Tumor Response In Breast Cancer Research Articles

Abstract 5721: Dual targeting of CDK4/6 and CDK7 pathways augments tumor response in breast cancer

Abstract CDK7 plays a pivotal role in cell proliferation, serving as both a cell-cycle CDK regulator and a transcription machinery component. Clinical trials are currently exploring CDK7 inhibitors (CDK7i) as a second-line treatment for hormone receptor-positive (HR+) breast cancer post-CDK4/6 inhibitor (CDK4/6i) therapy progression and as a first-line treatment in triple-negative breast cancer (TNBC). This study evaluates the impact of CDK7i on transcription and CDKs activities and the synergistic potential of CDK7i in combination with CDK4/6i. Kinetic analyses indicate that CDK7i preferentially target global transcription over CDKs activities. Furthermore, a combination of CDK7i and CDK4/6i effectively suppresses cell proliferation in drug-naïve cells, albeit without the same efficacy in CDK4/6i-resistant cells. Our findings provide valuable insights into the evolving field of CDK inhibition strategies and provide critical guidance on the potential therapeutic application of CDK7i in breast cancer treatment. Citation Format: Eugene Son, Sungsoo Kim, Haram Park, Minah Kim, Hee Won Yang. Dual targeting of CDK4/6 and CDK7 pathways augments tumor response in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5721.

EXPLORING BREAST CANCER RESPONSE PREDICTION TO NEOADJUVANT SYSTEMIC THERAPY USING MRI-BASED RADIOMICS: A SYSTEMATIC REVIEW

Breast cancer affects more than one out of every ten persons diagnosed with cancer each year, making it the most common type of cancer in women. It is the second most common cause of cancer-related death among females worldwide. The milk-producing glands are placed in front of the chest wall, according to breast anatomy. Breast cancer progression is almost often missed. The majority of people find out they have the illness through a normal test. Others may present with an unintentional breast lump, a change in the shape or size of their breasts, or a discharge from their nips. When compared to adjuvant chemotherapy, NST allows for in vivo tumor response, tumor size reduction (allowing for breast-conserving therapy where mastectomy was recommended), and pathologic complete response (pCR). Breast cancer tumor response to NST can be predicted using imaging modalities. Breast magnetic resonance imaging (MRI) is the most effective imaging modality for evaluating tumors and predicting response. Its precision in evaluating and forecasting tumor response to NST is insufficient to change clinical treatment. NST tumor response cannot be predicted using pretreatment MRI. As a result, breast MRI accuracy must be continuously enhanced. Despite large methodological heterogeneity in each step of the radiomics workflow, studies focusing on MRI-based radiomics for tumor response prediction to NST in breast cancer patients yielded promising results.

Use of Ultrasound and Ki-67 Proliferation Index to Predict Breast Cancer Tumor Response to Neoadjuvant Endocrine Therapy.

Prediction of tumor shrinkage and pattern of treatment response following neoadjuvant endocrine therapy (NET) for estrogen receptor positive (ER+), Her2 negative (Her2-) breast cancers have had limited assessment. We examined if ultrasound (US) and Ki-67 could predict the pathologic response to treatment with NET and how the pattern of response may impact surgical planning. A total of 103 postmenopausal women with ER+, HER2- breast cancer enrolled on the FELINE trial had Ki-67 obtained at baseline, day 14, and surgical pathology. A total of 70 patients had an US at baseline and at the end of treatment (EOT). A total of 48 patients had residual tumor bed cellularity (RTBC) assessed. The US response was defined as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). CR or PR on imaging and ≤70% residual tumor bed cellularity (RTBC) defined a contracted response pattern. A decrease in Ki-67 at day 14 was not predictive of EOT US response or RTBC. A contracted response pattern was identified in one patient with CR and in sixteen patients (33%) with PR on US. Although 26 patients (54%) had SD on imaging, 22 (85%) had RTBC ≤70%, suggesting a non-contracted response pattern of the tumor bed. The remaining four (15%) with SD and five with PD had no response. Ki-67 does not predict a change in tumor size or RTBC. NET does not uniformly result in a contracted response pattern of the tumor bed. Caution should be taken when using NET for the purpose of downstaging tumor size or converting borderline mastectomy/lumpectomy patients.

Note of the methodological flaws in the paper entitled "GSTT1 and GSTM1 polymorphisms predict treatment outcome for breast cancer: a systematic review and meta-analysis".

With great interest, we read the paper "GSTT1 and GSTM1 polymorphisms predict treatment outcome for breast cancer: a systematic review and meta-analysis" (by Hu XY et al.), which has reached important conclusions that GSTM1 null and GSTT1/GSTM1 double null polymorphisms might be significantly associated with an increased tumor response in breast cancer. The result is encouraging. Nevertheless, several methodological flaws in this meta-analysis are worth noticing.

Abstract P5-04-06: Oral immunomodulatory agents prevent tumor growth and increase tumor CD8 T cell infiltrate; bexarotene further improves tumor response to conventional chemotherapy in breast tumors

Abstract The tumor immune environment is important in breast cancer with greater than 50% immune infiltrate (LPBC) prior to neoadjuvant chemotherapy predicting improved pathologic complete response, and LPBC and CD8 infiltrate prior to adjuvant therapy predicting improved survival. Unfortunately, the majority of breast cancers do not have LPBC or robust CD8+ infiltrate. Evidence has emerged that conventional chemotherapy can increase CD8+ T cells therefore discovering ways to boost this response should further enhance the anti-tumor function. Three oral agents have modest anti-tumor function: metformin (oral biguanide), bexarotene (retinoic receptor agonist), and celecoxib (COX2 inhibitor). In vitro data suggest a role for these agents in increasing Th1 immunity: metformin was shown to increase MHC class I expression on tumor cells, bexarotene was shown to decrease CD8+ T cell apoptosis, and celecoxib has been shown to decrease MDSC cells. The goal of this study was to demonstrate whether addition of these oral agents to conventional chemotherapy enhanced the anti-tumor function of chemotherapy, possibly by modifying the immune environment in the transgenic mouse mammary tumor model TgMMTV-neu (genetically similar to luminal breast cancer). Two active chemotherapies in human breast cancer, doxorubicin and paclitaxel, inhibited tumor growth and increased CD8+ T cell tumor infiltrate in transgenic mice. Treatment of mice with 100 mm3 tumors with doxorubicin (5 mg/kg weekly for four weeks) showed a 32% increase in CD8+ T cells and 85% decrease in tumor growth as compared to control mice (p=0.0001) and treatment with paclitaxel (10 mg/kg weekly for four weeks) showed a 40% increase in CD8+ tumor infiltrate (p=0.0068) and 60% decrease in tumor growth as compared to control treated mice (p=0.0026). A third chemotherapy cyclophosphamide (100 mg/kg weekly for four weeks) increased CD8+ tumor infiltrate by 45% (p=0.011) but did not show a significant decrease in tumor volume (p=0.57). Metformin and bexarotene also demonstrated increased CD8+ tumor infiltration and decreased breast tumor growth but celecoxib did not. Metformin treated mice had a 46% increase in CD8+ tumor infiltrate (p=0.001) and a 52% decrease in mean tumor volume (p=0.011) as compared to controls (75 mg/m2 of metformin for four weeks). Bexarotene treated mice had 44% increase in CD8+ tumor infiltrate (p=0.05) and 60% decrease in mean tumor growth (p=0.03) compared to control (treated with 50 mg/m2 bexarotene for four weeks). Of all three oral therapies, bexarotene was most effective inhibiting spontaneous tumor growth in the mice. Furthermore, addition of bexarotene to chemotherapy was superior to chemotherapy alone. Adding bexarotene to weekly doxorubicin decreased tumor growth by 98% (p=0.008 compared to doxorubicin alone), adding bexarotene to weekly paclitaxel decreased tumor growth by 86% (p=0.02 compared to paclitaxel alone), and adding bexarotene to weekly cyclophosphamide inhibited tumor growth by 82% (p=0.04 compared to cyclophosphamide alone). These results suggest that addition of bexarotene, a well-tolerated oral agent, to chemotherapy may improve tumor response in breast cancer. Citation Format: Sasha E Stanton, Ekram Gad, Edmond Marzbani, Lauren Rastetter, Mary L Disis. Oral immunomodulatory agents prevent tumor growth and increase tumor CD8 T cell infiltrate; bexarotene further improves tumor response to conventional chemotherapy in breast tumors [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-04-06.

Abstract P4-01-05: 3’-deoxy-3’-[18F]fluoro-thymidine (18F-FLT) positron emission tomography (PET): An accurate and effective tool for assessing tumor response in breast cancer

Abstract Objectives : A French multicenter study was promoted by the national French cancer federation (Unicancer R&D) to assess the potential of [18F]FLT (positron emission tomography (PET) biomarker of proliferation)to manage breast cancer neoadjuvant chemotherapy (NAC). The main objective was to compare changes in tumor [18F]FLT uptake to histopathological changes induced by NAC, assuming an arrest of tumor growth related to the effectiveness of NAC. Methods : 97 patients (age 48.6 +/- 10.2 y.) were included in 13 nuclear medicine centers. All patients were eligible to anthracycline-based NAC for a de novo unifocal breast cancer (ductal n = 84, lobular = 11, other type = 2; stage II n = 75, stage III n = 21 et stage IV n = 1). 90 patients underwent a baseline PET before the onset of NAC (PET1) and a final PET after the end of NAC and before surgery (PET3). PET acquisitions were performed 60±7min after FLT injection. SUVmax (maximum standardized uptake value), SUVpeak (1 cm3 ROI including pixel max) and SUV41 (isocontour 41% of pixel max) were computed. Changes in SUV on PET3 vs PET1 were analyzed in relation to histopathological findings at the end of NAC (Sataloff criteria). Results : Tumor FLT uptake decreased markedly between TEP1 and TEP3 (SUVmax = 6.2±4.8 vs 1.3±1.2 respectively; SUVpeak = 4.6±3.2 vs 0.9±0.9; SUV41 = 3.6±2.8 vs 0.8±0.7). Total or near-total therapeutic effect (grade A) were obtained in 20 patients, more than 50% therapeutic effect but less than total or near-total effect (grade B) in 37 patients, less than 50% therapeutic effect but visible effect (grade C) in 22 patients, or no therapeutic effect (grade D) in 11 patients. SUVmax decreased dramatically (87.5%) to background levels in all patients with a complete response (grade A). Overall, changes in SUV differed depending on the type of histological response (p<0.01) i.e. SUVmax changes were more pronounced as pathological responses were good: 61% for grade D; 65.7% grade C and 69.8% grade B. The same results were obtained with the two other SUV types. Conclusions : Pathologic response to NAC in breast cancer can be assessed accurately by FLT. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-01-05.

Evaluation of tumor cell death response in locally advanced breast cancer patients to chemotherapy treatment by scattering property estimates using ultrasound backscatter

Breast cancer tumor response to chemotherapy in twenty nine patients was examined using quantitative ultrasound techniques. Backscatter parameters, such as the average scatterer diameter (ASD) and average acoustic concentration (AAC), were estimated from regions-of-interest in tumors prior to treatment onset and at four times during neoadjuvant chemotherapy treatment (weeks 1, 4, 8 and prior to surgery). Gaussian and Anderson form factor models were used over an analysis bandwidth of 4.5 to 9 MHz to obtain ASD and AAC estimates. The Gaussian model did not fit with the measured data as well as Anderson model. The AAC estimates yielded significant differences with therapy times in clinically treatment responded patients. Data indicated increases of 6.6 dB/cm in acoustic concentration obtained maximum at week 8 in treatment responding tumors. Non-responding tumors didn't show any significant difference in the parameters during treatment. This study demonstrates that the scattering parameters have the potential to being used in quantifying the changes in tumors during treatment noninvasively and distinguishing treatment responders and non-responders early after of treatment initiation.

Development of 99mTc-EC-tyrosine for Early Detection of Breast Cancer Tumor Response to the Anticancer Drug Melphalan

Radiolabeled tyrosine analogues that have been successfully used in tumor imaging accumulate in tumor cellsvia an upregulated L-type amino acid transporter system. The anticancer drug melphalan is an L-type amino acid transporter substrate. Therefore, radiolabeled tyrosine analogues may have great potential in evaluating treatment responses to melphalan. In this study, a (99m)Tc-labeled tyrosine analogue, (99m)Tc tyrosine using N,N'-ethylene-di-L-cysteine (EC) as a chelator, was developed and its potential for noninvasively assessing tumors' early response to melphalan determined. EC-tyrosine was synthesized in a three-step procedure and labeled with (99m)Tc. To assess cellular uptake kinetics, the percentage uptake of (99m)Tc-EC-tyrosine in the rat breast cancer cell line 13762 was measured. Planar imaging was performed in rats with 13762 cell-derived tumors. To determine the transport mechanisms of (99m)Tc-EC-tyrosine, a competitive inhibition study using L-tyrosine as an inhibitor was performed invitro and invivo. To assess tumors' response to melphalan, tumor-bearing rats were treated with different doses of melphalan, and planar imaging was performed 0 and 3 days after treatment. Immunohistochemical analyses were conducted to determine expressions of L-type amino acid transporter 1 and cellular proliferation marker Ki-67. L-tyrosine significantly inhibited (99m)Tc-EC-tyrosine uptake invitro and invivo. Tumor volume decreased in a dose-dependent manner with melphalan, and tumor/muscle ratios of (99m)Tc-EC-tyrosine were significantly reduced in treated groups. Immunohistochemical data indicated that about 70% of tumor cells in the melphalan-treated groups underwent apoptosis, and the changes in tumor/muscle ratios reflected the decreased percentage of viable cells in treated tumors. These findings suggest that (99m)Tc-EC-tyrosine has great potential for monitoring tumor response to melphalan in breast tumor-bearing rats.

What is new in breast MRI spectroscopy

A review of breast spectroscopy and its metabolite imaging – MRS is useful for clinical evaluation in neoadjuvant chemotherapy for the treatment of breast cancer. Why has it not been implemented on all clinical breast MRI scanners? Doing MRI/MRS on smaller breast cancers is difficult and cannot be done on breast cancers less than 6mm × 6mm × 6mm. High field magnets are used in single voxel spectroscopy (laser) for beast quantitative results (3T or 4T). The MRI/MRS latest results from I-SPY I (NIH/ACRIN) are not yet published for the multi-centered trial. Also having to shim the magnet and preset sequences for optimizing MRS has been an issue and requires a MRI physicist to do these studies. Choline measurements on 1.5T magnets that are shimmed well can detect choline within a large tumor (>2–3 cm). However, it is difficult to quantitate the choline with the breast cancer using 1.5T magnets. The results from the first MRS trial at the University of Minnesota Center for Magnetic Resonance Research will be published at the San Antonio Breast Meeting (December 2012). The report will be on 60 MRI/MRS cases and 5 year survival data. MRI/MRS neoadjuvant breast cancer imaging can be evaluated by three MRI methods to get to the RECIST evaluation: (1) L/D – longest diameter; (2) MRS – metabolite imaging and (3) Volume imaging of contrast (3D). All these methods have difficulty with non-mass like tumors. Making objective measurements of changes in breast tumor size can be challenging. The spectrum of breast tumor morphology and appearance on MRI creates difficulty generating accurate objective measurements which is used by oncology RECIST criteria to track tumor response in breast cancer. Depending on morphology and enhancement of an individual lesion an objective LD comparison may be problematic as seen in the following abstract. Inter-observer agreement in assessment of breast cancer response to neoadjuvant chemotherapy on MRI: Qualitative versus quantitative evaluation (11/28/11 RSNA, Chicago, IL). Volume Imaging: MRI tumor volume for predicting response to neoadjuvant chemotherapy in locally advanced breast cancer: findings from ACRIN 6657/calgb 15007 (2009 Asco) Noxla Hilton. Tumor response measured volumetrically by MRI is a stronger and earlier predictor of pathologic response after (NACT) than clinical exam or tumor diameter. Volumetric MRI imaging must use accurate volume (3D) placement of a voxel under MRI guidance. This procedure is not yet automated and must be completed by an experienced MRI radiologist. If the clinical trial shows that the pathologic response is very good (in 1–2 weeks) then this test may not be as sensitive for predicting (NACT) response. (Chemotherapy drugs work extremely well and the tumor decreases gadolinium uptake to zero.)

Abstract 4720: Incremental increase in VEGFR1+ and VEGFR2+ hemangiogenic progenitor cells predict relapse and tumor response in breast cancer (BC) patients

Abstract Background: BC can relapse years after initial diagnosis. In animal models, bone marrow (BM)-derived VEGFR1+ cells define the premetatastic niche and VEGFR2+ cells are critical for the transition from micro- to macrometastatic disease. We sought to define the temporal relationship of these circulating hemangiogenic progenitor cells in a cohort of BC patients (pts) that developed recurrent disease and whether quantitative changes in these cells could predict response to therapy in pts with established metastases. Methods: 125 pts with Stages I to IV BC enrolled in 2 studies. In Study #1 circulating VEGFR1+ (CD45+/CD34+/VEGFR1+) hematopoietic progenitor cells (HPCs) and VEGFR2+ (CD45dim/CD133+/ VEGFR2+) endothelial progenitor cells (EPCs) of adjuvant patients were assessed at baseline (BL), every 3 months (mo) for the first year, then every 6 mo. Stage IV pts had levels measured at BL (defined as when initiating new treatment (tx)), with subsequent 1 mo interval blood draws and accompanied by a clinical evaluation. Tx could include chemo-, hormone or biologic therapy. In Study #2, these cells were examined monthly in pts without overt evidence of BC. HPCs/EPCs were quantified from peripheral blood mononuclear cells using flow cytometry with commercially available antibodies. Statistical analysis is by Wilcoxon signed-rank test. Results: Data from both studies were combined to analyze 1) pts without overt BC who relapse and 2) stage IV pts according to response. Seven pts without evidence of BC based on physical exam, labs, and imaging developed recurrence while on study. In all 7 pts, there was a median (med) increase of 1,111% in HPCs preceding overt relapse (range 283% to 5800%). Med HPCs at BL 0.65/ul (range 0.02 to 1.22/ul) increased to 2.90/ul prior to relapse (range 1.18 to 34.94/ul), p=0.016. In 5 of 7 relapsed pts a 433% increase in EPCs occurred as HPCs decreased: med EPCs at BL 0.03/ul (range 0.015 to 0.21/ul) and at relapse 0.16/ul (range 0.03 to 0.27/ul). This pattern was not seen in non-relapsed pts. In 22 stage IV pts, HPCs and EPCs were evaluated over the course of 40 tx. For the 20 tx (16 pts) in which progression of disease (POD) was the outcome, HPCs increased prior to POD (median 7.45/ul, range 0.37 to 77.6/ul) from BL (med 1.70/ul, range 0.01 to 16.47/ul), p=0.001. Similarly, EPCs increased at relapse (med 0.07/ul, range 0 to 0.62/ul) from BL (med 0.03/ul, range 0 to 0.21/ul), p=0.04. For the 12 tx (11 pts) with disease responding to systemic tx, there was a reduction in HPCs (BL med 6.15/ul, range 0.91 to 85.1/ul) to a 3 mo time point (med 0.63/ul, range 0.05 to 18.1/ul), p=0.05. A trend was noted in med EPCs (0.05/ul at BL to 0.02/ul at 3 mo), p=0.37. There was no change in HPCs/EPCs in 8 tx (6 pts) with stable disease. Conclusion: BM-derived progenitor cells are important in the metastatic cascade and may represent a novel biomarker in following disease status and a new target for therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4720. doi:10.1158/1538-7445.AM2011-4720

Enhancing HER2/neu Specific T-cell Therapy by Targeting the Tumor Endothelium (41.11)

Abstract Success of adoptive T cell therapy for cancer can be hindered by the tumor stroma, which consists of factors that not only promote tumor growth but also prevent egress of tumor-specific T cells into the tumor parenchyma. We recently demonstrated that T cell transit through tumor vasculature is regulated by the endothelin B receptor (ETBR). In addition, the endothelin axis plays a major role in tumor cell growth, apoptosis, angiogenesis and metastasis. The purpose of this study was to determine if, in breast cancer, targeting endothelin-1 via ETBR blockade might abrogate the endothelial barrier and increase T cell homing to tumors, thereby augmenting the efficacy of HER2/neu antigen specific Type 1 helper (Th1) cell therapy of spontaneous HER2/neu+ mammary tumors. By reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC), we found overexpression of ETBR in peritumoral stroma of spontaneous mammary tumors derived from HER2/neu transgenic mice. We treated tumor-bearing mice with HER2/neu specific T cells alone or HER2/neu specific T cells + BQ-788, a specific ETBR inhibitor peptide. The addition decreased tumor growth by 84%. Thus, in this model of HER2/neu mediated breast cancer, targeting the tumor endothelium can significantly enhance the clinical efficacy of HER2/neu specific Th1 cells. Studies are underway to evaluate the biological mechanisms induced by endothelin targeting that cooperate with T cell therapy in the resulting significant success of the combined treatment. The data provide a rationale for combining tumor antigen specific T cell therapy with endothelin blockade to induce an effective anti tumor response in breast cancer.