Positive Subtypes Research Articles

Risk factors for loco-regional recurrence in breast cancer patients: a retrospective study.

BackgroundAlthough fairly uncommon, loco-regional recurrence in breast cancer (BC) has major consequences for the patient. Several predictors for locoregional have been previously reported from large randomized clinical trials mainly from Europe & North America; data from other geographical areas are somewhat scarce. Here we performed a retrospective review of medical records in a single academic center in Chile, searching for predictors of breast tumor recurrence.ResultsMedian patient follow up was 61 months, 5 year overall survival (OS) rate was 94.2% (95% CI 93–95.3). We found that 108 out of 2,754 (5.3%) patients had loco-regional recurrence. The 2-year loco-regional control was 98% (95% CI 97.3–98.7) and 5-year was 94% (95% CI 92.6–95.4). Univariate analysis showed a correlation between recurrence and being <50 year-old, positive surgical margins, advanced stage, subtype, and presence of LVI and omission of adjuvant radiotherapy. Only the absence of adjuvant RT was predictor of locoregional recurrence in multivariable (p < 0.001).ConclusionsOur study population presents high local control of BC. Age, surgical margins, stage, molecular subtype and absence of adjuvant radiotherapy were associated with loco-regional recurrence. Prospective trials and long-term follow up are required in order to confirm these results.Materials and MethodsWe analyzed medical records from 2,201 BC patients at the Pontificia Universidad Católica de Chile from 1997 to 2016. Collected data included: age at diagnosis, tumor size, axillary involvement, molecular subtype, margin status, histological grade, lympho-vascular invasion (LVI) and ipsilateral recurrence.

Value of Systemic Staging in Asymptomatic Early Breast Cancer.

Metastases are rare in early breast cancer (EBC), and international guidelines recommend against routine systemic staging for asymptomatic patients. However, imaging exams remain widely employed in the clinical practice. The aim of the present study is to evaluate the value of imaging for systemic staging in EBC. A retrospective analysis of newly-diagnosed breast cancer (BC) patients was performed. Clinical data including BC subtype, stage, presence of symptoms at diagnosis and instrumental procedures performed for staging were recorded. A total of 753 patients were included, with a median age of 57 years. The majority of the patients underwent at least 1 imaging procedure (91%); had invasive ductal carcinoma (83.5%); histological grade 2 (51.4%); stage II (61.8%); and luminal subtype (67.9%). Among the 685 (91%) patients who underwent any radiologic staging, distant metastases (DMs) were detected in 32 (4.7%). In the univariate analyses, stage IIb and pathological lymph node involvement (pN1) showed a statistically significant association with the presence of DMs, versus only a trend for triple negative and human epidermal growth factor receptor 2 (Her2) positive subtype. In an exploratory analysis performed in this same subgroup, when unfavorable biology (triple negative or Her2 positive) was present, patients had a DM rate of 14.4%, one of the highest reported at this stage of the disease. Early breast cancer has a low prevalence of DM at the initial evaluation, and systemic staging of asymptomatic, unselected patients is not warranted as a routine practice. However, we have identified subgroups of patients to whom a full staging could be indicated.

PO-525 Molecular signatures of circulating microRNAs as early breast cancer biomarkers

IntroductionBreast cancer is the leading cause of cancer death among women. The number of human diagnosed with breast cancer has been increased specially in middle and low countries. Early detection is a key to reduce cancer deaths. Biological fluids such as blood hold good opportunities to identify new non-invasive biomarkers. One the new and the promising classes of circulating cancer biomarkers is the microRNAs (miRNAs). These molecules are tissue-specific, are remarkably stable in several biological samples and have others intrinsic characteristics that make attractive as biomarkers. Thus to identify molecular signatures of circulating miRNAs that can be correlated with molecular subtypes of breast cancer in early stages can be an useful in clinical practice. We applied a new screening technology to determine the expression profile of circulating RNAs and to correlate molecular subtypes of early stage breast cancer and compare with healthy women.Material and methodsFifty-four patients with early-stage breast cancer paired with twenty-seven women without breast cancer risk (controls). Total RNA was obtained from serum of cases and controls and the expression profile of differentially expressed serum miRNAs was obtained using the nCounter panel from NanoString Technology. Statistical analyses were performed in program R. The interaction networks miRNAs-genes predicted were constructed in the Cytoscape program and the functional enrichment analysis was applied to identify the molecular pathways related with onset and cancer progression.Results and discussionsWe identify miRNAs significantly differentially expressed specific for each molecular subtype: 19 miRNAs for the luminal A subtype, 8 miRNAs for the luminal B subtype, 10 miRNAs for the luminal B HER 2 positive subtype and 4 miRNAs for the subtype in HER2-enriched. In addition, in silicoanalyses showed genes targets of miRNAs in important molecular pathways associated with carcinogenicity by molecular subtypes.ConclusionOur results showed that there is a group of circulating miRNAs as potential of early biomarkers in breast cancer patients associated with molecular subtypes of breast cancer when compared with healthy women.

Number of Risky Lifestyle Behaviors and Breast Cancer Risk.

BackgroundLifestyle factors are associated with overall breast cancer risk, but less is known about their associations, alone or jointly, with risk of specific breast cancer subtypes.MethodsWe conducted a case–control subjects study nested within a cohort of women who participated in the Norwegian Breast Cancer Screening Program during 2006–2014 to examine associations between risky lifestyle factors and breast cancer risk. In all, 4402 breast cancer cases subjects with information on risk factors and hormone receptor status were identified. Conditional logistic regression was used to estimate odds ratios (ORs), with 95% confidence intervals (CIs), in relation to five risky lifestyle factors: body mass index (BMI) of 25 kg/m² or greater, three or more glasses of alcoholic beverages per week, ever smoking, fewer than four hours of physical activity per week, and ever use of menopausal hormone therapy. Analyses were adjusted for education, age at menarche, number of pregnancies, and menopausal status. All statistical tests were two-sided.ResultsCompared with women with no risky lifestyle behaviors, those with five had 85% (OR = 1.85, 95% CI = 1.42 to 2.42, Ptrend < .0001) increased risk of breast cancer overall. This association was limited to luminal A–like (OR = 2.20, 95% CI = 1.55 to 3.12, Ptrend < .0001) and luminal B–like human epidermal growth factor receptor 2 (HER2)–positive (OR = 1.66, 95% CI = 0.61 to 4.54, Ptrend < .004) subtypes. Number of risky lifestyle factors was not associated with increased risk of luminal B–like HER2-negative, HER2-positive, or triple-negative subtypes (Ptrend > .18 for all).ConclusionsNumber of risky lifestyle factors was positively associated with increased risk for luminal A–like and luminal B–like HER2-positive breast cancer.

Abstract 953: LRRC15 is a novel antigen in sarcoma and the therapeutic target of the antibody-drug conjugate (ADC) ABBV-085

Abstract Background: Leucine rich repeat containing 15 (LRRC15) is a TGFβ-regulated structural protein that is highly expressed on cancer-associated fibroblasts (CAFs) in the stromal microenvironment of many solid tumors, as well as directly on cancer cells of mesenchymal origin. Soft tissue sarcomas (STS) and bone sarcomas (BS) represent a diverse family of mesenchymal malignancies that can develop at any anatomic site and that comprise more than 70 histopathologic subtypes. After screening LRRC15 expression across a variety of sarcoma histologies, we evaluated the antitumor activity of ABBV-085, an MMAE (monomethyl auristatin E) containing antibody-drug conjugate directed against LRRC15 (mouse, cyno, human), in patient-derived xenograft (PDX) models of selected sarcomas with varying levels of LRRC15 expression. Methods: LRRC15 expression/intensity in sarcoma histologies was performed by immunohistochemical (IHC) staining (Leica Bond RX, Bond Polymer Refine Kit) with a human LRRC15 specific mouse IgG2b antibody. Based on LRRC15 expression levels, STS and BS tumor fragments (PDXs) were implanted into NSG mice. Mice with growing tumors were then selected to evaluate the in vivo efficacy of ABBV-085 monotherapy (6 mg/kg). Results: LRRC15 expression was evaluated in 340 human sarcoma tumors representing a variety of STS and BS histologic subtypes. LRRC15 IHC expression was determined by scoring the percentage of positive cells, together with the intensity of staining (score of 0 for negative, 1 for weak, 2 for moderate, and 3 for strong staining), for the cancer cells and stroma, respectively. A stringent cut-off for strong LRRC15 positivity was defined as ≥2+ intensity in ≥50% of the cancer or stromal area. Strong LRRC15 expression was observed in several sarcoma subsets: 67% (14/21) of osteosarcoma (OS) tumor samples, 64% (23/36) of undifferentiated pleomorphic sarcoma (UPS), 18% (8/44) of leiomyosarcomas (LMS) and 17% (6/35) of liposarcomas (LPS). Significant antitumor activity including regressions and cures was induced by ABBV-085 in LRRC15-positive STS and BM PDX models, when compared with isotype-control treated mice. The ABBV-085-induced efficacy in osteosarcoma PDX models was superior to current standard-of-care therapies when dosed maximally in mice. In addition, ABBV-085 demonstrated efficacy in different LRRC15 positive STS subtypes including UPS, LMS and LPS. ABBV-085 was well tolerated with minimal to no body weight loss observed. Conclusions: LRRC15 is highly expressed in the majority of human osteosarcomas and undifferentiated pleomorphic sarcomas, as well as in a range of other STS and BS subtypes. ABBV-085 demonstrates promising preclinical antitumor efficacy in LRRC15-positive PDX models of STS and BS. ABBV-085 is currently being investigated in an ongoing phase 1 study in soft tissue sarcomas (including undifferentiated pleomorphic sarcoma) and osteosarcoma. Citation Format: Eytan Ben-Ami, Ying Huang, Prafulla C. Gokhale, Benjamin Eschle, Lisa Durkin, Jonathan Hickson, Mien Sho, Susan Morgan-Lappe, Kurt Gish, Dominic W. Lai, Randy R. Robinson, Diane Hollenbaugh, Eric D. Hsi, Debra T. Chao, George D. Demetri, James W. Purcell. LRRC15 is a novel antigen in sarcoma and the therapeutic target of the antibody-drug conjugate (ADC) ABBV-085 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 953.

Abstract 5188: MDM2 and MDMX promote p53-independent initiation of circulating tumor cells from triple negative breast cancers

Abstract Many human breast cancers overexpress the E3 ubiquitin ligase MDM2 and its homolog MDMX. The Cancer Genome Atlas (TCGA) shows that high MDM2 and MDMX expression correlates with both estrogen receptor positive (ER+) and triple negative breast cancer (TNBC) subtypes. Overexpression of MDM2 and MDMX can drive breast cancer progression through molecular pathways that do not require wild-type p53 degradation. ER positive breast cancers often express wild-type p53 but 80% of TNBC express mutant p53 (mtp53). It has not been determined how MDM2 and MDMX expression in different sub-types of breast cancer, with mutant p53, influence proliferation and metastasis. We compared MDM2 and MDMX-dependent biological outcomes for mtp53 expressing ER+ T47D (mtp53 L194F) and TNBC cell type MDA-MB-231 (mtp53 R280K). In the ER+ cells no change was detected for real time cell migration or E-cadherin protein levels when MDM2 was knocked down by stable shRNA expression but cell proliferation was reduced. In support of this in vitro data, these MDM2 knockdown cells tested in an orthotopic xenograft model in NSG mice demonstrated no MDM2-mediated change in primary tumor invasiveness but did show a reduced tumor volume. Importantly, in the TNBC MDA-MB-231 cells, knocking down either MDM2 or MDMX did not reduce cell proliferation in vitro but greatly blocked cell migration. In support of this in vitro data, these MDA-MB-231 cells with either MDM2 or MDMX knockdown in NSG mice did not show a reduced primary tumor volume but showed a significant inhibition of the production of circulating tumor cells (CTCs). Our data shows that in different subtypes of breast cancers, MDM2 and MDMX can promote alternative p53-independent biological outcomes. The estrogen-activated MDM2 strongly promotes cell proliferation while MDM2 and MDMX overexpression in TNBC promotes circulating tumor cells and potentially metastasis. Understanding the alternative p53-independent roles of MDM2 and MDMX in ER+ and triple negative breast cancers will provide insight for the development of MDMs-targeted theranostics. Citation Format: Chong Gao, Gu Xiao, Ale Piersiga, Jiangtao Gou, Olorunseun Ogunwobi, Jill Bargonetti. MDM2 and MDMX promote p53-independent initiation of circulating tumor cells from triple negative breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5188.

Retrospective analysis of the impact of anthracycline dose reduction and chemotherapy delays on the outcomes of early breast cancer molecular subtypes

BackgroundThe objective of study was to determine the effect of anthracycline dose reduction and chemotherapy delays on 5-year overall survival in patients with stage I-III breast cancer, to establish the impact of molecular subtypes on the anthracycline modification effects and to analyze reasons for such chemotherapy scheme modifications.MethodsMedical records of patients with stage I-III breast cancer were reviewed. Inclusion criteria involved stage I- III breast carcinoma; radical surgery performed and 4 courses of AC regimen (doxorubicin and cyclophosphamide), or at least 6 courses of FAC regimen (fluorouracil, doxorubicin and cyclophosphamide) completed; no neoadjuvant chemotherapy applied; no taxane group medications administered; medical records maintain comprehensive data on treatment and follow-up. 5- year overall survival were analyzed using Kaplan-Meier and Cox proportional hazards models.ResultsSignificant 3.17 times higher death risk at 5 year period in patients who experienced anthracycline dose reduction compared with patients who did not experience any modifications was established (HR = 3.17, 95% CI 1.7–5.9, p < 0.001). Increased death risk in patients who experienced both chemotherapy dose reduction and treatment delays compared with patients who did not experience any modifications was also established (HR = 2.76, 95% CI 1.3–5.6, p < 0.05). 5- year overall survival was affected by anthracycline dose reduction by more than 15% in ER-HER2- group (80% v. 55.6%, p = 0.015), ER + HER2- group (90.7% v. 64.9%, p < 0.01) and ER+/-HER2+ group (100% v. 84.4%, p = 0.019). 5-year overall survival was affected by chemotherapy delays more than 2 cycles in ER-HER2- group (79.2% v. 51.4%, p = 0.002), ER + HER2- group (86.3% v. 58.8%, p = 0.014) and there was no difference in ER+/-HER2+ group. Main reasons for chemotherapy scheme modifications (in decreasing order) were the following: neutropenia, modifications with no objective medical reasons, thrombocytopenia, anaemia, fatigue, infection.ConclusionsAnthracycline dose reduction in patients with stage I- III breast cancer were associated with higher mortality risk and significantly decreased 5- year absolute survival in all molecular subtypes. Chemotherapy delays alone were not associated with decreased survival only in HER2 positive subtype. The most common reason for dose reduction or chemotherapy delays was neutropenia.

Long-term heart-specific mortality among 347476 breast cancer patients treated with radiotherapy or chemotherapy: a registry-based cohort study.

Breast cancer survival has improved throughout the last decades, but treatment-induced cardiotoxicity remains a major concern. This study aimed to investigate competing causes of death and prognostic factors within a large cohort of breast cancer patients and to describe the heart-specific mortality in relation to the general population. In this registry-based cohort study, women diagnosed with breast cancer between 2000 and 2011, who were treated with radiotherapy or chemotherapy and followed until 2014, were identified from the Surveillance, Epidemiology, and End Results-18 (SEER-18) database. Cumulative mortality functions were computed. To investigate heart-specific mortality relative to the general population, long-term (≥10 years) standardized mortality ratios (SMRs) were calculated. Prognostic factors for heart-specific mortality were assessed by calculating cause-specific hazard ratios (HRcs) with corresponding 95% confidence intervals using the Cox proportional hazards regression. Subgroup analysis on intermediate-term mortality according to molecular subtypes, for which information was available since 2010, was performed. In total, 347476 breast cancer patients were eligible to be included in the study. Among all possible competing causes of death, breast cancer accounted for the highest cumulative mortality. Compared with the general population, heart-specific mortality of breast cancer patients treated with radiotherapy or chemotherapy was lower [SMRoverall 0.84 (0.79-0.90)]. In subgroup analysis, human epidermal growth factor receptor 2 (HER2)-positive subtype was not associated with increased heart-specific mortality relative to HER2-negative patients [HRcs 0.96 (0.70-1.32)]. Heart-specific mortality among breast cancer survivors is not increased compared with the general population. Human epidermal growth factor receptor 2-positive patients do not have increased heart-specific mortality compared to HER2-negative patients.

Fluorescent Based Tracing of Sensory Nerve Subtypes in Brainstem

Processing vagal and trigeminal afferent inputs in the brainstem is essential for regulating reflexes including those from the respiratory tract. Afferent nerves can be categorized into several subtypes depending on the ganglionic origin of cell bodies (placodal vs. neural crest), conduction velocity and response patterns to stimuli. These various nerve subtypes convey different types of information which is integrated at the brainstem to control respiratory reflexes. Vagal afferent nerve subtypes express particular ion channels/receptors which are stimulated by various stimuli resulting in different information being relayed to the brainstem. For example, stimulation of vagal jugular C‐fiber nociceptors evokes cough, whereas stimulation of vagal nodose C‐fiber nociceptors inhibits cough. Vagal afferents are known to innervate the nucleus of the solitary tract in the dorsal medulla. However, the innervation patterns may vary depending on the subsets of vagal afferents. The variation makes it difficult to understand how distinct peripheral vagal afferent inputs are processed in the central nervous system.In the current study, we focused on developing a neuroanatomical map of various sensory afferent nerve subtypes using a transgenic mouse model system. Cre‐LoxP reporter system allows us to target the specific ion channel/receptor positive sensory nerve subtypes enabling tracking of afferent nerve subtypes throughout medulla. Transient receptor potential vanilloid 1 (Trpv1), tachykinin 1 (Tac1) and 5‐hydroxytriptamine receptor 3 (5HT3) Cre strains were bred with Floxed Ai9 ROSA tdTomato; thus, expressing red fluorescent specific to Trpv1, Tac1 and 5HT3 positive cells. Mice (6 to 8‐week‐old) were euthanized and tissue was collected. Brainstem were cryosectioned at 30 μm thickness and slide mounted sequentially. Additionally, we used a passive tissue clearing technique (CLARITY‐PACT) to visualize the sensory nerve projections in dissected whole medulla. Images were taken using Nikon Eclipse microscope and Olympus FV1200 confocal microscope. The 3D images were processed with Imaris software.As a result, we were able to identify each sensory nerve subtype in the medulla and define their projections to different regions of medulla ‐ these include the nucleus of solitary tract (NTS), paratrigeminal nucleus (Pa5) and spinal trigeminal tract (sp5). While brainstem projection of the Trpv1, Tac1 and 5ht3 Cre/Rosa strains showed similarities in gross regional expression, the patterns of these projections were distinct depending on the strains. For example, Trpv1‐tdTomato projections were found in the commissural NTS but not the medial NTS, whereas Tac1‐tdTomato projections were largely absent from the commissural NTS but were abundantly present in the medial NTS. The only overlap of Trpv1 and Tac1 projections was not in the NTS, but rather in Pa5 and sp5, suggesting that vagal jugular C‐fiber nociceptors may terminate in Pa5 as opposed to the NTS. The cleared whole medulla from each strain were consistent with the medulla sections and were used to yield 3D maps of the sensory afferent nerve projections. Based on these observations, a genetic tool using Cre‐LoxP reporter system allowed us to define the neuronal circuitry of major vagal sensory afferent nerve subtypes. This information may be useful to study functionalities of each sensory nerve subtypes to better understand the mechanism of respiratory reflexes.Support or Funding InformationNIH Common Fund SPARC OT2This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Diagnostic and prognostic values of contrast‑enhanced ultrasound combined with diffusion‑weighted magnetic resonance imaging in different subtypes of breast cancer.

The present study aimed to investigate the diagnostic and prognostic values of contrast-enhanced ultrasound (CEUS) combined with diffusion-weighted magnetic resonance imaging (DW-MRI) in different subtypes of breast cancer (BC). CEUS and DW-MRI were conducted in 232 patients with BC prior to surgical treatment. Patients were categorized as having the luminal A subtype, the luminal B subtype, triple-negative subtype or the human epidermal growth factor receptor 2 (Her-2)-positive subtype according to their expression of the estrogen receptor (ER), progesterone receptor (PR) and Her-2, as detected by immunohistochemistry. The CEUS and DW-MRI parameters of patients with different subtypes of BC were obtained and analyzed. The risk factors for the prognosis of patients with different subtypes of BC were analyzed using Kaplan-Meier and COX regression analyses. The diagnostic accuracy rate of CEUS combined with DW-MRI (93.10%) was higher than that of CEUS (88.79%) or DW-MRI (82.33%) alone. The local recurrence rate and distant metastasis rate of the Her-2-positive subtype were the highest among all the subtypes. Furthermore, patients with Her-2-positive BC exhibited a higher proportion of lesions with indistinct margins and histological grade III. Lymph node metastasis and BC subtype were independent risk factors for the prognosis of BC. The overall survival and disease-free survival of patients with the luminal A subtype were higher than those of patients with the Her-2-positive subtype. The results of the current study therefore indicate that CEUS combined with DW-MRI is more effective at diagnosing the different subtypes of BC than either CEUS or DW-MRI alone.

Primer in Genetics and Genomics, Article 7-Multifactorial Concepts: Gene-Gene Interactions.

Most common disorders affecting human health are not attributable to simple Mendelian (single-gene) inheritance patterns. Rather, the risk of developing a complex disease is often the result of interactions across genes, whereby one gene modifies the phenotype of another gene. These types of interactions can occur between two or more genes and are referred to as epistasis. There are five major types of epistatic interactions, but in human genetics, additive epistasis is most often discussed and includes both positive and negative subtypes. Detecting epistatic interactions can be quite difficult because seemingly unrelated genes can interact with and influence each other. As a result of this complexity, statistical geneticists are constantly developing new methods to enhance detection, but there are disadvantages to each proposed method. In this article, we explore the concept of epistasis, discuss different types of epistatic interactions, and provide a brief introduction to statistical methods researchers use to uncover sets of epistatic interactions. Then, we consider Alzheimer's disease as an exemplar for a disease with epistatic effects. Finally, we provide helpful resources, where nurses can learn more about epistasis in order to incorporate these methods into their own program of research.

Four distinct immune microenvironment subtypes in gastric adenocarcinoma with special reference to microsatellite instability

IntroductionProgrammed death-ligand 1 (PD-L1) can be overexpressed in tumours other than Epstein-Barr virus (EBV)-positive (EBV+) or microsatellite instability-high (MSI-H) gastric cancer (GC) subtypes. We aimed to determine the tumour immune microenvironment (TME) classification of GC to better understand tumour–immune interactions and help patient selection for future immunotherapy with special reference to MSI-H.MethodsImmunohistochemistry (IHC) for PD-L1 and CD8+ T cells in three distinct subtypes of GC (43 EBV+, 79 MSI-H and 125 EBV−/MSS) were performed and analysed. In 66 MSI-H GC, mutation counts were compared with PD-L1 expression and survival of the patients.ResultsGC TME divided by PD-L1 IHC and tumour-infiltrating lymphocytes (TIL) measured by intratumoural CD8 density showed: (1) about 40% of GC are type I (PD-L1+/TIL+) consisting ~70% of MSI-H or EBV+ GC, and ~15% of EBV−/microsatellite stable (MSS) GC patients show the best survival in both disease-free (HR 2.044) and overall survival (HR 1.993); this type would respond to a checkpoint blockade therapy; (2) almost 30% of GC are type II (PD-L1−/TIL−) with the worst survival; (3) approximately 10% of GC are type III (PD-L1+/TIL−); and (4) up to 20% are type IV (PD-L1−/TIL+) and, unexpectedly, ~25% of EBV+ or MSI-H GC are within this subtype. In MSI-H GC, frequent frameshift mutations were observed in ARID1A, RNF43, NF1, MSH6, BRD3, NCOA3, BCORL1, TNKS2 and NPM1 and the numbers of frameshift mutation correlated significantly with PD-L1 expression (P<0.05).DiscussionGC can be classified into four TME types based on PD-L1 and TIL, and numbers of frameshift mutation correlate well with PD-L1 expression in MSI-H GC.

Abstract P1-13-14: Triple positive breast cancer ; a distictive subtype and consideration of systemic therapeutic approach

Abstract Introduction: Triple positive breast cancer is one of intrinsic subtype in breast cancer that is defined namely, ER/PR/Her2 positive tumors. It has multiple strategies for systemic therapy according to the characteristics of hormonal and anti-HER2 responsiveness. Each targeted therapy plays cross-talks between HER-2 and estrogen receptor signaling pathway resulting in endocrine resistance and anti Her2 resistance. Methods: We compared the triple positive subtype to the other breast cancer intrinsic subtypes to distinguish the uniqueness in their position among other breast cancer subtypes using retrospective analysis of two different cohorts; Korea Breast Cancer Society (KBCS) Breast cancer registry data (N=31266, Jan. 2006 – Dec. 2010) and database from St. Mary`s hospital Breast cancer registry (N=2216, Apr. 2009 – Mar. 2016). Results: Median follow up duration of 76 months in KBCS cohort (2006-2010) showed the overall survival graph of triple positive breast cancer located in the middle in between Luminal A intrinsic subtype and HER2 enriched subtype(P&amp;lt;.001). Also HER2 directed trastuzumab therapy did not improve the overall survival in triple positive breast cancer patients (P=.899) in contrast to the improved overall survival using trastuzumab therapy in HER2 enriched subtype (P=.018). Like the preceding results, CMC breast cancer data showed the similar results in recurrence free survival (P&amp;lt;.001). and no recurrence free survival improvement using trastuzumab therapy in triple positive breast cancer patient during the median follow up of 33 months (P=0.800). Conclusion: 1) Anti-HER2 therapy seems less beneficial in Triple positive breast cancer subtype regardless of breast cancer stage. 2) Triple positive breast cancer may require different therapeutic approaches 3) Other targeted agents (mTOR inhibitor, CDK4/6 inhibitor, PIK3CA inhibitor) can be a substitute option for the Trastuzumab therapy in triple positive breast cancer. Citation Format: Kim JS, Kim YS, You SH. Triple positive breast cancer ; a distictive subtype and consideration of systemic therapeutic approach [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 P1-13-14.

Abstract P4-02-04: Quantitative MRI features analysis for differentiation of triple negative and HER2 positive subtypes of breast cancer

Abstract Objective: The aim of this study was to evaluate ability of quantitative analysis of MRI features to distinguish triple negative (TN) and HER2 positive (HER2+) subtypes of breast cancer, which have different biological characteristics, exhibiting different growth patterns and response to treatment. Materials and Method: Breast cancer patients, who had MRI exam of the breast in our institution at the time of staging for breast carcinoma and who subsequently had surgery (segmentectomy or mastectomy) from January 1, 2008 through December 31, 2015 were identified. All lesions were evaluated by radiologists in accordance with the BI-RADS lexicon. The patient's age, breast cancer histology, multifocality/multicentricity (MF/MC), lesion size, axillary lymphadenopathy (LAN), MRI morphologic and enhancement characteristics were documented. Quantitative MRI feature analysis was performed using shape, texture, and histogram based features. Machine-learning-based (Xgboost) models were used to predict subtypes, and Leave-one-out cross-validation (LOOCV) was used to avoid model overfitting. Statistical significance was determined using the Student's t-test. Results: Total of 105 patients, 51 patients with TN and 54 patients with HER2+ breast cancer were included in analysis. Mean age for TN was 50 (range 29-79)) years old and for HER2+ was 49 (range 25-70) years old. Axillary LAN and MF/MC disease was seen more commonly in HER2+ patients when compared to TN patients, but didn't reach statistical significance (13 vs 7, p=0.9; and 31 vs 20, p=0.06, respectively). Mass rim enhancement was associated with TN subtype and irregular mass enhancement was associated with HER2+ subtype of breast cancer (p&amp;lt;0.05). Quantitative analysis showed that six out of the top 10 ranked MRI features: surface to volume ratio, difference variance, difference entropy, inverse difference moment, 75 percentile in histogram and sum average, were significantly different between these 2 subtypes with p&amp;lt;0.05. When the significant features were incorporated to distinguish TN and HER+ subtypes, use of the top 2 features achieved the best accuracy on LOOCV of 0.69. Conclusion: The quantitative MRI features show promise in distinguishing TN and HER2+ breast cancer subtypes reflecting their underlying biological characteristics and may be used as predictive quantitative biological markers. Further studies in a larger cohort evaluating associations with treatment response are underway. FeatureIndexP-valueSurface to volume ratioShape30.005Difference VarianceGLCM110.005Difference EntropyGLCM100.009Inverse Difference MomentGLCM50.01875 percentile in histogramHistogram50.043Sum AverageGLCM60.044Median in histogramHistogram 30.08025 percentile in histogramHistogram 40.095VolumeShape10.104Max in histogramHistogram 10.105 Citation Format: Rauch GM, Li H, Zhu H, Adrada BE, Santiago L, Candelaria RP, Wang H, Leung J, Thompson A, Litton J, Wu Y, Lim B, Moulder S, Mittendorf EA, Yang W. Quantitative MRI features analysis for differentiation of triple negative and HER2 positive subtypes of 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 P4-02-04.

Abstract P1-17-01: Development of brain metastases in breast cancer patients treated in the neoadjuvant trials Geparquinto and Geparsixto

Abstract Background: The incidence of brain metastases (BM) in breast cancer patients is rising and has become a major clinical challenge. So far, the incidence of BM after modern neoadjuvant treatment is not clear. Materials and Methods: In Geparquinto, patients with untreated HER2-positive breast cancer (n=615) received either lapatinib or trastuzumab, patients with HER2 negative breast cancer (n=1925) received bevacizumab in addition to an anthracycline and taxane-containing regimen and those not responding paclitaxel and everolimus (n=32). In Geparsixto, patients with HER2-positive tumors (n=273) received trastuzumab and lapatinib and patients with triple-negative tumors (n=315) received bevacizumab in addition to chemotherapy. We analyzed clinical factors associated with the occurrence of BM as first site of metastatic relapse after neoadjuvant treatment in both trials (n=3160). Results: After a median follow-up of 61 months, 108 (3%) of a total of 3160 patients developed BM as first site of recurrence and 411 (13%) patients had distant metastases outside the brain. Brain metastases as first site of recurrence occurred later than other metastases (3--year-relapse free-rate 96.7% for patients who developed BM and 89.5% for patients who developed metastases outside the brain). Regarding subtypes of the primary tumor, 1% of luminal A (11/954), 2% of luminal B (7/381), 4% of HER2 positive (34/809) and 6% of triple-negative patients (56/1008) developed BM as first site of recurrence. In multivariate analysis, risk factors for the development of BM were larger tumor size (cT3-4; HR 1.9, 95%-CI 1.3-2.8, p=0.0022), node positive disease (HR 2.8, 95% CI 1.8-4.4, p&amp;lt;0.0001), no pCR after neoadjuvant chemotherapy (HR 2.7, 95% CI 1.6-4.7, p=0.0003) and HER2 positive (HR 3.8, 95% CI 1.9-7.8, p=0.0002) or triple-negative subtype (HR 8.1, 95% CI 4.2 – 15.8, p&amp;lt; 0.0001). Breast cancer subtype remained the most relevant risk factor for BM. Patients who developed BM were more often HER2 positive or triple-negative tumors compared with patients who developed metastases outside the brain (HER2 positive subtype 32 vs. 19%, triple-negative subtype 52 vs. 40%, p&amp;lt; 0.001). Conclusion: Especially patients with HER2-positive and triple negative tumors are at risk of developing BM despite active systemic treatment. A better understanding of the underlying mechanisms is required in order to develop potential preventive strategies. Citation Format: Witzel ID, Laakmann E, Fasching PA, Rezai M, Schem C, Solbach C, Tesch H, Klare P, Schneeweiss A, Zahm D, Blohmer J, Ingold-Heppner B, Huober J, Hanusch C, Jackisch C, Reinisch M, Untch M, von Minckwitz G, Müller V, Loibl S. Development of brain metastases in breast cancer patients treated in the neoadjuvant trials Geparquinto and Geparsixto [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 P1-17-01.

Abstract P3-10-09: The association age-related parity and HER2 over-expression in breast cancer

Abstract Backgrounds Reproductive factors, such as age at menarche, parity, age at first birth, and breast feeding, are known to be associated with risk of breast cancer. Recent studies show the association between the reproductive factors and the molecular subtypes of breast cancer, especially in luminal-like subtypes. Nulliparity is known a risk factor of breast cancer, multiparity is considered a protective factor. However, pregnancy associated breast cancers show the high expression of HER2, Therefore, we hypothesized the number of birth (multiparity) is correlated with the over-expression of HER2. Methods We reviewed the database of 2,594 breast cancer patients were over 20 years of age, diagnosed between January 2000 and April 2017 at Korea University of Anam Hospital, Seoul, Korea. According the number of birth, nulliparous (the number of birth = 0; 271 patients), primiparous (the number of birth = 1; 420 patients) and multiparous (the number of birth≥2; 1,903 patients) groups were classified. Results The median age (range) of nulliparous, primiparous and multiparous groups was 43 (22-77), 48 (27-87) and 51 (26-86) years (P&amp;lt;0.001). In univariate analysis, the number of birth was associated with the expression of ER and HER2, nulliparous patients showed higher ER positivity (P=0.013) and multiparous patients showed higher HER2 overexpression (P=0.048). There was no association with PR and Ki-67 level. In logistic regression with age, the parity was negative correlation with ER positivity (OR 0.83, 95% CI 0.72-0.95, P=0.010) and positive correlation with HER2 overexpression (OR1.18, 95% CI 1.02-1.36, P=0.021) P=0.009) and multiparity was higher HER2 overexpression (OR 1.41, 95% CI 1.02-1.94, P=0.033). By subgroup analysis with menopausal status, there was statistically significance in only premenopausal women, not in postmenopausal women. In premenopausal women, the parity was negatively associated with ER positivity (OR 0.78, 95%CI 0.64-0.94, P=0.010) and multiparity was associated with HER2 overexpression (OR 1.72, 95%CI 1.12-2.63, P=0.013), there was no difference in HER2 overexpression between nulliparous and primiparous patients. Conclusion Parity was associated with ER and HER2 expression, multiparous patients were associated with ER negativity and HER2 overexpression, especially in premenopausal women. This suggests that pregnancy could affect risk of breast cancer, especially in HER2 positive breast cancer subtype (ER- HER2+ tumors), before menopause. We need further investigation and evaluation. Citation Format: Bae SY, Kim J, You JY, Jung SP, Bae JW. The association age-related parity and HER2 over-expression in 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 P3-10-09.

Abstract P2-05-14: Young breast cancer patients (&amp;lt;40 yo) have unfavorable subtypes, higher stage and worse survival

Abstract BACKGROUND: Over the last 40 years, the incidence of breast cancer in young women in the U.S. has been relatively low and stable, but the absolute number of young women with breast cancer is increasing because of the growing population. Some epidemiological studies have shown that breast cancer diagnosed before age 40 have significantly worse overall 5-year survival. Disease free survival is also inferior in young women, and they have more aggressive cancers in general. This study aims to validate these findings using genomic analysis of large databases. MATERIALS AND METHODS: The Cancer Genome Atlas (TCGA; n= 1095) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; n=1894) were used for analysis. We divided the database into the Young (&amp;lt;40 yo) and Non-Young (&amp;gt;40 yo) cohorts, based on age at diagnosis. The following analysis will give the TCGA and METABRIC results in each category, respectively. RESULTS: There were 8.9% (98) and 6% (116) patients who were found to be Young. In the Young cohort, 69.5% (64) and 37.9% (44) were ER(+), whereas 77.9% (742) and 79.5% (1415) in the Non-Young cohort were ER(+). Further, 60.8% (56) and 31.9% (37) were PR(+) in the Young cohort, compared to 68.4% (641) and 54.4% (972) in the Non-Young cohort. Her2(+) cancers were noted in 22.2% (12) and 25% (29) in the Young cohort, whereas 22.6% (152) and 11.6% (207) were Her2(+) in the Non-Young cohort. Our group developed a pipeline to calculate PAM50 from the RNA-Seq dataset. Utilizing this calculated PAM50 in TCGA, we found that there were less Luminal A and B patients in the Young cohort, 41.6% (42) and 17.8% (18) compared to 49.7% (377) and 22.9% (174) in the Non-Young cohort. This was also the case in METABRIC where 17.2% (20) and 9.5% (11) were Luminal A and B, compared to 36.9% (659) and 25.2% (450) in the Non-Young group. In contrast, there were more basal-like subtypes in the Young group, 17.8% (18) and 28.4% (33), as compared to the Non-Young group, 16.1% (122) and 9.3% (166). These results agree with previous epidemiological studies that showed that hormone receptor positive tumors increase and basal-like subtypes decrease with age. The number of Stage I patients was lower in Young patients 13.5% (13) and 25.3% (22), than in Non-Young patients 17.3% (169) and 34.4% (453). Similarly, there were less Stage II patients in the Young 54.2% (52) and 58.6% (51) compared to 58.3% (569) and 56.9% (749) in the Non-Young. This reverses in Stage III where the incidence is increased in the Young at 31.2% (30) and 16.1% (14) compared to 22.4% (219) and 7.7% (101) in the Non-Young. Young patients had a lower median disease-free survival than Non-Young patients (NA vs 214.7 mo, p=0.027); however, there was no statistical significance in median survival. Young patients had a lower median disease-specific survival than non-young patients of 221.1 months vs 282.6 months (p=0.00123) in METABRIC. CONCLUSION: We used large datasets to examine survival in very young breast cancer patients (&amp;lt;40 yo) vs older patients and found that young patients are likely to have unfavorable subtypes, higher stage, and a lower overall survival and DFS as compared to their older counterparts. Further analysis with genomics is needed. Citation Format: Young JS, Kawaguchi T, Yan L, Qi Q, Liu S, Takabe K. Young breast cancer patients (&amp;lt;40 yo) have unfavorable subtypes, higher stage and worse survival [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 P2-05-14.

Abstract PD2-09: Association of quantitative MRI features with tumor infiltrating lymphocytes and treatment response prediction in HER2 positive subtype of breast cancer

Abstract Objectives: To evaluate associations between qualitative and quantitative MRI features and tumor infiltrating lymphocytes (TIL) levels in HER2+ subtype of breast cancer, as potential prognostic non-invasive imaging markers for treatment response prediction. Materials and Methods: Retrospective review of breast cancer patients who had MRI at staging, neoadjuvant chemotherapy and surgery from January 1, 2008 through December 31, 2015 was performed. BI-RADS lexicon was used for lesion evaluation. Demographic, imaging, and pathologic data including TIL levels were documented. Quantitative MRI texture analysis was performed using 3 types of textural features (TF): local binary patterns (LBP), gray-level co-occurrence matrix (GLCM), and threshold adjacency statistics (TAS). Associations between MRI quantitative TF, TIL levels, and pathologic complete response (pCR) were evaluated by Pearson correlation and logistic regression. Results: There were 50 HER2+ patients (median age 51 years, range 29-59) with pretreatment MRI and TIL status for analysis; 27 patients had pCR at surgery. Qualitative MRI analysis showed that mass rim-enhancement (p&amp;lt;0. 05) and fast early enhancement kinetics (p&amp;lt;0.01) were associated with higher TIL levels. No association between qualitative MRI features and pCR was found. Nine TF significantly correlated with pCR (p&amp;lt;0.05): angular 2nd moment (GLCM), 75 percentile (LBP), standard deviation (GLCM), adjacency 0-5 (TAS). This is indicative of association of tumor heterogeneity with pCR. Three TF were significantly associated with high TIL levels (p&amp;lt;0.05): standard deviation, adjacency 1 and 2. Additional four TF had high association with TIL (p&amp;lt;0.1): sum entropy, adjacency 0, 3 and 4. These findings showed that increased heterogeneity, complexity and entropy were associated with high TIL level. Three TF were significantly associated with both, pCR and TIL (p&amp;lt;0.05): 75 percentile, standard deviation, adjacency 8. Conclusion: Quantitative tumor texture analysis based on statistical modeling showed specific nine TF indicative of tumor heterogeneity associated with pCR; and seven TF indicative of increased heterogeneity, complexity, and entropy associated with high TIL levels in HER2+ breast cancer. Analysis of associations of MRI quantitative TF with pCR and TIL in HER2+ breast cancer may help to develop prognostic non-invasive imaging markers for treatment response prediction. Citation Format: Rauch GM, Zhu H, Li H, Adrada BE, Santiago L, Candelaria RP, Wang H, Leung J, Litton J, Wu Y, Murthy R, Mittendorf EA, Yang W. Association of quantitative MRI features with tumor infiltrating lymphocytes and treatment response prediction in HER2 positive subtype of 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 PD2-09.

Abstract P3-08-07: Margins in breast conserving surgery after neoadjuvant therapy

Abstract Background:The margin consensus guideline for patients undergoing primary breast conserving surgery (BCS) and whole breast radiotherapy defines a negative margin as no tumor on ink and concludes that wider margins do not improve local recurrence (LR) rates. There are few studies examining BCS margin width after neoadjuvant chemotherapy (NAC).We sought to determine the impact of margin width on LR and survival rates after NAC and BCS. Methods: Institutional database were reviewed to identify patients with stage I-III breast cancer treated with NAC and BCS from 2002-2014. Patients with inflammatory breast cancer were excluded. Chart review was performed to collect detailed patient and treatment factors. Margins widths were collected as reported and grouped as: positive (ink on tumor), close (&amp;lt;2mm), and negative (&amp;gt;2mm), for the purposes of this analysis. Cox regression was used to determine the relationship between margin width and local recurrence, disease free survival (DFS) and overall survival (OS). Result: 395 patients underwent NAC followed by BCS during the study period. The result was same as below. results Patients, n (%)Age at diagnosis (yrs)51 [22;79]Initial tumor size (cm)3.0 [0.6;11.0]Clinical node status - negative207 (52.4%)- positive188 (47.6%)subtype - HR-/Her2-148 (37.5%)- HR-/Her2+48 (12.2%)- HR+/Her2-124 (31.4%)- HR+/Her2+72 (18.2%)- unclassified3 ( 0.8%)pCR* status - pCR97 (24.6%)- non pCR295 (74.7%)- unclassified3 ( 0.8%)Final margin state - no residual tumor in breast108 (27.3%)- positive8 ( 2.0%)- close (≤2)99 (25.1%)- negative (&amp;gt;2)180 (45.6%)*pCR was defined as no invasive or in situ disease in breast and no tumor in axillary node Median patient age was 51 yrs (range 22-79); median tumor size at presentation was 3.0 cm (range 0.6-11.0) and 188 (47.6%) patients (pts) presented with clinically node positive disease. Breast cancer subtypes included 148 (37.5%) pts with HR-/Her2-, 48 (12.2%) pts with HR-/Her2+, 124 (31.4%) pts with HR+/Her2- and 72 (18.2%) pts with HR+/Her2+, disease. Among all patients the pCR rate, defined as no invasive or in situ disease, in the breast was 27.3% (108/395) and the pCR rate in the breast and axillary nodes was 24.6% (97/395). Final margin status included 8 (2.0%) pts with positive margins, 99 (25.1%) with close &amp;lt;2mm and 180 (45.6%) with negative (&amp;gt;2mm) margins. Among the patients with “positive margins”; all were noted to be posterior or anterior and the surgeon noted that re-excision was not possible. At a median follow-up of 53.0 months the LR rate was 2.8% and DFS was 87.4%. On cox regression, HR positive subtype (p=0.048), pCR (p=0.035), and pathologic negative node (p&amp;lt;0.001) were correlated with favorable DFS and pathologic negative node (p&amp;lt;0.001) was correlated with favorable OS. There was no difference in LR rate, DFS or OS between 'close/positive margin' and '&amp;gt;2mm margin groups. Conclusion: In this cohort of patients treated with NAC followed by BCS, LR rates were very low and there was no difference in DFS between patients with margins &amp;lt; 2mm or &amp;gt; 2mm. Further studies are needed to confirm the effect of margin width in the NAC setting. Citation Format: Choi J, Golshan M, Hu J, Gagnon HC, Densantis S, Barry B, King T. Margins in breast conserving surgery after neoadjuvant therapy [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 P3-08-07.

Abstract P6-06-06: Immunogenomics approach elucidating clinical significance of DNA repair genes and tumor infiltrating immune cells in breast cancer

Abstract Backgrounds: Evading the immune system is one of the Hallmarks of Cancer. Indeed, tumor infiltrating immune cells has been shown to play critical roles in suppression of cancer progression. Genetic aberration of DNA repair genes is known to increase immunogenicity in breast cancer. However, the patient survival relevance of tumor infiltrating immune cells in regard to DNA repair genes has not yet elucidated in large cohort of breast cancer patients. We hypothesized that DNA repair gene deficiency is related to increased global genomic instability that leads to increased mutation burden, which recruits infiltrating immune cells to tumor microenvironment that result in better prognosis of breast cancer. Patients and Methods: Integrated and unbiased transcriptomics approach was conducted on genomic and clinicopathological information of 3614 breast cancer patients. We utilized The cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) to evaluate the association between the aberration of DNA repair genes and tumor infiltrating immune cell composition in breast cancer tumors, as well as its significant clinical relevance, utilizing bioinformatics and biostatistics pipelines. Results:Low expression level of double-strand break repair genes; BRCA1, PRKDC, and RECQL4,demonstrated significantlybetter prognosis in TCGA cohort (p=0.018, p=0.036, and p=0.0002, respectively). This result was consistent in METABRIC cohort (p=0.021, p=0.00021, and p&amp;lt;0.000001, respectively). Utilizing CIBERSORT system that estimate the fraction of 22 immune cell types, we found that low expression of BRCA1 significantly associated with high levels of CD8 positive cell composition in both cohorts (TCGA, p=4.67E-08; METABRIC, p=0.0038), which implicate that tumor infiltrating lymphocytes are attracted to BRCA1 low expressing tumors. Further, low expression of BRCA1 showed significantly better survival in HER2 positive subtype population, but not in the other populations (TCGA, p=0.027; METABRIC, p=0.13). Finally, significantly poor prognosis was observed in breast cancers low in immune-response markers; PD-1, PD-L1, TIM3, LAG3, and CTLA4, in combination with high expression of BRCA1 (p=0.0016, p=0.0041, p=0.015, p=0.0041, and p=0.0043, respectively), which is in agreement with the dogma that intact DNA repair induce less immune-response that result is worse survival. Conclusions: We conclude that our immunogenomics approach identify the interplay between DNA repair genes, especially gene expression of BRCA1, and tumor infiltrating immune cells, and it could have significant prognostic relevance in breast cancer. Citation Format: Takabe K, Kawaguchi T, Yan L, Peng X, Qi Q, Okano M, Young J, Liu S. Immunogenomics approach elucidating clinical significance of DNA repair genes and tumor infiltrating immune cells in 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 P6-06-06.