HER2-enriched Tumors Research Articles

HER2-Low Breast Cancer: Molecular Characteristics and Prognosis.

Simple SummaryThe dichotomous classification of HER2 status is experiencing a paradigm change, leading to the identification of the so-called “HER2-low” category. The aim of our retrospective, observational study was to characterize intrinsic PAM50 subtypes within HER2-low primary breast tumors extracted from The Cancer Genome Atlas (TCGA) dataset and to describe the prognostic impact of HER2-low on survival outcomes. We evaluated 804 breast cancers and we identified 410 HER2-low tumors (336 with positive hormonal receptor status (HR+) and 74 with negative HR status (HR−)). HER2-enriched tumors were more frequent in HER2-low/HR− and HER2-low/HR+ subtypes, compared to HER2-negative/HR− and HER2-negative/HR+ subtypes, respectively (13.7% versus 1.6% and 1.2% versus 0.5%, respectively). We observed no significant differences in prognosis between HER2-low subtypes and each non-HER2-low subtype when paired by HR status. Our characterization of PAM50 intrinsic subtypes within HER2-low breast cancer ultimately supports further investigation of new treatment strategies in the HER2-low category, with new promising drugs being tested in the context.Background: We aimed to determine the distribution of intrinsic subtypes within HER2-low breast cancer (BC), and to describe the prognostic impact of HER2-low status on survival outcomes. Methods: This is a retrospective, observational study of primary BC extracted from The Cancer Genome Atlas dataset. We described the distribution of PAM50 intrinsic subtypes within HER2-low BC subtype according to hormonal receptor status (positive (HR+) and negative (HR−)). Secondly, we assessed the impact of HER2-low on survival outcomes (progression-free interval (PFI), disease-free interval (DFI), and overall survival (OS)). Results: We analyzed 804 primary BCs, including 410 (51%) HER2-low BCs (336 HR+ and 74 HR−). The proportion of HER2-enriched tumors was higher in the HER2-low/HR− group compared to HER2-low/HR+ (13.7% versus 1.2%, respectively). HER2-enriched tumors were more frequent in HER2-low/HR− and HER2-low/HR+ subtypes, compared to HER2-negative/HR− and HER2-negative/HR+ subtypes, respectively (13.7% versus 1.6% and 1.2% versus 0.5%, respectively). We observed no significant differences in PFI, DFI, and OS between HER2-low subtypes and each non-HER2-low subtype paired by HR status. Conclusions: Our characterization of PAM50 intrinsic subtypes within HER2-low breast cancer may explain the different clinical behaviors and responses to treatment, and ultimately support further investigation of new treatment strategies in the HER2-low category. Moreover, it highlights the importance of considering HR status in the HER2-low category.

Breast cancer liver metastasis: current and future treatment approaches.

Nearly all fatalities arising from breast tumors are attributable to distant metastases. Breast cancer liver metastasis (BCLM) is associated with poor prognoses, with the median survival time being 2 to 3years. Tumor intrinsic subtype directs preferential metastasis to specific organs, with HER2-enriched tumors demonstrating the highest rates of metastasis to the liver, though all subtypes can grow in the liver. There is no singular established standard-of-care for BCLM; therapeutic selection is driven by histologic and molecular hallmarks of the primary tumor or biopsied metastasis samples. Given the poor prognosis of patients with hepatic spread, pre-clinical studies are necessary to identify and evaluate promising new treatment strategies. It is critical that these laboratory studies accurately recapitulate the BCLM disease process, standard progression, and histological attributes. In this review, we summarize the histologic and molecular characteristics of BCLM, evaluate the efficacy of existing surgical and medical treatment strategies, and discuss future approaches to preclinical study of BCLM.

Abstract PS1-15: Does breast cancer subtype impact margin status in patients undergoing partial mastectomy?

Abstract BACKGROUND: It is known that breast cancer subtype (e.g., luminal vs. triple negative (TN)) can affect response to systemic therapy and prognosis; however, it is less well-understood whether these subtypes affect margin status and should therefore alter surgical management. METHODS: Data from two randomized trials evaluating cavity shave margins (CSM) on margin status in patients undergoing partial mastectomy (PM) were used for this analysis. The data were restricted to patients who had invasive carcinoma present in the PM specimen, and in whom data for all three receptors (ER, PR and HER-2) were known. Patients were classified as luminal if they were ER and/or PR+, HER-2 enriched if they were ER and PR negative but HER-2 positive, and TN if they were negative for all three receptors. We evaluated the impact of subtype on the margin status at the time the surgeon had completed their standard PM, prior to randomization to CSM vs. no CSM. Non-parametric statistical analyses were performed using SPSS Version 26. RESULTS: 350 patients were included in this cohort for analysis. The median patient age was 64 (range; 32-94 years) and the median invasive tumor size was 1.2 cm (range; 0.6-8.0 cm). 326 (93.1%) were luminal type, 22 (6.3%) were triple negative, and 2 (0.6%) were HER-2 enriched. Subtype was significantly correlated with race (black patients were more likely to have TN disease than white patients, 22.2% vs. 3.8%, p=0.001), palpability (TN tumors were more likely to be palpable than luminal cancers 54.5% vs. 29.8%, p=0.007) and grade (78.9% of TN cancers were high grade vs. 13.5% of luminal cancers p<0.001). Subtype did not correlate with Hispanic ethnicity, node positivity, nor lymphovascular invasion (p>0.05 for all). While patients with TN and HER-2 enriched tumors were more likely to receive neoadjuvant therapy, this did not reach statistical significance (p=0.117). Surgeons were no more likely to take selective margins on the basis of molecular subtype (p=0.413). In this cohort, the overall positive margin rate was 33.7%. This did not vary based on molecular subtype (positive margin rate: 33.7% for patients with luminal tumors vs. 36.4% for those with TN tumors, p=0.425). On multivariate regression controlling for molecular subtype, race, grade and palpability, the only factor which predicted positive margin status was grade (p=0.005), with high grade tumors being significantly more likely to have a positive margin than low grade tumors, independent of other factors (OR=3.503, 95% CI: 1.638-7.494, p=0.001). CONCLUSION: While molecular subtype correlates with race, tumor grade and palpability, it does not predict margin status. Therefore, molecular subtype should not, independent of other factors, influence surgical decision-making. Citation Format: Andrew Fenton, Elisabeth Dupont, Theodore Tsangaris, Carlos Garcia-Cantu, Marissa Howard-McNatt, Akiko Chiba, Adam Berger, Edward Levine, Jennifer Gass, Kristalyn Gallagher, Sharon Lum, Ricardo Martinez, Alliric Willis, Sonali Pandya, Eric Brown, Amanda Mendiola, Mary Murray, Naveenraj Solomon, Maheswari Senthil, David Ollila, David Edmonson, Melissa Lazar, Jukes Namm, Fangyong Li, Meghan Butler, Noreen McGowan, Maria Herrera, Yoana Avitan, Brian Yoder, Laura Walters, Tara McPartland, Victor Haddad, Hongwei Ma, Ming Xie, Anees Chagpar. Does breast cancer subtype impact margin status in patients undergoing partial mastectomy? [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS1-15.

Abstract PS6-46: Correlation of Tumor-infiltrating lymphocytes with clinicopathological features and treatment outcomes in non-metastatic breast cancer patients

Abstract Background Breast cancer is the second most common cancer in the world and most frequent among women. Tumor-infiltrating lymphocytes (TILs) can impact tumor progression and response to therapies. Here we aimed to study TILS using the International Immunooncology Biomarkers Working Group guidelines and correlating the TILS with clinicopathological characteristics, disease free and overall survival in non-metastatic breast cancer patients. Methods Non metastatic breast cancer patients (N = 86) who presented to our department between (2013 - 2015) were retrospectively evaluated. The assessment of TILS distribution was based on the TILS International Working Group 2014 recommendations. The eligible patients were reviewed retrospectively regarding the demographic status and clinical parameters and primary treatment information were extracted from the medical records. For all of the available patients, disease-free survival (DFS) and overall survival (OS) were calculated. Results In the study the majority of the patients were 45 years of age or less. The TILS percentage was measured using image analysis. All samples had a range of 1-100%, with a mean 22%. There was 9.3% of the patients having lymphocyte predominant breast cancer (≥50%), while 90.3% had TILS percentage of <50%. Dividing the patients into low (0-20%), intermediate (20-<50%) and high (50-100%). TILS percentage gave us 62.7%, 27.9% and 9.3% of the patients respectively. The distribution of TILS according to age showed a trend towards decreasing TILS with increasing age, and this was not statistically significant. The majority of tumors in the study were T2 (60.5%) followed by T1 (15.1%).. T1 and T2 tumors had significantly higher TILS percentages compared to T3 and T4, mean 24.94% versus mean 13.37% respectively. Using the t-test this showed a p<0.006. The majority of patients in the study were N1 at 62.8% followed by an equal percentage of 17.4% as both N0 and N2. Patients who were N0 had a significantly higher TILS percentage when compared with N1 and N2, mean 33.07% versus mean 20.0% respectively. This was statistically significant using the t-test with a p<0.032 (table 1). Also in this study, there were 74.4% tumors of the luminal subtype, 11.6% of the Her-2 enriched subtype and 12.8% of the triple negative subtype. Although there was no statistically significant correlation between any molecular subtype and TILS, there was a tendency for Her-2 enriched tumors and triple negative tumors to have a higher percentage of TILS in comparison with luminal subtypes as seen in table 1. We noticed that there is a subgroup of patients with exceptionally high TILS, (called LPBC with TILS ≥50%) had a beneficial response to treatment and confers additional survival benefit; every incremental increase of 10% also resulted in benefit to treatment and delayed relapse. High level of TILS associated with delayed relapse and a survival benefit. Conclusions We demonstrated that increasing TILS confer a relapse free benefit of breast cancer patient, regardless of the tumor subtype, indicating that TILS represent an breast cancer the patients. Keywords Tumor-infiltrating lymphocyte, Breast cancer, outcome of management Table 1:FinalNTumor infiltrating lymphocytes (TILS %)Min. - Max.Mean ± SD.MedianERNegative (0)212.0 - 100.027.33 ± 28.9318.0Weak (1+)63.0 - 40.019.67 ± 16.2917.0Moderate (2++)135.0 - 62.024.38± 20.6317.0Strong (3+++)451.0 - 87.019.78 ± 17.9217.0N/A15.0PRNegative (0)282.0 - 100.024.86 ± 26.1916.50Weak (1+)36.0 - 12.08.33 ± 3.217.0Moderate (2++)171.0 - 87.022.12 ± 22.1017.0Strong (3+++)371.0 - 62.021.68 ± 17.5518.0N/A15.0HER-2Negative (0)441.0 - 100.022.84 ± 22.9717.50Weak (1+)16.0Moderate (2++)114.0 - 87.025.09 ± 23.7625.0Strong (3+++)232.0 - 65.018.70 ± 17.1312.0N/A74.0 - 53.026.71 ± 22.1225.0BC subtypesLuminal A401.0 - 62.021.28 ± 17.9217.50Luminal B242.0 - 87.019.75 ± 18.9013.50Her2 Enriched104.0 - 65.023.20 ± 21.3616.50Triple -ve112.0 - 100.031.09 ± 35.0819.0N/A15.0 Citation Format: Neamat Elsayed Hegazy, Haitham Mohsen Abdel Motal, Hanan Yehia Tayel, Abdelsalam A Ismail. Correlation of Tumor-infiltrating lymphocytes with clinicopathological features and treatment outcomes in non-metastatic breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-46.

The importance of SUVmax in predicting prognosis of invasive breast carcinoma-no special types

Aim: We aimed to investigate the relationship between FDG uptake and clinicopathological characteristics of invasive breast carcinoma-no special type in the present study.Materials and Methods: One hundred seventy invasive breast carcinoma-no special type cases who underwent PET-CT before surgery between 2011-2019 were included in the study. The clinicopathological features and SUVmax of the patients were compared.Results: We observed a strong relationship between the size, grade, pathological stage groups and SUVmax of the tumors and revealed that the SUVmax increased as the size, grade, and pathological stage groups of the tumors increased (p0.001). Carcinomas with high Ki67 proliferation index and ER and PR negative carcinomas exhibited higher SUVmax (p0.001). Triple negative and HER2-enriched molecular subtypes had distinctly higher SUVmax than Luminal A and Luminal B ones (p0.001). HER2-enriched tumors, the cases that were 40 years old and advanced stage designated higher SUVmax (p0.05). Conclusion: It is observed that invasive breast carcinoma-no special type with good prognostic factors have low SUVmax, while carcinomas with poor prognostic features have high SUVmax. It can be suggested that PET/CT can be use to predict the prognosis of invasive breast carcinoma-no special type.

Molecular Subtypes of Breast Cancer: A Review for Breast Radiologists.

Gene expression profiling has reshaped our understanding of breast cancer by identifying four molecular subtypes: (1) luminal A, (2) luminal B, (3) human epidermal growth factor receptor 2 (HER2)-enriched, and (4) basal-like, which have critical differences in incidence, response to treatment, disease progression, survival, and imaging features. Luminal tumors are most common (60%-70%), characterized by estrogen receptor (ER) expression. Luminal A tumors have the best prognosis of all subtypes, whereas patients with luminal B tumors have significantly shorter overall and disease-free survival. Distinguishing between these tumors is important because luminal B tumors require more aggressive treatment. Both commonly present as irregular masses without associated calcifications at mammography; however, luminal B tumors more commonly demonstrate axillary involvement at diagnosis. HER2-enriched tumors are characterized by overexpression of the HER2 oncogene and low-to-absent ER expression. HER2+ disease carries a poor prognosis, but the development of anti-HER2 therapies has greatly improved outcomes for women with HER2+ breast cancer. HER2+ tumors most commonly present as spiculated masses with pleomorphic calcifications or as calcifications alone. Basal-like cancers (15% of all invasive breast cancers) predominate among "triple negative" cancers, which lack ER, progesterone receptor (PR), and HER2 expression. Basal-like cancers are frequently high-grade, large at diagnosis, with high rates of recurrence. Although imaging commonly reveals irregular masses with ill-defined or spiculated margins, some circumscribed basal-like tumors can be mistaken for benign lesions. Incorporating biomarker data (histologic grade, ER/PR/HER2 status, and multigene assays) into classic anatomic tumor, node, metastasis (TNM) staging can better inform clinical management of this heterogeneous disease.

Breast Cancer Detection and Treatment Monitoring Using a Noninvasive Prenatal Testing Platform: Utility in Pregnant and Nonpregnant Populations.

Numerous publications have reported the incidental detection of occult malignancies upon routine noninvasive prenatal testing (NIPT). However, these studies were not designed to evaluate the NIPT performance for cancer detection. We investigated the sensitivity of a genome-wide NIPT pipeline, called GIPSeq, for detecting cancer-specific copy number alterations (CNAs) in plasma tumor DNA (ctDNA) of patients with breast cancer. To assess whether a pregnancy itself, with fetal cell-free DNA (cfDNA) in the maternal circulation, might influence the detection of ctDNA, results were compared in pregnant (n = 25) and nonpregnant (n = 25) cancer patients. Furthermore, the ability of GIPSeq to monitor treatment response was assessed. Overall GIPSeq sensitivity for detecting cancer-specific CNAs in plasma cfDNA was 26%. Fifteen percent of detected cases were asymptomatic at the time of blood sampling. GIPSeq sensitivity mainly depended on the tumor stage. Also, triple negative breast cancers (TNBC) were more frequently identified compared to hormone-positive or HER2-enriched tumors. This might be due to the presence of high-level gains and losses of cfDNA or high ctDNA loads in plasma of TNBC. Although higher GIPSeq sensitivity was noted in pregnant (36%) than in nonpregnant women (16%), the limited sample size prohibits a definite conclusion. Finally, GIPSeq profiling of cfDNA during therapy allowed monitoring of early treatment response. The results underscore the potential of NIPT-based tests, analyzing CNAs in plasma cfDNA in a genome-wide and unbiased fashion for breast cancer detection, cancer subtyping and treatment monitoring in a pregnant and nonpregnant target population.

Quantitative Mammographic Density Measurements and Molecular Subtypes in Chinese Women With Breast Cancer.

Studies investigating associations between mammographic density (MD) and breast cancer subtypes have generated mixed results. We previously showed that having extremely dense breasts was associated with the human epidermal growth factor receptor-2 (HER2)-enriched subtype in Chinese breast cancer patients. In this study, we reevaluated the MD-subtype association in 1549 Chinese breast cancer patients, using VolparaDensity software to obtain quantitative MD measures. All statistical tests were 2-sided. Compared with women with luminal A tumors, women with luminal B/HER2- (odds ratio [OR] = 1.20, 95% confidence interval [CI] = 1.04 to 1.38; P = .01), luminal B/HER2+ (OR = 1.22, 95% CI = 1.03 to 1.46; P = .03), and HER2-enriched tumors (OR = 1.30, 95% CI = 1.06 to 1.59; P = .01) had higher fibroglandular dense volume. These associations were stronger in patients with smaller tumors (<2 cm). In contrast, the triple-negative subtype was associated with lower nondense volume (OR = 0.82, 95% CI = 0.68 to 0.99; P = .04), and the association was only seen among older women (age 50 years or older). Although biological mechanisms remain to be investigated, the associations for the HER2-enriched and luminal B subtypes with increasing MD may partially explain the higher prevalence of luminal B and HER2+ breast cancers previously reported in Asian women.

Clinicopathologic Features and Survival Analysis of Non-metastatic Breast Cancer Patients in Guatemala

Background: Breast cancer (BC) is a leading cause of cancer related death worldwide. Unfortunately, data concerning clinicopathologic features of this malignancy in non-developed countries is scarce. This study aims to characterize a cohort of Guatemalan female patients with non-metastatic BC and to determine risk factors for overall survival (OS).Methods: We retrieved data on consecutive patients from the Instituto Guatemalteco de Seguridad Social that were treated from 2008 to 2014. Clinical features and long-term outcomes were retrieved from medical records. Univariate and multivariate Cox regression analyses were conducted to identify variables associated with OS. Results: 954 BC patients were identified during the time frame. A total of 436 women (46%) were younger than 50 years old. BC molecular subtypes categorized 537 patients (56.3%) with luminal A disease, 186 (19.5%) patients with triple negative tumors, 153 cases (16.1%) with HER-2 enriched tumors, and 78 patients (8.2%) with luminal B tumors. Clinical stage at presentation was stage I: 4.7% (n=45); stage II: 48.1% (n=459), and stage III: 47.2% (n=450). The overall 5-year survival rate was 75.2% (95% Confidence Interval: 72.0–78.3). In the multivariate analysis clinical stage, triple negative tumors and HER2 enriched tumors were independently associated with poor survival.Conclusion: The majority of patients with non-metastatic BC are diagnosed with advanced disease and many of them are younger than 50 years old. OS in this cohort of Guatemalan patients is lower than that reported in developed countries.

Combined LIM kinase 1 and p21-Activated kinase 4 inhibitor treatment exhibits potent preclinical antitumor efficacy in breast cancer.

LIM kinase 1 (LIMK1) and p21-activated kinase 4 (PAK4) are often over-expressed in breast tumors, which causes aggressive cancer phenotypes and unfavorable clinical outcomes. In addition to the well-defined role in regulating cell division, proliferation and invasion, the two kinases promote activation of the MAPK pathway and cause endocrine resistance through phosphorylating estrogen receptor alpha (ERα). PAK4 specifically phosphorylates LIMK1 and its functional partners, indicating possible value of suppressing both kinases in cancers that over-express PAK4 and/or LIMK1. Here, for the first time, we assessed the impact of combining LIMK1 inhibitor LIMKi 3 and PAK4 inhibitor PF-3758309 in preclinical breast cancer models. LIMK1 and PAK4 pharmacological inhibition synergistically reduced the survival of various cancer cell lines, exhibiting specific efficacy in luminal and HER2-enriched models, and suppressed development and ERα-driven signals in a BT474 xenograft model. In silico analysis demonstrated the cell lines with reliance on LIMK1 were the most prone to be susceptible to PAK4 inhibition. Double LIMK1 and PAK4 targeting therapy can be a successful therapeutic strategy for breast cancer, with a unique efficiency in the subtypes of luminal and HER2-enriched tumors.

Do histopathological features of breast cancer in Australian Indigenous women explain the survival disparity? A two decade long study in the Northern Territory.

In the Northern Territory (NT) of Australia, Indigenous women have a lower incidence of breast cancer, but a higher mortality than Non-indigenous women. The aim of this study was to describe and compare breast cancer pathological features related to stage and biological aggression between the two groups. Subjects were identified by extract from the NT Cancer Registry in two separate cohorts, cohort 1 (1991-2000) and cohort 2 (2001-2010). Data from cohort 1 included age, stage, tumor grade and estrogen receptor status (ER) and treatment completion. Additional pathological variables including tumor size, HER2 status, lymphovascular invasion and derived tumor phenotype were available for cohort 2. BivariateP values for categoric variables were calculated using Fisher's exact tests. The Wilcoxon rank-sum test was used to compare cohort 2. Logistic regression was used to calculate odds ratios. There were 359 (44 indigenous) eligible women in cohort 1 and 526 (100 indigenous) for cohort 2. In cohort 1, in both cohorts, indigenous women were more likely to present at an advanced stage, but there was no difference in ER status or tumor grade. When derived phenotypes were compared, indigenous women were less likely to have better prognosis luminal A tumors, and more likely to have HER2-enriched tumors. This two decade long comparison of the pathological features of breast cancer between indigenous and nonindigenous women of the NT has confirmed that Indigenous women not only present at a later stage than NI women but are also afflicted by poorer prognosis tumors, particularly HER2 enriched.

Multicenter Italian bone metastasis database: First prospective data on breast cancer patients.

e13072 Background: Bone Metastases (BM) are still the main cause of morbidity and morbility in cancer patients because of their complications defined as skeletal-related events (SREs).SREs reduce pts quality of life and are associated with an increasing in social and health costs. At present, data concerning BM are mainly obtained retrospectively from monocentric experiences. Methods: We performed a multicentre prospective observational study of patients with BM from breast cancer (BC) with at least 6 month (m)'s follow-up who were registered in a prospective BM database (BMDB). Detailed information on patients at first diagnosis of BM was recorded in a custom-built software system, updated every 6 m by participating centres and reviewed by the coordinator centre.All pts have signed an informed consent. Results: Since October 2014,618 pts with BM from solid tumors were enrolled of whom 220 have BC as primitive site with a 6 m follow-up. Median age was 62 y (range 26-86). Median Follow up was 34 m (6-149). At enrolment 109 (50%) had only BM and 109 (50%) pts had concomitant visceral and BM. Median time to first BM was 47 m (range 0-312) in Bone only disease and 78.6 m in pts with visceral bone metastases. Disease Free interval (DFI) was different according to BC molecular subtypes and stage. The univariate hazard ratio (HR) for visceral or bone metastasis was higher in luminal B tumors (1.56, 95% confidence interval [CI]:1.1-2.3) (p = 0.002), basal-like (2.50, 95% CI:1.1-6.0) (p = 0.043), and HER2-enriched tumors (1.37, 95% CI:0.78-2.4) (p = 0.273). DFI for pts with stage I disease at diagnosis of primary BC was longer than that for stage III pts (median 67.2 m, 95%CI:53.1-96.1, vs. 58.1 m, 95%CI:41.9-73.4), with a HR of 1.84 (95% CI:1.1-3.0) (p = 0.015) for the stage III group, and 0.98 (95% C.I.:0.6-1.5) (p = 0.930) for the stage II group. During BM disease, 98 pts had at least 1 SREs . Zoledronate was used in 69.1% and Denosumab in 28.3% of cases. First line treatment was hormone-based (n = 105, 50.7%) chemo-based therapy (n = 80, 38.7%) and chemo+ormono based (n = 20, 9.7%). During follow up progression disease occurred in 167 pts. Median progression-free (mPFS) and overall survival calculated from metastatic disease diagnosis (mOS) were 15.1 m (95%CI 12.6-18.4) and 66.8 m (95%CI 52.1-79.2),respectively. Conclusions: This study presents prospective data about a cohort of BC pts enrolled at the first BM occurrence and followed over the time, extrapolated by the multicentric observational BMDB in order to better understed the clinical history of breast cancer and bone metastases.

The association between race and intrinsic subtype on hormone receptor-positive breast cancer among young black women.

e12591 Background: Hormone receptor-positive, HER2-negative breast cancer (HR+/HER2- BC) has the highest incidence and mortality rate across all racial/ethnic groups. HR+/HER2- BC is clinically and biologically heterogenous. Gene expression profiling assays can provide prognostic information and predict risk of late recurrence among women with HR+/HER2- BC. Prior studies have shown worse clinical outcomes among black women with HR+/HER2- BC. We sought to compare the distribution of intrinsic subtypes among young black women with HR+/HER2- BC, compared to published data from a young white cohort in the Carolina Breast Cancer Study (CBCS). Methods: Two population-based cohorts of black women diagnosed with BC between 2002 to 2012 at or below age 50 years were analyzed. Participants were recruited from twelve Southeastern states. All participants were asked to complete release of medical records and tissue/tumor forms to verify clinical information and to obtain primary tumor samples for future analyses. We compared the distribution of intrinsic subtypes and associations to clinical characteristics as compared to white female counterparts using Pearson chi-squared test. Results: Of 569 black participants, 124 women had HR+/HER2- BC and tumor samples available for analysis. There were 66 Luminal A (53%), 35 Luminal B (28%), 19 Basal (15%), and 4 HER2-enriched (3%) tumors. Black women with non-Luminal A tumors were younger ( &lt; 40) with larger tumors ( &gt; 2cm) and had higher risk of recurrence (ROR-T) scores as compared to black women with Luminal A tumors (p = 0.065, 0.006, and &lt; 0.001, respectively). Compared to young white women in the CBCS, black women in our study had a significantly higher percentage of non-Luminal HR+/HER2- BC (p = 0.037). Conclusions: Our results suggest that among young women with HR+/HER2- BC, black women have a higher proportion of non-Luminal tumors compared to their white counterparts. Non-Luminal HR+/HER2- tumors (i.e., basal and HER2-enriched) are more aggressive and may be less sensitive to endocrine therapy. These results suggest that overrepresentation of aggressive HR+/HER2- BC subtypes may contribute to the racial survival disparity observed among black women.

The Prosigna 50-gene profile and responsiveness to adjuvant anthracycline-based chemotherapy in high-risk breast cancer patients

The DBCG89D trial randomized high-risk early breast cancer patients to adjuvant CMF (cyclophosphamide, methotrexate and fluorouracil) or CEF (cyclophosphamide, epirubicin and fluorouracil). Prosigna assays were performed by researchers with no access to clinical data. Time to distant recurrence (DR) was the primary endpoint, time to recurrence (TR) and overall survival (OS) secondary. Among the 980 Danish patients enrolled, Prosigna results were obtained in 686. Continuous ROR score was associated with DR for CMF (adjusted hazard ratio (HR) 1.20, 95% CI 1.09–1.33), and for CEF (HR 1.04, 95% CI 0.92–1.18), Pinteraction = 0.06. DR was significantly longer in CEF compared to CMF treated patients with Her2-enriched tumors (HR 0.58, 95% CI 0.38–0.86), but not in patients with luminal tumors. Heterogeneity of treatment effect was significant for TR and OS. In this prospective-retrospective analysis, patients with Her2-enriched breast cancer derived substantial benefit from anthracycline chemotherapy whereas anthracyclines are not an essential component of chemotherapy for patients with luminal subtypes. The benefit of CEF vs. CMF correlated with increasing ROR Score.

Abstract P5-08-20: Association between quantitative mammographic density and breast cancer subtypes among Chinese breast cancer patients

Abstract High mammographic density (MD) is a strong risk factor for breast cancer; however, data on the association between MD and breast cancer subtypes has been inconsistent and most studies have been conducted using data from Western women. Studies have shown that Asian women, who in general have denser breasts compared with Western women, were more likely to develop luminal B and HER2-enriched tumors. We previously reported that higher MD, assessed using Breast Imaging Reporting and Data System (BI-RADS) categories, was associated with HER2-enriched tumors among Chinese breast cancer patients, which may at least partially explain the higher incidence of HER2-enriched tumors observed in Asian women. Since BI-RADS MD measurement is categorical and known to be subjective, in this study, we aimed to re-evaluate the MD-subtype association using an automated quantitative density metric. The analysis included 1,549 women with invasive breast cancer who were diagnosed and treated in a tertiary hospital in Beijing, China. Subtypes were defined as Luminal A (n=606): ER+ and PR+, HER2-, and low Ki-67 (&amp;lt;30% positive staining)/grade (grades 1 or 2); luminal B/HER2- (n=446): ER+ and/or PR+, HER2-, and high Ki-67 (≥30%)/grade (grade 3); luminal B/HER2+ (n=182): ER+ and/or PR+, HER2+ (regardless of Ki-67/grade); HER2-enriched (n=121): ER-, PR-, and HER2+; Triple-negative (TN, n=194): ER-, PR-, and HER2-. Quantitative measures of MD for the contralateral unaffected breast, including total breast volume, fibroglandular volume, and Volpara Density Grade (VDG, based on predetermined cut-points from volumetric percent density that shows moderate agreement with visual BI-RADS categories), were obtained using VolparaDensity software. Polychotomous logistic regression was used to assess the association between MD (per 1-unit standard deviation increase) and breast cancer subtypes with the adjustment of age, menopausal status, parity, and body mass index (BMI). Compared with luminal A cases, cases with luminal B/HER2- (Odds ratio [OR], 1.15; 95% confidence interval [CI], 1.01-1.32; p=0.04), luminal B/HER2+ (OR, 1.22; 95% CI, 1.02-1.44; p=0.03), and HER2-enriched (OR, 1.32; 95% CI, 1.08-1.60; p=0.01) tumors had significantly higher fibroglandular dense volume, and these associations were stronger in women with normal BMI. In contrast, cases with TN tumors had lower non-dense volume compared with luminal A cases (OR, 0.83; 95% CI, 0.69-1.00; p=0.05). Percent density did not vary significantly by subtypes. When comparing dense versus non-dense breasts using VDG, we found that dense breasts were significantly associated with HER2-enriched tumors (OR, 2.49; 95% CI, 1.40-4.42; p=0.002). Our data suggest that increasing dense volume was associated with luminal B and HER2-enriched subtypes among Chinese breast cancer cases. These results may provide insight into the distinct distribution of breast cancer subtypes in Asian populations. Citation Format: Xiaohong R Yang, Yuan Tian, Jennifer Guida, Hela Koka, Ariane Chan, Changyuan Guo, Erni Li, Eric Tang, Hyuna Sung, Ning Lu, Nan Hu, Gretchen Gierach, Jing Li. Association between quantitative mammographic density and breast cancer subtypes among Chinese breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-08-20.

Abstract P3-08-07: Expression of the novel tumor suppressor gene SAMHD1 correlates with favourable clinical outcome in basal-like (BL) early breast cancer

Abstract Introduction: The SAM domain and HD domain 1 (SAMHD1) protein is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase initially described to restrict human immunodeficiency virus type 1 (HIV-1) in the immune cells through depletion of intracellular dNTP substrates required for HIV-1 replication. Because of its ability to deplete the dNTP pool, SAMHD1 may operate as a tumor suppressor in cancer. Mutations of SAMHD1 gene have been associated with Aicardi-Goutières syndrome and have been detected in certain hematologic malignancies. However, the potential role of SAMHD1 in breast oncogenesis as well as its expression patterns and clinical significance are not yet known. Methods: SAMHD1 expression was investigated at the mRNA and protein levels in a large cohort consisting of 562 patients diagnosed with primary breast cancer between 1997-2005 in Stockholm health care region. Gene expression profiling was performed using DNA microarrays (GSE48091). SAMHD1 protein expression was assessed by a previously validated double immunostaining method (SAMHD1/CD68) using tissue microarrays (TMA) that included duplicate cores from each tumor and specific antibody (SAMHD1, Bethyl laboratories; #A303-691A). CD68+ macrophages known to be strongly positive for SAMHD1 served as positive controls in each tumor core. Any nuclear staining for SAMHD1 was considered positive with either weak (1), intermediate (2), or strong (3) staining intensity. At least 500 neoplastic cells were counted in order to determine the percentage of SAMHD1+ tumor cells. The latter was combined with the staining intensity into the quickscore method, and a positive cutoff of greater or equal to 3 was used to dichotomize SAMHD1 protein expression. Survival analyses were performed using the Kaplan-Meier method (SAMHD1 mRNA level cutoff: median) and Cox proportional hazards models (univariate and multivariable analysis; SAMHD1 mRNA level was evaluated as continuous variable). Distant metastasis-free survival (DMFS) was used as the clinical endpoint. Results: Evaluable immunohistochemical (IHC) data for SAMHD1 were available for 439 of 562 (78%) patients. In the entire study group, SAMHD1 mRNA and protein levels were significantly correlated (Mann-Whitney p=5.2e-5). SAMHD1 mRNA level was higher in HER2-enriched (PAM50) tumors compared to the other subtypes (Kruskal-Wallis p=2.5e-12). By IHC, SAMHD1 was positive in 33/192 (17%) Luminal A, 17/85 (20%) Luminal B, 10/49 (20%) HER2-enriched, and 26/99 (26%) basal-like (BL). In the entire cohort, SAMHD1 expression was not associated with DMFS. However, in the group of BL subtype (n=122), high SAMHD1 mRNA level (logrank p=0.026) or SAMHD1 protein expression (logrank p=0.025) were associated with favourable DMFS. Using the Cox proportional hazards model, high SAMHD1 mRNA level (HR=0.68; 95% CI=0.48-0.96; p=0.029) and high SAMHD1 protein expression (HR=0.22; 95% CI=0.05-0.95; p=0.042; reference: SAMHD1 negative) were associated with improved survival in patients with BL subtype of breast cancer. In the multivariable analysis, SAMHD1 mRNA level was independently associated with survival (HR=0.66; 95% CI=0.47-0.94; p=0.021), after adjustment for lymph node status and tumor size, along with lymph node status (HR: 3.29; 95% CI=1.58-6.83; p=0.001; reference: lymph node negative) in the BL subgroup. At the meeting we will also present data on prognosis in relation to given adjuvant therapies.Conclusions: SAMHD1 gene is differentially expressed at the mRNA and protein levels among the breast cancer subtypes. SAMHD1 expression is significantly and independently associated with favourable clinical outcomes in breast cancer of BL subtype. Citation Format: Maria Kouvaraki, Emmanuil G Sifakis, Ioannis Zerdes, Nikolas Herold, Jonas Bergh, George Z. Rassidakis, Theodoros Foukakis. Expression of the novel tumor suppressor gene SAMHD1 correlates with favourable clinical outcome in basal-like (BL) early breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-07.

Abstract P2-08-27: Clinicopathologic characteristics of native vs. foreign-born breast cancer patients in a contemporary cohort

Abstract Introduction: Previous studies have found clinicopathologic differences in foreign-born women diagnosed with breast cancer compared to those who are native to the United States. A few studies have documented that the foreign-born women with breast cancer have limited information regarding their family history due to decreased contact with their relatives. The purpose of our study was to look at a contemporary cohort of women who are newly diagnosed with breast cancer and compare the clinical and tumor characteristics among the women who are foreign-born compared to those who are born in US in our institution. Methods: The Institutional Breast Cancer Database includes patients diagnosed with breast cancer between 2010-2018. Variables of interest included nativity and clinical and tumor characteristics. Statistical analyses included age and race adjusted logistic regression at the α=0.05 level. Results: Out of 3,199 BC patients, 984 (30.8%) were foreign-born and 2215 (69.2%) were native-born. We found that the foreign-born patients immigrated to the US mainly from Europe (35.7%), Asia (32.8%), and Central/South America (26.1%). Compared to the native-born patients, there was a significantly higher proportion of foreign-born patients with minority race (p&amp;lt;0.001), lower education (p&amp;lt;0.001), and lower income (&amp;lt;0.001). Foreign-born patients were less likely to have a personal history of BC (OR=0.70, 95% 0.52-0.95, p=0.020), personal history of other cancer (OR=0.68, 95% CI 0.52-0.88, p=0.003), family history of BC (FHBC) with a first-degree relative (OR=0.66, 95% CI 0.55-0.80, p&amp;lt;0.001) or have undergone genetic testing (OR=0.52, 95% 0.43-0.64, p&amp;lt;0.001). Upon further investigation of the personal history of other cancers, we found that the native-born patients were significantly more likely to have a previous history of skin cancer (OR=2.93, 95% CI 1.76-4.87, p&amp;lt;0.001). Foreign-born patients were more likely to have HER2 enriched molecular subtype (OR=1.69, 95% CI 1.09-2.61, p=0.049). Among those with hormone sensitive cancers, the foreign-born patients were more likely to have a lower Oncotype Dx Recurrence Score &amp;lt;18 (OR=1.67, 95% CI 1.15-2.42, p=0.021). Age at diagnosis, BRCA1/2 status, palpability, tumor stage, histology, tumor size, Ki-67, and recurrence were not significantly different between the foreign and native-born cohorts. Conclusions: In a contemporary cohort of women with newly diagnosed breast cancer, we found that our foreign-born patients appeared to have adequate information regarding their family history of breast cancer. This may be a result of enhanced digital and global communication in the 21st century. There was a significantly higher proportion of native-born patients with a strong FHBC (17.4% vs. 9.7%). We also found a significant proportion of foreign-born patients to have ER/PR-negative and HER2 enriched tumor molecular subtypes (10.6% vs. 6.3%). This observation did not reflect a higher proportion of BRCA mutation carriers, suggesting other possible mechanisms for this finding. Further investigation is warranted in a larger global cohort of foreign-born breast cancer patients from diverse populations, including Africa and the Middle-East. Citation Format: Jennifer Chun, Elianna Kaplowitz, Grace Gibbon, Jenny Goodgal, Amber Guth, Deborah Axelrod, Daniel Roses, Richard Shapiro, Freya Schnabel. Clinicopathologic characteristics of native vs. foreign-born breast cancer patients in a contemporary cohort [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-08-27.

Abstract P4-07-01: Tumor expression and microenvironment in HER2-positive breast cancer before and on HER2-targeted therapy: Analysis of microarray expression data from the TRIO-US B07 trial

Abstract Background: Neoadjuvant HER2-targeted therapy in combination with chemotherapy is a standard treatment approach for early-stage HER2-positive breast cancer. Proposed biomarkers to predict pathologic complete response (pCR), and thereby inform which patients may benefit from de-escalation of therapy, include expression-based subtyping and immune enrichment scores. Little is known about how tumors and their microenvironment may change with HER2-targeted therapy alone, and whether these changes may predict outcome. Methods: The TRIO-US B07 phase II trial randomized 128 participants with stage I-III HER2-positive breast cancer to trastuzumab (N=34), lapatinib (N=36), or the combination (N=58) for three weeks, followed by six cycles of docetaxel and carboplatin with continued HER2-targeted therapy. Fresh-frozen core biopsies of the tumor prior to therapy (N=110) and after 14-21 days of HER2-targeted therapy alone (N=89) were collected, and RNA was extracted and subjected to Agilent Whole Human Genome 44K 2-color chip. The pre-treatment tumor RNA was normalized against a mixed breast tumor reference, and the on-treatment tumor RNA against the matched pre-treatment sample. Absolute intrinsic molecular subtyping was used to determine intrinsic subtype, the iC10 expression-based classifier to determine integrative subtype, gene set enrichment analysis (GSEA) to assess signature changes across treatment, single-sample GSEA to compare individual gene signature scores between tumors, and CIBERSORT to quantify immune cell populations before and on treatment. Results: Primary trial results have been reported previously and showed a pCR rate of 47% with trastuzumab, 25% with lapatinib, and 52% with the combination. Prior to treatment, 56% of tumors classified as the HER2-enriched intrinsic subtype and 78% as the iC5 integrative subtype. HER2-enriched tumors trended toward a higher rate of pCR relative to other intrinsic subtypes (50% vs 33%, P=0.12), as did iC5 tumors relative to other integrative subtypes (48% vs 25%, P=0.08). However, in multivariate analysis, HER2 FISH ratio (P=0.04) and hormone receptor status (P=0.02), each associated themselves with intrinsic and integrative subtype, proved the most valuable in predicting pCR, with little information added by expression-based subtyping. Immune cell signatures correlated with pCR in the trastuzumab-containing arms only. Of 65 gene signatures tested, 47 changed across HER2-targeted therapy with false discovery rate &amp;lt; 0.1, driven by decreasing tumor proliferation, increasing immune cell signatures, and increasing stromal cell/epithelial mesenchymal transition signatures. Quantification of immune cell populations suggested the immune changes were both anti-tumor (CD8+ T cells) and pro-tumor (M2 macrophages). Intrinsic subtype changed in 54% of tumors (79% of these converting to normal-like) and integrative subtype changed in 26%. Change in subtype, proliferation, or immune infiltration with targeted therapy did not correlate with pCR. A higher proportion of tumors treated with trastuzumab alone maintained their proliferation (42%), compared with lapatinib alone (20%; P=0.16) or the combination (16%; P=0.04). Conclusions: In the TRIO-US B07 study, the biomarkers most predictive of response to neoadjuvant HER2-targeted therapy were hormone receptor status in combination with HER2 FISH ratio. Multiple changes in the tumor and its microenvironment occurred with HER2-targeted therapy, but these changes did not predict pCR. Tumors treated with lapatinib tended to decrease proliferation more than tumors treated with trastuzumab, despite trastuzumab being more effective in preventing recurrence, an observation with implications for window of opportunity studies. Citation Format: Jennifer L. Caswell-Jin, Katherine L. McNamara, Judy Dering, Hsiao-Wang Chen, Robert Dichmann, Alejandra Perez, Ravindranath Patel, Eran Kotler, Jason J. Zoeller, Joan S. Brugge, Michael F. Press, Dennis J. Slamon, Christina Curtis, Sara A. Hurvitz. Tumor expression and microenvironment in HER2-positive breast cancer before and on HER2-targeted therapy: Analysis of microarray expression data from the TRIO-US B07 trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-07-01.

Mammography correlates to better survival rates in breast cancer patients: a 20-year experience in a University health institution.

Breast cancer (BC) is the most common malignancy in women. We retrieved medical records from >2,000 Chilean BC patients over the 1997–2018 period. The objective was to assess changes in clinical presentation or prognosis of our patients throughout these 20 years of practice. Although most variables did not display significant variations, we observed a progressive increase in stage IV BC over this period. Our data showed that tumour stage III/IV or HER2-enriched subtype tumours were associated with poorer prognosis. In contrast, we found that patients diagnosed by mammography had better overall survival. We speculate that better screenings and more sensitive imaging could explain the unexpected rise in stage IV cases. Our results support mammography screenings as an effective measure to reduce BC-related mortality.

Phenotypic changes of HER2-positive breast cancer during and after dual HER2 blockade

The HER2-enriched (HER2-E) subtype within HER2-positive (HER2+) breast cancer is highly addicted to the HER2 pathway. However, ∼20–60% of HER2+/HER2-E tumors do not achieve a complete response following anti-HER2 therapies. Here we evaluate gene expression data before, during and after neoadjuvant treatment with lapatinib and trastuzumab in HER2+/HER2-E tumors of the PAMELA trial and breast cancer cell lines. Our results reveal that dual HER2 blockade in HER2-E disease induces a low-proliferative Luminal A phenotype both in patient’s tumors and in vitro models. These biological changes are more evident in hormone receptor-positive (HR+) disease compared to HR-negative disease. Interestingly, increasing the luminal phenotype with anti-HER2 therapy increased sensitivity to CDK4/6 inhibition. Finally, discontinuation of HER2-targeted therapy in vitro, or acquired resistance to anti-HER2 therapy, leads to restoration of the original HER2-E phenotype. Our findings support the use of maintenance anti-HER2 therapy and the therapeutic exploitation of subtype switching with CDK4/6 inhibition.