Receptor-negative Tumors Research Articles

Estrogen Receptor Positive and Progesterone Receptor Negative Breast Cancer: the Role of Hormone Therapy.

ER+/PR- (estrogen receptor positive and progesterone receptor negative) tumors constitute only a small portion of the breast cancer population. Patients with ER+/PR- tumors, however, are characterized by worse survival compared to patients with ER+/PR+ (estrogen receptor positive and progesterone receptor positive) tumors. Controversy exists regarding the efficacy of hormone blocking therapy for patients with ER+/PR- tumors. The NCDB was queried between 2004 and 2015, and patients with invasive ER+/PR- tumors were identified. We employed univariate Cox proportional hazards to compare outcomes among patients that did or did not receive hormone blocking therapy. We identified 138,398 patients with invasive ER+/PR- tumors, 32,044 (23%) of whom did not receive hormone blocking therapy. The reasons for not receiving hormone blocking therapy included contraindications to treatment, death, patient refusal, and unknown. There were no significant differences in race, income quartile, or education quartile between patients who did and did not receive hormone blocking therapy. Patients who did not receive hormone blocking therapy underwent surgical assessment of the axilla more frequently than those who did receive hormone therapy. Our analysis demonstrated that hormone blocking therapy administration was associated with increased overall survival for up to 10years of follow up (HR: 0.58; 95% CI: 0.56-0.59, p < 0.001). Hormone blocking therapy may be associated with increased survival for breast cancer patients with ER+/PR- tumors. Although this benefit may last for years after completion of the course, up to 25% of patients do not receive this treatment. Strategies to increase the utilization and adherence to hormone blocking therapy regimens may improve patient survival outcomes.

Abstract D094: Associations among state-level racial inequality, individual-level unfair treatment, and incident breast cancer in a risk-enriched cohort

Abstract Background: There is a small but growing body of evidence suggesting that structural inequality is associated with racial disparities in breast cancer stage at diagnosis and mortality. Less is known about the potential relationship between structural inequality and breast cancer incidence or subtypes. To address this gap, we developed a multidimensional state-level measure of racial inequality and assessed whether higher levels of inequality are associated with 1) higher odds of an invasive breast cancer diagnosis, and 2) among those diagnosed, higher odds of an estrogen receptor negative (ER-) vs. positive (ER+) tumor. Methods: The Sister Study is a longitudinal cohort of women who had a sister diagnosed with breast cancer, but did not have a personal history of the disease at enrollment. Leveraging this cohort, we generated state-level composite scores (range = 1-5) summarizing differences between non-Hispanic white and black residents across four domains: educational attainment, employment &amp; occupational status, political participation, and incarceration. Data for the racial inequality measure were drawn from publicly available sources and linked to the participants’ state of residence at the time of enrollment. An individual-level measure of unfair treatment due to race was included as a proximal exposure to racial inequality. Invasive breast cancer diagnoses and subtypes were recorded through September 2016. The final analytic sample was limited to non-Hispanic white (n= 38,760) and black (n=4,061) Sister Study participants and their states of residence (n=40). Two-level population average models were constructed to assess the relationship among state- and individual-level factors and the odds of 1) an invasive breast cancer diagnosis (n=1,475) and 2) ER subtype among women with invasive breast cancer (1,278 ER+ cases; 197 ER- cases). Results: Adjusting for self-reported race, education, age, and epidemiologic risk factors (e.g., breast feeding history, menopausal status), we found that women residing in states with higher levels of racial inequality did not have higher odds of invasive breast cancer. However, among women diagnosed with an invasive breast cancer, we found higher odds of ER- vs. ER+ subtype among women living in states with higher levels of racial inequality (OR range = 1.7 – 2.6 for inequality composite scores of 3-5 vs. 1; p-values of &amp;lt;0.001 to 0.04). The proximal measure of unfair treatment due to race was also a significant factor in the fully-adjusted model, with women reporting 2 or more incidents of unfair treatment having a 2.6 times higher odds of an ER- diagnosis than women reporting no such incidents. Conclusions: In this relatively small sample of invasive breast cancer cases, structural and interpersonal experiences with racial inequality were associated with greater odds of the ER- vs. ER+ subtype, but not with the overall odds of an invasive breast cancer diagnosis. Reanalysis using a longer follow-up period may provide greater insight into this novel association. Citation Format: Erin Linnenbringer, Sarah Humble, Sarah Gehlert, Dale P Sandler. Associations among state-level racial inequality, individual-level unfair treatment, and incident breast cancer in a risk-enriched cohort [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D094.

Abstract C046: Dietary calcium and vitamin D and sun exposure with the risk of breast cancer among African American women

Abstract Background: Compared to European American women, African American (AA) women have a higher incidence of breast cancer (BrCa) under age 45, and are more likely to develop estrogen receptor-negative (ER-) tumors, a more aggressive BrCa subtype. Experimental studies drew attention to the potential antitumorigenic properties of calcium and vitamin D. Darker skin color reduces the cutaneous synthesis of vitamin D upon sun exposure. This, together with the tendency of AAs to consume less vitamin D and calcium from food and supplement sources, places AAs at risk for vitamin D and calcium deficiency. However, data are limited regarding the impact of calcium and vitamin D on risk of BrCa and specific subtypes among AA women. Objective: To evaluate calcium intake and vitamin D exposure (through food, supplements and sunlight) with the risk of BrCa and its subtypes among AA women. Methods: We evaluated these associations among 1033 BrCa cases and 391 controls of AA descent recruited since March 2012 in the Women's Circle of Health Study. Cases were identified by rapid case ascertainment in 10 counties in New Jersey. Controls were identified by random-digit-dialing and community-based recruitment, and were frequency matched by age group and county of residence. Dietary information over the year prior to diagnosis (for cases) or the reference date (for controls) was assessed via a validated food frequency questionnaire through in-person interviews. Supplemental intakes including multivitamin sources and daily hours spent outdoors in daylight were also collected. Hormone receptor status was obtained from pathology reports. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) adjusting for relevant sociodemographic, reproductive, and lifestyle risk factors. Results: Vitamin D intake from food was not associated with BrCa risk. However, for supplemental vitamin D intake, we observed a significant decreased overall BrCa risk for users of ≤800 IU/day vs. nonusers (OR=0.73, 95% CI: 0.54, 0.98), which was limited to estrogen receptor-positive (ER+) BrCa (OR=0.69, 95% CI: 0.50, 0.94), but not for ER- or triple-negative BrCa. More daylight hours spent outdoors in a year predicted a lower risk of pre- and postmenopausal BrCa [comparing the highest quartile (Q4) vs. lowest (Q1): OR=0.37, 95% CI: 0.20-0.68, p-trend: 0.002; OR=0.46, 95% CI: 0.30-0.71, p-trend: 0.001, respectively]. The significant inverse associations were observed for both ER+ and ER- BrCa, but not for triple-negative BrCa. Calcium intake was not associated with BrCa risk. Conclusion: Our findings suggest that moderate intake of supplemental vitamin D may decrease the risk of ER+ BrCa. Sun exposure may decrease the risk of BrCa among AA women, which does not appear to differ by menopausal status and ER status. Citation Format: Bo Qin, Baichen Xu, Nan Ji, Karen Pawlish, Song Yao, Christine Ambrosone, Kitaw Demissie, Chi-Chen Hong, Elisa V. Bandera. Dietary calcium and vitamin D and sun exposure with the risk of breast cancer among African American women [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C046.

Human epidermal growth factor receptor 2 positive rates in invasive lobular breast carcinoma: The Singapore experience.

BACKGROUNDInvasive lobular carcinomas (ILC) form 5%-10% of breast cancer and rarely show overexpression of human epidermal growth factor receptor 2 (HER2).AIMTo describe the prevalence and prognostic factors of HER2 positive (HER2+) ILC in an Asian population.METHODSA retrospective review of patients with ILC seen between January 1985 and March 2018 at various SingHealth medical institutions was conducted. Demographic and clinical data were collected from medical records. We examined clinicopathological characteristics and survival in relation to HER2 status.RESULTSA total of 864 patients were included. Prevalence of HER2 positivity was 10.1% (87 patients). Compared with HER2 negative (HER2-) ILC, HER2+ ILC was associated with a higher proportion of estrogen receptor negative (24.4% vs 5.9%, P < 0.001), progesterone receptor negative (PR-) (40.2% vs 24%, P = 0.002) and grade 3 tumours (Grade 3, 29.0% vs 10.2%, P < 0.001). Overall survival rate was poorer in patients with HER2+ compared to HER2- ILC (56.7% vs 72.9% alive at 10 years; hazard ratio 1.87, 95% confidence interval: 1.21-2.90, P = 0.004). Based on multivariate analysis, negative prognostic factors for overall survival included HER2 positivity, PR negativity, older age, Indian ethnicity and higher tumour stage.CONCLUSIONPrevalence of HER2+ ILC was 10.1%. HER2+ ILC was more likely to have poorer prognostic features such as estrogen receptor negative, PR- and higher tumour grade, and have a poorer survival.

Prediction of pathologic complete response using image-guided biopsy after neoadjuvant chemotherapy in breast cancer patients selected based on MRI findings: a prospective feasibility trial.

Accurate prediction of pathologic complete response (pCR) in breast cancer using magnetic resonance imaging (MRI) and ultrasound (US)-guided biopsy may aid in selecting patients who forego surgery for breast cancer. We evaluated the accuracy of US-guided biopsy aided by MRI in predicting pCR in the breast after neoadjuvant chemotherapy (NAC). After completion of NAC, 40 patients with near pCR (either tumor size ≤ 0.5cm or lesion-to-background signal enhancement ratio (L-to-B SER) ≤ 1.6 on MRI) and no diffused residual microcalcifications were prospectively enrolled at a single institution. US-guided multiple core needle biopsy (CNB) or vacuum-assisted biopsy (VAB) of the tumor bed, followed by standard surgical excision, was performed. Matched biopsy and surgical specimens were compared to assess pCR. The negative predictive value (NPV), accuracy, and false-negative rate (FNR) were analyzed. pCR was confirmed in 27 (67.5%) surgical specimens. Preoperative biopsy had an NPV, accuracy, and FNR of 87.1%, 90.0%, and 30.8%, respectively. NPV for hormone receptor-negative and hormonereceptor-positive tumors were 83.3% and 100%, respectively. Obtaining at least 5 biopsy cores based on tumor size ≤ 0.5cm and an L-to-B SER of ≤ 1.6 on MRI (27 patients) resulted in 100% NPV and accuracy. No differences in accuracy were noted between CNB and VAB (90% vs. 90%). Investigation using stringent MRI criteria and ultrasound-guided biopsy could accurately predict patients with pCR after NAC. A larger prospective clinical trial evaluating the clinical safety of breast surgery omission after NAC in selected patients will be conducted based on these findings.

Evaluation of pathogenetic mutations in breast cancer predisposition genes in population-based studies conducted among Chinese women

PurposeLimited studies have been conducted to evaluate pathogenetic mutations in breast cancer predisposition genes among Chinese women. To fully characterize germline mutations of these genes in this population, we used the whole-exome sequencing data in a population-based case–control study conducted in Shanghai, China.MethodsWe evaluated exonic, splicing, and copy number variants in 11 established and 14 candidate breast cancer predisposition genes in 831 invasive breast cancer cases and 839 controls. We identified 55 pathogenic variants, including 15 newly identified in this study.ResultsApproximately 8% of the cases and 0.6% of the cancer-free controls carried these pathogenetic variants (P = 3.05 × 10−15). Among cases, 3.7% had a BRCA2 pathogenic variant and 1.6% had a BRCA1 pathogenic variant, while 2.5% had a pathogenic variant in other genes including ATM, CHEK2, NBN, NF1, CDH1, PALB2, PTEN, TP53 as well as BARD1, BRIP, and RAD51D. Patients with BRCA1/2 pathogenic variants were more likely to have a family history of breast cancer and hormone receptor negative tumors compared with patients without pathogenic variants.ConclusionsThis study highlighted the importance of hereditary breast cancer genes in the breast cancer etiology in this understudied population. Together with previous studies in East Asian women, this study suggested a relatively more prominent role of BRCA2 compared to BRCA1. This study also provides additional evidence to design cost-efficient genetic testing among Chinese women for risk assessment and early detection of breast cancer.

Preoperative Predictive Factors of Positive Margin Status After Breast Conserving Therapy (BCT) with Intraoperative Radiation Therapy (IORT): A Retrospective Study of 400 Patients

IntroductionSingle-fraction intraoperative radiation therapy (IORT) has emerged as a therapeutic option in patients undergoing breast conserving therapy (BCT) for early stage breast cancer, often eliminating the need for postoperative external beam radiation therapy. However, if a positive margin is encountered after BCT, the patient will ultimately require external beam radiation therapy. The purpose of this study was to identify preoperative factors from patient demographics, preoperative workup, or biopsy results that may be predictive of postoperative margin status. Materials and MethodsA retrospective chart review was performed on 396 patients who underwent BCT with IORT. Logistic regression models were utilized for statistical analysis. ResultsThe majority of studied variables were similar; however, differences were noted for high-grade tumors, in situ status, and progesterone receptor-negative (PR−) tumors. Grade 3 tumors were significantly associated with positive margin status when compared with Grade 1 (odds ratio, 2.30; P = .036). PR− status tumors were found to be approximately 2 times more likely to have a positive margin (P = .028). Patients with in situ (stage 0) status tumors were 1.986 times more likely to have positive margins when compared with those with an invasive tumor (P = .030). ConclusionsHigher grade PR− tumors are at increased risk of having a positive margin, which should be taken into consideration when considering treatment with IORT.

Dose-dense adjuvant chemotherapy in early breast cancer patients: 15-year results of the Phase 3 Mammella InterGruppo (MIG)-1 study

BackgroundAdjuvant chemotherapy is the standard of care in high-risk early breast cancer patients. Dose-dense should be the preferred schedule of administration. However, its long-term benefit is unknown.MethodsIn the Italian multicentre Phase 3 randomised MIG-1 trial, node-positive and high-risk node- negative breast cancer patients were randomised to receive six cycles of adjuvant fluorouracil, epirubicin and cyclophosphamide regimen administered every 3 (FEC21) or 2 (FEC14) weeks. The primary endpoint was overall survival (OS), and the secondary endpoint was event-free survival (EFS).ResultsFrom 1992 to 1997, 1214 patients were included. Median follow-up was 15.8 years. In all, 15-year OS was 71% and 68% in the FEC14 and FEC21 groups, respectively (HR = 0.89; p = 0.25). In all, 15-year EFS was 47% and 43% in the FEC14 and FEC21 groups, respectively (HR = 0.87; p = 0.18). In a pre-planned subgroup analysis, among patients with hormone receptor-negative tumours, 15-year OS was 70% and 65% in the FEC14 and FEC21 groups, respectively (HR = 0.73; 95% CI: 0.51–1.06); 15-year EFS was 58% and 43% in the FEC14 and FEC21 groups, respectively (HR = 0.70; 95% CI: 0.51–0.96).ConclusionsUpdated results from the MIG-1 study are numerically in favour of dose-dense chemotherapy, and suggest a long-term benefit of this approach in high-risk early breast cancer patients.

Abstract P5-01-25: Potential prognostic value of exosomal Beta Protein 1 in breast cancer

Abstract Background: Beta protein 1 (BP1), discovered in our lab, is an isoform protein of the DLX4 gene that is a member of the homeobox gene family. Previous work showed BP1 mRNA was activated in 80% of invasive ductal breast (IDC) tumors, where 100% of estrogen receptor (ER) negative tumor tissues and 73% of ER positive tumor tissues were BP1 positive. Moreover, high BP1 levels were associated with tumor cell survival, breast cancer aggressiveness and metastasis. BP1 overexpression was found to stimulate known oncogenes including BCL2 and c-Myc. Exosomes are nano-sized membrane-bound vesicles released by various cells and play important roles in intercellular communication. In addition, researchers found that exosomal proteins have unique characteristics compared to traditional biomarkers for carcinoma diagnosis and prognosis. Therefore, we hypothesized that BP1 protein may be packed in exosomes, and analysis of exosomal BP1 protein could provide a novel biomarker for diagnosis or prognosis of breast cancer. Materials and Methods: Exosomes were isolated using the commercially available Exosome Precipitation Solution. In cell line experiments, fluorescent immunohistochemistry was used to detect the location of BP1 protein. Levels of BP1 protein were determined in cell extracts (CE) and conditioned media (CM) using Western Blot analysis. The hypothesis that exosomal BP1 protein may be related to the development of breast cancer was investigated with clinical serum samples purchased from Capital Bioscience. Total exosomal protein levels in the serum were analyzed using BCA assay, and exosomal BP1 protein levels were determined using Western blot. In order to develop a method that could be easily used in the clinic, an ELISA assay was also designed to assess exosomal BP1 protein concentrations in the serum from metastatic breast cancer patients and normal controls. Results: It was observed that BP1 protein is localized to the nucleus, the cytoplasm and the conditioned media of MCF-7 cells. In addition, experiments with cell lines showed that the secreted BP1 protein could be internalized by cells and exhibited mitogenic activity, which is related to cancer metastasis. Moreover, it was observed that exosomal BP1 is included in secreted BP1 protein in the conditioned media. Experiments with serum samples demonstrated that the total exosomal protein levels have no significant differences between that in breast cancer patients and in normal controls. However, the results of Western blot and ELISA both showed exosomal BP1 protein levels were significantly higher in breast cancer samples compared to normal controls (P &amp;lt; 0.05). Moreover, Western blot results suggested that ER positive patients have much more (P &amp;lt; 0.05) exosomal BP1 protein in the serum compared to ER negative patients. Conclusion: It was shown for the first time that BP1 protein is exosomally packaged in breast cancer patients’ serum. The significant difference in the exosomal BP1 protein levels between the serum from women with metastatic breast cancer and that from normal controls indicated that exosomal BP1 protein in the serum could be a potential prognostic biomarker for breast cancer. Furthermore, the ELISA assay, designed to be easily used for exosomal BP1 protein quantification, may have many uses in the clinic through aiding in prognosis, monitoring therapy and early detection. Citation Format: Yaoxian Lou, Paul Goldsmith, Jinguen Rheey, Patricia E. Berg. Potential prognostic value of exosomal Beta Protein 1 in 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 P5-01-25.

Abstract P2-16-32: A phase 2 study of de-escalated neoadjuvant therapy with nanoparticle albumin-bound paclitaxel and trastuzumab for low risk pure HER2 breast cancer

Abstract Background: Neoadjuvant anti-HER2 target agents combined with anthracycline and taxane is now considered a standard regimen for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. A less toxic, non-anthracycline regimen has been considered as a treatment option for patients with node-negative small tumors. Estrogen receptor-negative and HER2-positive (pure HER2) tumors are more likely to achieve a pathological complete response (pCR). This study evaluates the activity and safety of neoadjuvant nanoparticle albumin-bound paclitaxel (nab-PTX) plus trastuzumab for pure HER2 breast cancer in patients with low risk of relapse. Patients and Methods: We treated patients with tumors measuring ≤3 cm, node-negative, pure HER2 breast cancer using neoadjuvant nab-PTX 260 mg/m2 with trastuzumab every 3 weeks for 4 cycles. The primary endpoint was the pCR rate. The secondary endpoints included the clinical response rate, pathologic response rate (defined as pCR or minimal residual invasive disease only in the breast), breast-conserving surgery conversion rate, safety, and disease-free survival. Depending on the pathological findings of surgical specimens, the administration of adjuvant anthracycline could be omitted. The accrual of 30 patients was planned. This study was registered with ClinicalTrials.gov, number NCT02598310 and University hospital Medical Information Network-Clinical Trials Registry, number UMIN000019616. Results: This study was terminated without the expected number owing to slow accrual. In total, 18 patients were enrolled. No patient required dose delays or reductions; none showed disease progression, and all patients underwent surgery as scheduled. Of the 18 patients, 66.7% achieved pCR, and the adjuvant anthracycline regimen was omitted for all patients. The incidence of severe adverse events was quite low. Observed grade 3 adverse events included neutropenia (6%), liver enzyme elevation (11%), and allergic reaction to infusion of trastuzumab (6%). Notably, sensory peripheral neuropathy was observed in a substantial number of patients (88%), but there were no severe events. Discussion: The primary outcome observed in this study is not inferior to that reported in previous studies which were administered the standard regimens with trastuzumab combined with anthracycline and taxane. Therapeutic strategies that achieve pCR using efficient and effective neoadjuvant therapy with fewer adverse effects and lower cost are advantageous. On the other hand, originally, as many patients with small tumors who met eligible criteria of this study does not need mastectomy, they are less likely to benefit from breast conserving surgery due to tumor shrinkage effect by neoadjuvant therapy. It is conceivable that there were a certain number of patients who selected primary surgery rather than neoadjuvant therapy of this study. In conclusion, this less toxic, anthracycline-free regimen appears to be a significantly effective neoadjuvant therapy for patients with pure HER2 breast cancer at low relapse risk. Citation Format: Satoru Tanaka, Hirotaka Morishima, Naofumi Oda, Nobuki Matsunami, Tsutomu Takashima, Satoru Noda, Shinichiro Kashiwagi, Yukie Tauchi, Yuka Asano, Kosei Kimura, Hiruya Fujioka, Risa Terasawa, Kanako Kawaguchi, Ayana Ikari, Takashi Morimoto, Shintaro Michishita, Toshihiro Kobayashi, Junna Sakane, Toshikatsu Nitta, Nayuko Sato, Norihiro Hokimoto, Yukihiro Nishida, Mitsuhiko Iwamoto. A phase 2 study of de-escalated neoadjuvant therapy with nanoparticle albumin-bound paclitaxel and trastuzumab for low risk pure HER2 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 P2-16-32.

Abstract P1-19-09: Updated subgroup tumor response of abemaciclib plus aromatase inhibitor for hormone receptor positive (HR+), HER2 negative advanced breast cancer (MONARCH 3)

Abstract Background: Abemaciclib plus nonsteroidal aromatase inhibitors (AI) demonstrated efficacy with a tolerable safety profile as initial treatment for postmenopausal women with HR+, HER2− advanced breast cancer in the MONARCH 3 trial. In the intent-to-treat (ITT) population, the updated progression-free survival (PFS) with 12 months of additional follow-up was 28.2 versus 14.8 months (HR [95% CI]: 0.525 [0.415, 0.665]; p&amp;lt;.0001) in the abemaciclib plus AI versus placebo plus AI arms, respectively. Here we report data from the additional 12 months of follow-up on tumor response for the ITT population and exploratory subgroups previously identified as significantly prognostic (Di Leo et al. 2018). Methods: In MONARCH 3, a randomized, double-blind, phase III trial, 493 postmenopausal women with HR+, HER2− advanced breast cancer and no prior systemic therapy in the advanced setting, received an AI (anastrozole or letrozole) plus abemaciclib or placebo. From the October 31, 2018 cutoff, secondary endpoints including objective response rate ([ORR], complete response [CR] + partial response [PR]), time to response (TTR), and duration of response ([DoR], time from a confirmed CR or PR until disease progression or death) were assessed in the ITT population and exploratory subgroups previously reported as significantly prognostic. Waterfall plots will be used to illustrate the magnitude of change in tumor size for each subgroup (to be presented). Results: In patients with measurable disease, the ORR was 62.5% (95% CI: 56.7, 68.2) in the abemaciclib plus AI arm and 44.7% (95% CI: 36.2, 53.2) in the placebo plus AI arm (p≤.001). Additional follow-up confirmed that all prognostic subgroups received benefit from the addition of abemaciclib to AI, consistent with the ITT population, as evidenced by change in ORR, with the largest effects observed in subgroups of patients with liver metastases, progesterone receptor-negative tumors, high grade tumors, or treatment-free interval of &amp;lt;36 months (Table). Median TTR was similar between the two treatment arms (abemaciclib plus AI: 3.62 months; placebo plus AI: 3.65 months), and this was generally consistent across subgroups. Responses were more durable in the abemaciclib plus AI arm (median DoR: 32.71 months; 95% CI: 25.74, -) versus the placebo plus AI arm (median DoR: 17.49 months; 95% CI: 11.61, 22.19), including in poor prognostic subgroups. Conclusions: Extended follow-up in the MONARCH 3 trial further confirmed that the addition of abemaciclib to AI is associated with durable tumor responses, including those in patients with clinically poor prognostic characteristics.

Updated Bayesian Network Meta-Analysis of Adjuvant Targeted Treatment Regimens for Early Human Epidermal Growth Factor Receptor-2 Positive Breast Cancer.

PurposeCombining targeted agents with adjuvant chemotherapy prolongs survival in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients, but also increases the risk of adverse effects. The updated results of 3 randomized controlled trials (RCTs) were reported in 2019. Given the lack of adequate head-to-head pairwise assessment for anti-HER2 agents, network meta-analysis facilitates obtaining more precise inference for evidence-based therapy.MethodsRCTs comparing at least 2 anti-HER2 regimens in an adjuvant setting for HER2-positive early-stage breast cancer (EBC) were included. Hazard ratios for overall survival (OS) and disease free survival (DFS), with respective 95% confidence intervals were pooled for assessment of efficacy. A Bayesian statistical model was used, and odds ratios (ORs) for adverse events (AEs) were used to pool effect sizes.ResultsWe demonstrated that 1-year trastuzumab plus chemotherapy had increased efficacy compared to shorter or longer treatment duration. The OR of cardiac events gradually increased from 6 months to 1 and 2-year trastuzumab arms, relative to chemotherapy only. Compared to trastuzumab plus chemotherapy, dual HER2-targeting therapies increased DFS, especially for hormone receptor negative patients. Dual anti-HER2 blockade regimens revealed an increased probability of gastrointestinal reactions. As a second agent, pertuzumab showed significantly higher DFS and OS.ConclusionWe conclude that 1-year adjuvant trastuzumab should remain as the standard treatment for HER2-positive EBC patients, as it has greater efficacy and a manageable proportion of AEs. Clinical efficacy can be increased for hormone receptor-negative tumors by including a second HER2-targeted agent to the treatment regimen. For hormone receptor-positive cases with basal disease, it is acceptable to reduce the risk of cardiotoxicity by shortening the duration of trastuzumab.

Amphiregulin deletion strongly attenuates the development of estrogen receptor-positive tumors in p53 mutant mice.

The epidermal growth factor receptor ligand, Amphiregulin, is a transcriptional target of estrogen receptor alpha and is required for pubertal mammary gland development. Previous studies using immortalized human breast cancer cell line xenografts have suggested that Amphiregulin may be an important effector of estrogen receptor alpha during breast cancer development, at least in immune-compromised animals. Here, we evaluate the requirement for Amphiregulin in an immune-competent mouse model which is prone to developing estrogen receptor-positive tumors. We have intercrossed mice with mammary-specific mutation of p53 with mice deficient in Amphiregulin in order to assess the requirement for Amphiregulin in the initiation and progression of both estrogen receptor-positive and estrogen receptor-negative mammary tumors. Deletion of Amphiregulin significantly delayed the onset of palpable mammary tumors and also strongly reduced the proportion of estrogen receptor alpha-positive tumors formed. Upon necropsy, no substantial differences in the prevalence of non-palpable lesions were observed between cohorts, suggesting that the importance of Amphiregulin in mammary tumorigenesis is limited to the post-initiation phase. This study underlines the importance of the EGFR ligand, Amphiregulin, as a key mediator of estrogen receptor action in breast cancer.

NSABP FB-7: a phase II randomized neoadjuvant trial with paclitaxel + trastuzumab and/or neratinib followed by chemotherapy and postoperative trastuzumab in HER2+ breast cancer

PurposeThe primary aim of NSABP FB-7 was to determine the pathologic complete response (pCR) rate in locally advanced HER2-positive (HER2+) breast cancer patients treated with neoadjuvant trastuzumab or neratinib or the combination and weekly paclitaxel followed by standard doxorubicin plus cyclophosphamide. The secondary aims include biomarker analyses.Experimental designpCR was tested for association with treatment, gene expression, and a single nucleotide polymorphism (SNP) in the Fc fragment of the IgG receptor IIIa-158V/F (FCGR3A). Pre-treatment biopsies and residual tumors were also compared to identify molecular changes.ResultsThe numerical pCR rate in the trastuzumab plus neratinib arm (50% [95%CI 34–66%]) was greater than that for single-targeted therapies with trastuzumab (38% [95%CI 24–54]) or neratinib (33% [95%CI 20–50]) in the overall cohort but was not statistically significant. Hormone receptor-negative (HR−) tumors had a higher pCR rate than HR+ tumors in all three treatment arms, with the highest pCR rate in the combination arm. Diarrhea was the most frequent adverse event and occurred in virtually all patients who received neratinib-based therapy. Grade 3 diarrhea was reported in 31% of patients; there were no grade 4 events. Our 8-gene signature, previously validated for trastuzumab benefit in two different clinical trials in the adjuvant setting, was correlated with pCR across all arms of NSABP FB-7. Specifically, patients predicted to receive no trastuzumab benefit had a significantly lower pCR rate than did patients predicted to receive the most benefit (P = 0.03). FCGR genotyping showed that patients who were homozygous for the Fc low-binding phenylalanine (F) allele for FCGR3A-158V/F were less likely to achieve pCR.ConclusionsCombining trastuzumab plus neratinib with paclitaxel increased the absolute pCR rate in the overall cohort and in HR− patients. The 8-gene signature, which is validated for predicting trastuzumab benefit in the adjuvant setting, was associated with pCR in the neoadjuvant setting, but remains to be validated as a predictive marker in a larger neoadjuvant clinical trial. HR status, and the FCGR3A-158V/F genotype, also warrant further investigation to identify HER2+ patients who may benefit from additional anti-HER2 therapies beyond trastuzumab. All of these markers will require further validation in the neoadjuvant setting.Trials registrationClinicalTrials.gov, NCT01008150. Retrospectively registered on October 5, 2010.

Abstract A031: Association of tumor DNA in circulation with clinical characteristics and treatment response in HR+/HER2− advanced breast cancer

Abstract Background: The sensitivity of plasma-based oncological assays is influenced by the amount of tumor DNA shed into the circulation (ctDNA fraction). Higher ctDNA fraction has been shown to correlate with later-stage cancers and poorer overall survival (Bettegowda C, et al. Sci Transl Med. 2014; Dawson SJ, et al. N Engl J Med. 2014). Other factors affecting ctDNA fraction are poorly understood. We present results from three large Phase III breast cancer studies (MONALEESA-2, -3, and -7) to evaluate correlations between ctDNA fraction and clinical characteristics and impact on progression-free survival (PFS) and best overall tumor response. Methods: Baseline plasma samples were collected from patients (pts) in the MONALEESA-2, -3, and -7 studies, which are Phase III registration trials testing ribociclib, a cyclin-dependent kinase 4/6 inhibitor, in hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer. For each trial, cell-free DNA was extracted from plasma and sequenced using a validated next-generation sequencing assay targeting approximately 550 genes. ctDNA fraction was estimated by analyzing short-read sequences using PureCN (Riester M, et al. Source Code Biol Med. 2016) and tested for correlations with various tumor characteristics (size at baseline, Ki67 expression, number and type of metastatic sites, hormone receptor status) and pt characteristics (type of prior therapy, line of therapy, ECOG performance status, age, body mass index, race, histological grade, menopausal status). We also evaluated the prognostic value of ctDNA fraction on PFS and best overall response. To evaluate the prognostic effect on PFS, ctDNA fraction was binned into 3 categories (not detectable; low, 0.5%-10%; high, &amp;gt; 10%). Results: Higher ctDNA fractions were observed in pts with more metastatic sites (P &amp;lt; 0.0001), larger tumor diameter (P &amp;lt; 0.0001), higher Ki67 expression (P = 0.0001), higher lactate dehydrogenase levels (P &amp;lt; 0.0001), higher-grade tumors (P = 0.0004), worse ECOG performance status (P &amp;lt; 0.0001), progesterone receptor–negative tumors (P = 0.01), presence of liver metastases (P &amp;lt; 0.0001), and shorter disease-free intervals (P &amp;lt; 0.0001). ctDNA fractions were also higher in younger pts (continuous variable; P &amp;lt; 0.0001) and pts with lower BMI (P = 0.0003), prior chemotherapy (P = 0.002), and prior endocrine therapy (P = 0.01). Lower ctDNA fractions were observed in pts with better overall response (P &amp;lt; 0.0001), with median ctDNA fractions lowest in pts with complete responses followed by partial response, stable disease, and progressive disease. Pts with low (0.5%-10%) ctDNA fractions had longer PFS than pts with high (&amp;gt; 10%) ctDNA fractions (HR [95% CI], 0.63 [0.48-0.82], 0.64 [0.51-0.80], and 0.67 [0.52-0.86] in the MONALEESA-2, -3, and -7 trials, respectively). A more pronounced effect on PFS was observed in pts with undetectable levels of ctDNA vs pts with higher ctDNA fractions (HR [95% CI], 0.35 [0.23-0.52], 0.34 [0.21-0.55], and 0.31 [0.21-0.47] in the MONALEESA-2, -3, and -7 trials, respectively). Conclusions: Generally, higher ctDNA fraction was associated with more aggressive tumor characteristics and prior exposure to therapy. Lower ctDNA fraction was associated with longer PFS and better overall response. Together these data suggest that ctDNA fraction is a robust prognostic factor. Citation Format: Nadia Solovieff, Faye Su, Rebecca Leary, Alejandro Balbin, Arunava Chakravartty, Karen Rodriguez Lorenc, Tetiana Taran, Naveen Babbar. Association of tumor DNA in circulation with clinical characteristics and treatment response in HR+/HER2− advanced breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A031. doi:10.1158/1535-7163.TARG-19-A031

Occupational Chemical Exposure and Breast Cancer Risk According to Hormone Receptor Status: A Systematic Review.

Breast cancers include a heterogeneous group of diseases with clinical behaviors that may vary according to the hormonal receptor status. However, limited knowledge is available on the role of breast cancer environmental and occupational risk factors in the onset of specific molecular disease phenotypes. Therefore, the aim of this review was to provide an overview on the possible correlation between occupational chemical exposures and breast cancers with a specific receptor pattern. Pubmed, Scopus, and ISI Web of Science databases were systematically reviewed to identify all the studies addressing chemical exposure in workplaces and risk of breast cancer classified according to the presence of estrogen and/or progesterone receptors. Some positive associations were reported between solvent, polycyclic aromatic hydrocarbon, organophosphoric insecticide, and synthetic fiber exposure and estrogen receptor-positive cases, while other investigations demonstrated a relationship with receptor-negative tumors or failed to detect any significant effect. Overall, further investigation should overcome limitations due to the self-reported information on work histories, the chemical classification in general categories, and the lack of environmental or biological monitoring exposure data. This may support the development of suitable and individually “tailored” occupational risk assessment and management strategies to protect the health of exposed workers, particularly those with hypersusceptibility conditions.

Deregulating MYC in a model of HER2+ breast cancer mimics human intertumoral heterogeneity.

The c-MYC (MYC) oncoprotein is often overexpressed in human breast cancer; however, its role in driving disease phenotypes is poorly understood. Here, we investigate the role of MYC in HER2+ disease, examining the relationship between HER2 expression and MYC phosphorylation in HER2+ patient tumors and characterizing the functional effects of deregulating MYC expression in the murine NeuNT model of amplified-HER2 breast cancer. Deregulated MYC alone was not tumorigenic, but coexpression with NeuNT resulted in increased MYC Ser62 phosphorylation and accelerated tumorigenesis. The resulting tumors were metastatic and associated with decreased survival compared with NeuNT alone. MYC;NeuNT tumors had increased intertumoral heterogeneity including a subtype of tumors not observed in NeuNT tumors, which showed distinct metaplastic histology and worse survival. The distinct subtypes of MYC;NeuNT tumors match existing subtypes of amplified-HER2, estrogen receptor-negative human tumors by molecular expression, identifying the preclinical utility of this murine model to interrogate subtype-specific differences in amplified-HER2 breast cancer. We show that these subtypes have differential sensitivity to clinical HER2/EGFR-targeted therapeutics, but small-molecule activators of PP2A, the phosphatase that regulates MYC Ser62 phosphorylation, circumvents these subtype-specific differences and ubiquitously suppresses tumor growth, demonstrating the therapeutic utility of this approach in targeting deregulated MYC breast cancers.

Trends in Regional Nodal Management of Breast Cancer Patients with Low Nodal Burden.

American College of Surgeons Oncology Group Z0011 confirms the safety of omitting axillary lymph node dissection (ALND) and regional nodal irradiation (RNI) in breast cancer patients with one to two positive sentinel lymph nodes (SLNs), without compromising disease-free survival (DFS) and overall survival (OS). In contrast, the NCIC MA20 trial showed improved DFS in node-positive patients undergoing ALND and RNI. We sought to examine how these data have influenced the management of patients with limited nodal burden. Using the National Cancer Database, patients diagnosed between 2010 and 2015 and who met the criteria for Z0011 were identified. Logistic regression was used to analyze factors associated with practice patterns. The Cox proportional hazards model was used to assess the association of ALND and RNI with OS. Omission of ALND in Z0011-eligible patients reached 89.2% in 2015. This Z0011-compliant group was more likely to undergo RNI compared with the non-compliant group (36.4% vs. 31.3%; p < 0.05), with RNI increasing to 43.8% by 2015. Factors associated with the use of RNI included later year of diagnosis [odds ratio (OR) 1.8, 95% confidence interval (CI) 1.6-2.1], hormone receptor-negative tumor (OR 1.2, 95% CI 1.1-1.4), grade 3 tumor (OR 1.2, 95% CI 1.1-1.3), treatment at a non-academic site (OR 1.2, 95% CI 1.1-1.3) and two versus one positive SLN (OR 2.0, 95% CI 1.8-2.2). With 43months median follow-up, RNI was not associated with improved OS. Since the publication of Z0011, the omission of ALND has become widespread; however nearly half of these women now receive RNI. The optimal radiation therapy approach for this low nodal burden population warrants further study.

Impact of Nuclear Oestrogen Receptor Beta Expression in Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy.

Introduction Oestrogen receptor beta (ER-β) is abundantly expressed in breast cancer (BC), but its impact on neoadjuvant chemotherapy outcome is unknown. Patients and Methods Patients treated in the neoadjuvant GeparTrio trial with available tissue for immunohistochemical analyses were included. Nuclear ER-β expression was correlated with clinico-pathologic characteristics. The impact of its expression on pathological complete response (pCR [ypT0/ypN0]) and survival was determined. Results Samples of 570 patients were available. Low nuclear ER-β expression (IRS < 9) was observed in 48.4% of hormone receptor positive and 58.6% of hormone receptor negative tumours. Low nuclear ER-β expression was associated with higher pCR rates compared to high nuclear ER-β expression (16.1% vs. 4.7%, p = 0.026). Low ER-β expression was no independent predictor of pCR in multivariate analyses. Disease-free and overall survival were not statistically different between patients with high and low nuclear ER-β expression. Triple-negative BCs showed low nuclear ER-β expression in 57.7%, and pCR rates were 27.1% and 0% (p = 0.23) in low and high ER-β expressing tumours, respectively. Conclusion Low ER-β expression is associated with improved pCR rates in univariate analyses. However multivariate analyses and survival analyses do not indicate an impact of ER-β on survival in patients undergoing neoadjuvant chemotherapy. Further examination of ER-β as predictor for endocrine therapy might be of value.

The association of D-dimer with clinicopathological features of breast cancer and its usefulness in differential diagnosis: A systematic review and meta-analysis.

Studies have shown that D-dimer levels are significantly correlated with the differential diagnosis and clinicopathological features of breast cancer. However, the results are currently limited and controversial. Therefore, we performed this meta-analysis to evaluate the relationship between D-dimer levels and breast cancer. The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Chinese Biomedical Literature, and Wanfang databases were searched to find studies that assessed the association of D-dimer with clinicopathological features of breast cancer and its usefulness in aiding with differential diagnosis. The standardized mean difference (SMD) was applied as the correlation measure. A total of 1244 patients with breast cancer from 15 eligible studies were included in the meta-analysis. D-dimer levels were higher in the breast cancer group than in the benign (SMD = 1.02; 95% confidence interval [CI] = 0.53-1.52) and healthy (SMD = 1.27; 95% CI = 0.85-1.68) control groups. In addition, elevated D-dimer levels were associated with progesterone receptor-negative tumors (SMD = -0.25; 95% CI = -0.44--0.05). Similarly, there was a significant correlation between D-dimer levels and tumor node metastasis staging (n = 11, SMD = 0.82; 95% CI = 0.57-1.06) and lymph node involvement (n = 8, SMD = 0.79; 95% CI = 0.50-1.09). In contrast, other clinicopathological factors, including estrogen receptor expression and human epidermal growth factor receptor 2 expression, were not associated with D-dimer levels. The results of this meta-analysis indicate that plasma D-dimer levels can be used as an important reference for the early identification and staging of breast cancer.