor status, with estrogen-receptor positive (ER+) breast cancer making up approximately two-thirds of all breast cancers diagnosed. In advanced or metastatic disease, dependence on ER signaling is often retained even after multiple rounds of endocrine therapy, supporting the use of ER targeting agents for several lines of treatment prior to chemotherapy. Selective estrogen receptor degraders (SERDs) have gained recent attention as ER antagonists given their ability to target and degrade ER. Fulvestrant, the only approved SERD on the market, is currently used as a second-line therapy in the metastatic setting, however, the intramuscular route of administration and pharmacokinetic properties of fulvestrant have fueled the development of more potent and orally bioavailable SERDs. We have previously described elacestrant (RAD1901), a novel and orally bioavailable SERD, as an inhibitor of ER+ breast cancer growth in preclinical patient-derived xenograft (PDX) models, including those that are insensitive to fulvestrant. Here, we describe elacestrant activity in an ER+ PDX model that had been treated with multiple rounds of fulvestrant treatment.

Methods: An ER+/PR+ PDX model, MAXF-713, derived from a treatment-naïve patient, was passaged multiple times in the presence of fulvestrant over the course of a year. After each round of fulvestrant treatment, elacestrant or fulvestrant were evaluated for anti-tumor activity. Pharmacodynamic endpoints including changes in ER and ER target gene expression were also evaluated.

Results: Despite repeated exposure to fulvestrant, the PDX model retained sensitivity to elacestrant. In fact, regardless of the number of prior rounds of fulvestrant treatment, elacestrant produced consistent tumor growth inhibition within every passage, while the effects produced by fulvestrant exhibited a high degree of variability.

Conclusions: Our data demonstrate that elacestrant is a SERD that can inhibit tumor growth in a fulvestrant-resistant preclinical setting and provides rationale for examining elacestrant in the clinical setting in patients that have progressed on fulvestrant treatment.

Citation Format: Arlt H, Garner F, Bihani T. Elacestrant (RAD1901) demonstrates anti-tumor activity in a fulvestrant-resistant PDX model [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-04-17.
Abstract P4-06-06: Frequency of mutations in multi-gene panel testing of 3,011 breast cancer patients
Authors: Zhou AY , van den Akker J , Zimmer A , McFadden W
Published: February 2018

Objectives:

Here, we describe the characteristics of 3,011 individuals with a self-reported diagnosis of breast cancer who received a multi-gene panel genetic test for hereditary cancer risk.

Methods:

These 3,011 patients were referred physician order for a multi-gene, next generation sequencing panel for hereditary cancer risk. Analysis was limited to 19 genes associated with hereditary breast and ovarian cancer (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, TP53). All patient demographic information was collected via a self-reported online health history questionnaire.

Results: In this cohort, the median reported age at breast cancer diagnosis was 49.3. Overall, 360 pathogenic or likely pathogenic variants were identified and reported. A total of 344 individuals were found to carry a single pathogenic mutation in one of the 19 genes analyzed, and 8 individuals were found to carry two concurrent pathogenic mutations in different genes. Notably, 173 of the 360 mutations identified were reported in the BRCA1 and BRCA2 genes (48.1%), yielding an overall BRCA1 and BRCA2 mutation carrier rate of 5.7%. Additionally, 12.2% of the cohort reported having bilateral breast cancer. The mutation carrier rate amongst these individuals was 15.0% (50/334), 60.8% of the mutations found in these individuals were in BRCA1 or BRCA2, and the average age at breast cancer diagnosis was 49.4 (43.3 amongst mutation carriers). In the entire cohort, a pathogenic mutation was identified in 15 of the 19 genes analyzed.

Conclusion:

In summary, the overall mutation carrier rate in this cohort for breast and ovarian cancer risk genes was 11.7% (352/3,011). Taken together, these data support the recommendation that all patients with breast cancer should undergo germline testing for hereditary cancer risk.

Citation Format: Zhou AY, van den Akker J, Zimmer A, McFadden W. Frequency of mutations in multi-gene panel testing of 3,011 breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-06-06.
Abstract P4-06-09: Addition of a remote genetic counselor to the breast specialist's team improves clinical decision-making
Authors: Rosen B , O'Leary E , Shan Y , Pat W , Peter B
Published: February 2018

Background: There is a shortage of trained genetic counselors (GC) and often long wait times for appointments, resulting in other specialists frequently ordering genetic testing. However, non-genetic specialists, including breast surgeons, find it difficult to stay current in genetics due to rapid advances in gene discovery, expanded panel offerings, and frequent changes to professional guidelines. We tested a novel model for hereditary cancer risk assessment where breast surgeons had “on demand” access to a remote laboratory-based genetic counselor for peer to peer consultation. In this study we sought to determine the impact this model has on breast surgeons' routinely ordering genetic testing including test identification, ordering patterns, and medical management.

Methods: An IRB approved multi-center prospective study involved 14 community-based breast cancer surgeons experienced with hereditary cancer risk assessment without a genetic counselor as part of their practice. Cases were all discussed with a remote Invitae GC to determine testing eligibility and selection. Physicians had the option to utilize remote GCs to discuss results or to refer to traditional genetic counseling services. Pre and post-test surveys were completed for each patient by the testing physician. To protect patient privacy, a unique case ID was used to link patient test data with identifying data.

Results: A total of 192 patients were evaluated with median age of 52. Risk assessment via BRCAPRO and the Hughes Risk model were performed on 98% of patients by the physicians. 65% of patients met NCCN guidelines for testing. Pathogenic mutations were found in 14% of patients. Breast surgeons changed their test selection 21% of the time after discussion with a GC. They called to discuss results in 47% of cases and medical management changes were incorporated in 15% of these cases based on discussion with a remote GC.

Conclusions: Remote GC provider support assisted physicians in facilitating customized test selection, aided in navigating challenging counseling cases, and impacted clinical management. This service may serve as a viable, effective model for 'on demand' genetic counseling support and may be a novel opportunity to expand genetic testing in a breast surgery setting.

Citation Format: Rosen B, O'Leary E, Shan Y, Pat W, Peter B. Addition of a remote genetic counselor to the breast specialist's team improves clinical decision-making [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-06-09.
Abstract P4-06-12: Different patterns of risk reducing decisions in affected or unaffected BRCA mutation carriers
Authors: Lee EG , Kang H , Park SJ , Han JH , Jung S-Y , Lee S , Kang H-S , Park B , Kong S-Y , Lim MC , Park S-Y , Lee ES
Published: February 2018

BACKGROUND

Risk-reducing (RR) management decreases the risk of breast cancer and BRCA related gynecologic cancer. However, there are fewer reports on the RR management in Asia compared to Western countries.The aim of this study is to identify risk reducing management patterns with BRCA1 or BRCA2 mutation carriers.

METHODS

The study group consisted of all consecutive 1104 breast cancer, ovarian patients and their families of high-risk patients who underwent BRCA gene testing in National Cancer Center, Korea from 2008 to 2016. A total 220 BRCA mutations (19.9%) were detected with 125(11.3%) of BRCA1 gene and 95 (8.6%) of BRCA2 gene.

RESULTS

Out of 220 BRCA mutations carriers, they were consisted of 83 breast cancers, 10 ovarian cancers, 7 both cancers, and 120 unaffected carriers. Among them, 42 were men and 178 were women. About 90 % (198/ 220) had the familial history of breast, ovarian or both malignancies (113 in BRCA1 and 85 in BRCA2 mutation (p=0.821)).

All 42 men chose surveillance. Among 178 female BRCA mutation carriers, 98(55.1%) underwent risk reducing management including 18(10.1%) of chemoprevention, and 80(49.9%) had risk-reducing surgeries (RRSs) (1 case of risk-reducing mastectomy, 76 of risk reducing bilateral salphingo-oophorectomy (RRSO), and 3 of both) and 80 (54.9%) chose only intensive surveillance for both of breast and ovary cancer.

In affected carriers with breast cancer, 59 (71.1%) underwent RR management (1 case of risk reducing mastectomy, 53 of RRSO, 3 of both surgery, and 2 of chemoprevention). There was no risk reducing management in affected carrier with ovarian cancer patients. In 78 unaffected women carriers, 39(50.0%) women received RR management (23(29.5%) cases of RRSO and 16(20.5%) cases of chemoprevention). The rates of RRSs have increased annually since the 2013 year, (prior to 2013 vs. since 2013, RRSs 28.6% (6 cases/21 carriers) vs. 37.2% (74/199), p<0.01).

CONCLUSION

This study was conducted on the largest numbers of BRCA mutation carriers in Asian countries. RRSO is the more preferred management for affected carriers with breast cancer or unaffected carriers. The results might be explained by the severity of the illness and that RRSO was only reimbursed RR strategy from the Korean Government Insurance. Tailored genetic counseling and insurance policy may enhance overall levels of RR management.

Citation Format: Lee EG, Kang H, Park SJ, Han JH, Jung S-Y, Lee S, Kang H-S, Park B, Kong S-Y, Lim MC, Park S-Y, Lee ES. Different patterns of risk reducing decisions in affected or unaffected BRCA mutation carriers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-06-12.
Abstract P4-06-16: Frequency of pathogenic mutation in patients at high risk for hereditary breast cancer
Authors: Shin H-C , Yoo T-K , Lee H-B , Moon H-G , Noh D-Y , Han W
Published: February 2018

Background: Next-generation sequencing technology allows the simultaneous sequencing of multiple target genes. We developed a gene panel containing 64 genes which were associated with various hereditary cancers. This study was performed to evaluate the frequency of pathogenic mutations associated with hereditary cancer among Korean patients at high risk hereditary breast cancer using multi-gene sequencing panel.

Methods: A total of 252 breast cancer patients with high-risk hereditary cancer were included. Among them, 179 patients (71.0%) had multiple primary cancers including breast cancer, 27 patients (10.7%) were diagnosed with bilateral breast cancer at age 40 or younger. Thirty-five patients (13.9%) had breast cancer family history of more than 2 relatives. With the 64-gene panel, sequence variants were detected by next-generation sequencing technology.

Results: Sixty seven patients (26.8%) were found to have 77 germline pathogenic mutations, 12 in BRCA1, 13 in BRCA2, 9 in CDH1, 3 in FH, 5 in MSH2, 2 in MSH6, 4 in NAT1, 6 in PTCH1, 3 in RAD51, 7 in RET, 4 in SPINK1, 3 in TP53 and one each in ALK, BRIP1, CHEK2, MLH2, MUTYH, and PTEN. In 20 patients (4.0%), 2 (n=9) or 3 (n=1) pathogenic mutations were detected. In 227 patients with BRCA1/2 negative, CDH1 (n=7), RET (n=7), PTCH1 (n=5), and MSH2 (n=5) were the most prevalent pathogenic mutations.

Conclusions: The 64 gene panel detected germline pathogenic mutations in 26.8% of Korean breast cancer patients with feature of hereditary cancer. Mutations of BRCA1, BRCA2, CDH1, RET, and PTCH1 were the most prevalent variants.Mutation carriers were considered as high risk to develop malignancy and recommended to receive genetic counseling and intensive cancer screening.

Citation Format: Shin H-C, Yoo T-K, Lee H-B, Moon H-G, Noh D-Y, Han W. Frequency of pathogenic mutation in patients at high risk for hereditary breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-06-16.