Therapy In Breast Cancer Patients Research Articles

An analysis of PIK3CA hotspot mutations and response to neoadjuvant therapy in breast cancer patients from four prospective clinical trials.

The PI3K signaling pathway is frequently dysregulated in breast cancer (BC), and mutations in PIK3CA, are relevant for therapy resistance in HER2pos BC. Mutations in exons 9 or exon 20 may have different impact on response to neoadjuvant chemotherapy-based treatment regimens. We investigated PIK3CA mutations in 1691 early BC patients, randomized in four neoadjuvant multicenter trials: GeparQuattro (NCT00288002), GeparQuinto (NCT00567554), GeparSixto (NCT01426880) and GeparSepto (NCT01583426). The role of different PIK3CA exons and hotspots for pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) and patient survival was evaluated for distinct molecular subgroups and anti-HER2 treatment procedures. A total of 302 patients (17.9%) of the full cohort of 1691 patients had a tumor with a PIK3CA mutation, with a different prevalence in molecular subgroups: luminal/HER2neg 95 of 404 patients (23.5%), HER2pos 170 of 819 patients (20.8%) and TNBC 37 of 431 patients (7.9%). We identified mutations in PIK3CA exon 20 to be linked with worse response to anti-HER2 treatment (OR=0.507, 95%CI 0.320-0.802, p=0.004), especially in HR positive HER2 positive BC (OR=0.445, 95%CI 0.237-0.837, p=0.012). In contrast, exon 9 hotspot mutations p.E452K and p.E545K revealed no noteworthy differences in response therapy response. Luminal/HER2neg patients show a trend to have worse treatment response when PIK3CA was mutated. Interestingly, patients with residual disease after neoadjuvant treatment, have better survival when PIK3CA was mutated. PIK3CA hotspot mutation p.H1047R are associated with worse pCR rates after NACT in HER2pos BC, while hotspot mutations in exon 9 seems to have less impact.

The impact of online yoga on sleep and quality of life in women with breast cancer: a randomized trial.

There is growing evidence of the benefit of physical activity and mindfulness in breast cancer patients (HC et al. in BMC Complement Altern Med, 2017). Yoga offers a combination of both. The aim of this study was to establish an online yoga program for breast cancer patients and survivors. As the project was launched during the (COVID) pandemic restrictions, we intended to prove effective online yoga as a way to access supportive therapy independently of sanitary issues and geographic locations in rural regions. The two main outcomes were quality of life and sleep quality, and both were evaluated by standardized questionnaires (EORTC-QLQ 30 BR 23 and PSQI). Participants (n = 173) had breast cancer or a history of breast cancer and were randomized to either 6weeks online yoga, twice a week for 45min or a waiting control group. Our results show improved sleep quality in the PSQI score and improved subitems (dyspnea and physical activity) in the EORTC quality of life score. Online yoga seems to be a valid option in supportive therapy for breast cancer patients, as it improves physical fitness, dyspnea and overall sleep quality. It is also safe and cost effective as a remote intervention. Trial registration number and date of registration for prospectively registered trials: DRKS00029548, 07.07.2022.WHO International clinical trials registry platform number: DRKS00029548. The registration number of the ethical committee CAU in Kiel: D 589/20.

Statin use and risks of breast cancer recurrence and mortality.

Preclinical evidence suggests improved breast cancer survival associated with statin use, but findings from observational studies are conflicting and remain inconclusive. The objective of this study was to assess the association between statin use after cancer diagnosis and cancer outcomes among breast cancer patients. In this retrospective cohort study, 38,858 women aged ≥66 years who were diagnosed with localized and regional stage breast cancer from 2008 through 2017 were identified from the linked Surveillance, Epidemiology, and End Results Medicare database. Statin use was ascertained from Medicare Part D pharmacy claims data. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between post-diagnosis statin use and risks of breast cancer recurrence and breast cancer-specific mortality. Over a median follow-up of 2.9 years for recurrence and 3.7 years for mortality, 1446 women experienced a recurrence, and 2215 died from breast cancer. The mean duration of post-diagnosis statin use was 2.2 years. Statin use post-diagnosis was not associated with recurrence risk (HR, 1.05; 95% CI, 0.91-1.21), but was associated with a reduced risk of cancer-specific mortality (HR, 0.85; 95% CI, 0.75-0.96). The reduction was more pronounced in women with hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer (HR, 0.71; 95% CI, 0.57-0.88). These findings suggest that post-diagnosis statin use is associated with improved cancer-specific survival in women with breast cancer and should be confirmed in randomized trials of statin therapy in breast cancer patients.

Abstract PO3-02-14: The Safety of Breast Reconstruction: The Impact of Breast Reconstruction Surgery on Postoperative Adjuvant Therapy for Breast Cancer

Abstract Background: Postoperative adjuvant therapy is very important in treating breast cancer, and increasing numbers of patients are undergoing immediate breast reconstruction (IBR) at the same time as breast cancer surgery. However, the impact of breast reconstruction surgery on adjuvant therapy is controversial. In this multicenter cohort study led by the Japanese Breast Cancer Society, we examined the impact of reconstructive surgery on postoperative adjuvant therapy in breast cancer patients who underwent IBR. Methods: We examined the association between adjuvant therapy and complications of reconstructive surgery in 4726 patients with primary breast cancer who underwent IBR during the period from January 1, 2008 to December 31, 2016. Statistical analysis employed the χ2 test. Results: Of the 995 patients who received adjuvant chemotherapy, the median time from the date of surgery to the start of chemotherapy was 51.0 days, with 63 patients (6.2%) starting more than 90 days after surgery. Eighty-four IBR complications required surgery (8.4%), including infections and tissue expander (TE) removal. Of the 63 patients for whom chemotherapy was initiated 90 days or more after surgery, 10 patients (15.9%) had complications requiring surgery, significantly more than the 74 patients (7.9%) in the < 90 days group (P = 0.028). Post-mastectomy radiation therapy (PMRT) was performed after breast cancer surgery in 359 cases: 69 cases received autologous tissue irradiation, 46 TE irradiation, 241 silicone breast implant (SBI) irradiation, and 3 artificial material removal before irradiation. 5 cases given autologous tissue irradiation and 26 receiving artificial material irradiation (22 of whom the artificial material was removes) required surgery within 1 year after the cancer surgery due to complications of IBR. There was no significant difference in the frequency of complications requiring surgery between autologous tissue irradiation and artificial material irradiation (P=0.632). There were 33 complications (9.2%) requiring surgery in the irradiated group, significantly more than the 129 cases (3.0%) in the non-irradiated group (P< 0.001). Conclusion: Adjuvant chemotherapy was generally not delayed, but complications requiring surgery related to IBR were more frequent in those with delay beyond 90 days, suggesting that postoperative complications from breast reconstruction may have influenced the delay in initiating chemotherapy. Therefore, in cases for whom postoperative chemotherapy is anticipated, complications from breast reconstruction may have impacted outcomes, making preoperative risk assessment even more important. There was no difference in the frequency of reconstructive complication surgery according to whether autologous tissue irradiation or artificial material irradiation had been used, but further investigation is needed. Citation Format: Naomi Nagura, Akiko ogiya, Hiroko Nogi, Kazutaka Narui, Hiroki Mori, Shinsuke Sasada, Makoto Ishitobi, Naoto Kondo, Chikako Yamauchi, Ayaka Shimo, Miho Saiga, Hirohito Seki, Teruhisa Sakurai, Tadahiko Shien. The Safety of Breast Reconstruction: The Impact of Breast Reconstruction Surgery on Postoperative Adjuvant Therapy for Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-02-14.

Abstract PO5-04-13: Liquid Biopsy Testing in a Greek Cohort of ER-positive, HER2-negative metastatic breast cancer patients

Abstract AIM Endocrine therapy (ET) represents the first line treatment for patients with ER+, HER2- breast cancer, however disease progression is observed in many cases. PIK3CA and ESR1 are the most encountered mutated genes that have been associated with targeted molecular treatment, as well as with resistance to Endocrine Therapy. Liquid biopsy is a non-invasive procedure, that can provide “real-time” monitoring of disease progression and response to treatment. The aim of this study is to determine the mutation rate of ESR1 and PIK3CA genes in a selected cohort of 200 Greek breast cancer patients, using liquid biopsies and NGS technology. PATIENTS AND METHODS Liquid biopsies were collected from 200 ER-positive, HER2-negative metastatic breast cancer patients who have received at least one previous line of endocrine treatment. cfDNA was extracted using the QIAamp Circulating Nucleic Acid Kit (Qiagen). Library preparation was performed using Oncomine™ Breast cfDNA Research Assay (Thermofisher Scientific) and sequencing was carried out using Ion GeneStudio™ S5 System (Thermofisher Scientific). Ion Torrent Oncomine Knowledgebase Reporter was used in sequence analysis and interpretation of Copy number variations, SNPs, and indels. RESULTS Preliminary data of the first 49 examined samples demonstrated the prevalence of ESR1 and PIK3CA mutations in 20.4% (10/49) and 38.7% (19/49) of the cases respectively. The most frequently mutated codon in the ESR1 gene is the Y537, while in the PIK3CA gene, the H1047 codon is mainly altered. ESR1 and PIK3CA genes were co-mutated in 10.2% of the cases. Mutations in KRAS (6.1%) and TP53 (24%) were also detected. CONCLUSION More than 20% of the ER-positive, HER2-negative breast cancer patients with metastatic disease are eligible for targeted treatment with elacestrant. In addition, the high prevalence of mutations detected in our cohort indicates that liquid biopsy NGS panel testing can be used to monitor treatment response, track the development of resistance, and identify emerging genetic alterations that may guide treatment adjustments or the selection of alternative targeted therapies in breast cancer patients. REFERENCES Demir Cetinkaya B, Biray Avci C. Molecular perspective on targeted therapy in breast cancer: a review of current status. Med Oncol. 2022 Jul 14;39(10):149. doi: 10.1007/s12032-022-01749-1. PMID: 35834030; PMCID: PMC9281252. Liao H, Huang W, Pei W, Li H. Detection of ESR1 Mutations Based on Liquid Biopsy in Estrogen Receptor-Positive Metastatic Breast Cancer: Clinical Impacts and Prospects. Front Oncol. 2020 Dec 15;10:587671. doi: 10.3389/fonc.2020.587671. PMID: 33384956; PMCID: PMC7770162. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-elacestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast-cancer Citation Format: Nikolaos Tsoulos, Angeliki Meintani, Georgios Kapetsis, Chrysiis Chatzigiannidou-Florou, Aikaterini Tsantikidi, Stella Maxouri, Eleni Thanou, Kalliopi Aggelaina, Vasiliki Metaxa-Mariatou, Georgios Tsaousis, Ioannis Natsiopoulos, Vasileios Venizelos, Christos Markopoulos, Flora Zagouri, Eleftherios Kampletsas, Eirini Karyda, Dimitrios Tryfonopoulos, Konstantinos Papazisis, Dimitrios Ziogas, Ilias Athanasiadis, Eirini Papadopoulou, Georgios Nasioulas. Liquid Biopsy Testing in a Greek Cohort of ER-positive, HER2-negative metastatic breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-04-13.

The use of longitudinal CT-based radiomics and clinicopathological features predicts the pathological complete response of metastasized axillary lymph nodes in breast cancer

BackgroundAccurate assessment of axillary status after neoadjuvant therapy for breast cancer patients with axillary lymph node metastasis is important for the selection of appropriate subsequent axillary treatment decisions. Our objectives were to accurately predict whether the breast cancer patients with axillary lymph node metastases could achieve axillary pathological complete response (pCR).MethodsWe collected imaging data to extract longitudinal CT image features before and after neoadjuvant chemotherapy (NAC), analyzed the correlation between radiomics and clinicopathological features, and developed models to predict whether patients with axillary lymph node metastasis can achieve axillary pCR after NAC. The clinical utility of the models was determined via decision curve analysis (DCA). Subgroup analyses were also performed. Then, a nomogram was developed based on the model with the best predictive efficiency and clinical utility and was validated using the calibration plots.ResultsA total of 549 breast cancer patients with metastasized axillary lymph nodes were enrolled in this study. 42 independent radiomics features were selected from LASSO regression to construct a logistic regression model with clinicopathological features (LR radiomics-clinical combined model). The AUC of the LR radiomics-clinical combined model prediction performance was 0.861 in the training set and 0.891 in the testing set. For the HR + /HER2 − , HER2 + , and Triple negative subtype, the LR radiomics-clinical combined model yields the best prediction AUCs of 0.756, 0.812, and 0.928 in training sets, and AUCs of 0.757, 0.777 and 0.838 in testing sets, respectively.ConclusionsThe combination of radiomics features and clinicopathological characteristics can effectively predict axillary pCR status in NAC breast cancer patients.

Assessment of Chemotherapy-Induced Cardiac Dysfunction in Breast Cancer Patients: A Prospective Study.

Background Advances in cancer treatment have markedly improved survival rates but have also heightened morbidity due to treatment-related side effects. Despite this, the literature remains scarce on predicting the incidence of acute cardiac toxicity resulting from chemotherapy. We conducted a prospective evaluation to assess the incidence, timing, clinical correlates, global longitudinal strain (GLS), and response to heart failure (HF) therapy in patients experiencing cardiotoxicity. Aims and objectives Our study aimed to assess the cardiovascular complications of cancer therapy in breast cancer patients, with particular emphasis on therapy-related cardiac dysfunction. Materials and methods We conducted a prospective observational study to detect chemotherapy-related cardiac dysfunction (CTRCD) in breast cancer patients attending the outpatient department (OPD) or admitted to Dayanand Medical College and Hospital (DMCH), Ludhiana, Punjab, between March 1, 2020, and October 31, 2021. We assessed left ventricular ejection fraction (LVEF) at baseline, mid-chemotherapy, and post-chemotherapy. Patients who developed left ventricular dysfunction (LVD) had their chemotherapy regimen modified and were initiated on HF therapy. Results Ninety-seven patients (mean age: 50.74±10.30 years) were enrolled and categorized into the LVD group (n=13) and non-LVD group (n=84). CTRCD developed in 13 patients (13.4%). Patients with estrogen receptor (ER) positive, progesterone receptor (PR) positive, and human epidermal growth factor receptor 2 (HER2) positive status, as well as those in cancer stages III and IV, are at higher risk of developing LV dysfunction. Among the 13 patients, 10 (77%) experienced complete recovery, while three (23%) had partial recovery. Markers for partial recovery included cancer stages III-IV, younger age, lower body mass index (BMI), lower radiotherapy dosage, lower mean chemotherapy dosage, and left breast involvement. Conclusion Our findings suggest that acute cardiotoxicity is not linked to the cumulative dose of anthracyclines. Early detection, modification of chemotherapy regimens, and prompt initiation of CTRCD therapy can lead to substantial recovery of cardiac dysfunction.

Predictive Factors of Neoadjuvant Chemotherapy Response in Breast Cancer Validated by Three Anatomopathological Scores: Residual Cancer Burden, Chevallier System, and Tumor-Infiltrating Lymphocytes.

The aim of this retrospective, observational, descriptive study was to identify predictors of response to neoadjuvant therapy in breast cancer patients and to validate them using three anatomopathological scores, such as residual cancer burden (RCB) score, Chevallier system, and tumor-infiltrating lymphocytes (TIL) score. We conducted a study on 88 female patientsaged 37 to 78 years with confirmed breast cancerwho were indicated for neoadjuvant chemotherapy. We analyzed different individual variables (such as age, menarche, and menopause), clinical/imaging characteristics of the breast tumor and axillary nodes, immunohistochemical biomarkers (such as ER/PR/HER2 and Ki67), and histopathological features (such as subtype and grading) in relation to three anatomopathological scores calculated based on the surgical resection specimen. The percentage of patients who could have benefited from conservative surgery increased from 6% at the time of diagnosis to 20% post-primary systemic therapy (PST). Age under 49 (p = 0.01), premenopausal status (p < 0.01), no special type (NST) (p = 0.04), high Ki67 (p < 0.01), triple-negative breast cancer (TNBC) (p = 0.02) are positive predictive factors of neoadjuvant therapy, whilelobular/mixt carcinoma-type (p = 0.04), luminal A (p = 0.01), positive lymph node (p < 0.01), and low differentiation grade (p = 0.01) are negative predictive factors for the response to PST. There is a strong correlation between the RCB score and the Chevallier system for quantifying the response to PST, with most predictive factors being confirmed through appropriate statistical analysis for both.TIL score values correlated with only some of the predictors, most likely due to the importance of calculating this score on both biopsy specimens at diagnosis and resection specimens after chemotherapy.

Determining individual suitability for neoadjuvant systemic therapy in breast cancer patients through deep learning.

The survival advantage of neoadjuvant systemic therapy (NST) for breast cancer patients remains controversial, especially when considering the heterogeneous characteristics of individual patients. To discern the variability in responses to breast cancer treatment at the individual level and propose personalized treatment recommendations utilizing deep learning (DL). Six models were developed to offer individualized treatment suggestions. Outcomes for patients whose actual treatments aligned with model recommendations were compared to those whose did not. The influence of certain baseline features of patients on NST selection was visualized and quantified by multivariate logistic regression and Poisson regression analyses. Our study included 94,487 female breast cancer patients. The Balanced Individual Treatment Effect for Survival data (BITES) model outperformed other models in performance, showing a statistically significant protective effect with inverse probability treatment weighting (IPTW)-adjusted baseline features [IPTW-adjusted hazard ratio: 0.51, 95% confidence interval (CI), 0.41-0.64; IPTW-adjusted risk difference: 21.46, 95% CI 18.90-24.01; IPTW-adjusted difference in restricted mean survival time: 21.51, 95% CI 19.37-23.80]. Adherence to BITES recommendations is associated with reduced breast cancer mortality and fewer adverse effects. BITES suggests that patients with TNM stage IIB, IIIB, triple-negative subtype, a higher number of positive axillary lymph nodes, and larger tumors are most likely to benefit from NST. Our results demonstrated the potential of BITES to aid in clinical treatment decisions and offer quantitative treatment insights. In our further research, these models should be validated in clinical settings and additional patient features as well as outcome measures should be studied in depth.

Detecting Metastatic Patterns of Oligometastatic Breast Cancer: A Comparative Analysis of 18F-FDG PET/CT and Conventional CT Imaging.

Metastasis-directed therapy has the potential to improve progression-free and overall survival in oligometastatic disease (OMD). For breast cancer, however, randomized trials have failed so far to confirm this finding. Because the concept of metastasis-directed therapy in OMD is highly dependent on the accuracy of the imaging modality, we aimed to assess the impact of 18F-FDG PET/CT on the definition of OMD in breast cancer patients. Methods: Eighty patients with a total of 150 18F-FDG PET/CT images (between October 2006 and January 2022) were enrolled in this retrospective study at the Technical University of Munich. The inclusion criteria were OMD, defined as 1-5 distant metastases, at the time of 18F-FDG PET/CT. For the current study, we systemically compared the metastatic pattern on 18F-FDG PET/CT with conventional CT. Results: At the time of 18F-FDG PET/CT, 21.3% of patients (n = 32) had a first-time diagnosis of metastatic disease, 40.7% (n = 61) had a previous history of OMD, and 38% (n = 57) had a previous history of polymetastatic disease. In 45.3% of cases, the imaging modality (18F-FDG PET/CT vs. conventional CT) had an impact on the assessment of whether OMD was present. An identical metastatic pattern was observed in only 32% of cases.18F-FDG PET/CT detected additional metastases in 33.3% of cases, mostly in the nonregional lymph node system. Conclusion: The use of 18F-FDG PET/CT had a substantial impact on the definition of OMD and detection of metastatic pattern in breast cancer. Our results emphasize the importance of establishing a standardized definition for imaging modalities in future trials and clinical practices related to metastasis-directed therapy in breast cancer patients.

Efficacy of an aloe vera, chamomile, and thyme cosmetic cream for the prophylaxis and treatment of mild dermatitis induced by radiation therapy in breast cancer patients (the Alantel study)

ObjectivesRadiation-induced dermatitis (RD) is one of the most common toxicities in radiation therapy (RT) patients. Corticosteroids, immunosuppressants, and natural products (NPs) have been used as treatment. The objective was to evaluate the efficacy of a NPs-based cream (Alantel®) to reduce the incidence of RD in women with breast cancer undergoing RT treatment. DesignWe conducted a controlled, randomized, double-blind clinical trial. SettingRadiation Oncology Unit of the Reina Sofía Hospital and 5 Primary Care centers of the Cordoba and Guadalquivir Health District (Spain). InterventionsPatients assigned to the experimental group (GTA) were treated with Alantel, while those in the control group (GTE) were treated with a moisturizer and emollient cream. Main outcome measuresThe primary outcome variable was the incidence of RD. RD-free time, duration of RD, quality of life, and product safety were also assessed. ResultsSeventy patients were included in the study, 35 in the GTA and 35 in the GTE. The incidence of RD was lower in the GTA (71.4%) than in the GTE (91.4%) after 4 weeks of follow-up (RR = 0.78; NNT = 5; p < 0.031). The Skindex-29 questionnaire showed differences in the statement: “My skin condition makes it hard to work or do hobbies” (17.1% in the GTE vs. 2.9% in GTA; p = 0.024). ConclusionsThe higher efficacy of Alantel® compared to the control cream in reducing the incidence of RD in women with breast cancer has been demonstrated.

Assessing Agreement to the Use of Hormone Replacement Therapy for Breast Cancer Patients Experiencing Menopausal Symptoms

Assessing Agreement to the Use of Hormone Replacement Therapy for Breast Cancer Patients Experiencing Menopausal Symptoms

Establishment of patient-derived organoids for guiding personalized therapies in breast cancer patients.

Breast cancer has become the most commonly diagnosed cancer. The intra- and interpatient heterogeneity induced a considerable variation in treatment efficacy. There is an urgent requirement for preclinical models to anticipate the effectiveness of individualized drug responses. Patient-derived organoids (PDOs) can accurately recapitulate the architecture and biological characteristics of the origin tumor, making them a promising model that can overtake many limitations of cell lines and PDXs. However, it is still unclear whether PDOs-based drug testing can benefit breast cancer patients, particularly those with tumor recurrence or treatment resistance. Fresh tumor samples were surgically resected for organoid culture. Primary tumor samples and PDOs were subsequently subjected to H&E staining, immunohistochemical (IHC) analysis, and whole-exome sequencing (WES) to make comparisons. Drug sensitivity tests were performed to evaluate the feasibility of this model for predicting patient drug response in clinical practice. We established 75 patient-derived breast cancer organoid models. The results of H&E staining, IHC, and WES revealed that PDOs inherited the histologic and genetic characteristics of their parental tumor tissues. The PDOs successfully predicted the patient's drug response, and most cases exhibited consistency between PDOs' drug susceptibility test results and the clinical response of the matched patient. We conclude that the breast cancer organoids platform can be a potential preclinical tool used for the selection of effective drugs and guided personalized therapies for patients with advanced breast cancer.

Postmastectomy radiation therapy in breast cancer patients with micrometastatic disease in sentinel node dissection: A cohort study and meta-analysis

AimThe potential role of postmastectomy radiation therapy (PMRT) on prognosis in patients with T1-2 breast cancer and micrometastatic disease in sentinel lymph node dissection (SLND) has not yet been established. The aim of this study was to investigate the impact of PMRT on prognosis in patients with T1-2 breast cancer and micrometastatic in SLND. MethodA register- and population-based cohort was utilized by identifying eligible patients on the research database BcBase 3.0. Multivariate Cox regression models were applied for survival outcomes. In addition, a systematic literature review and meta-analysis including all relevant studies on this topic was performed. ResultsIn total, 956 patients fulfilling the inclusion criteria were found through the BcBaSe 3.0 with 237 (25.0 %) receiving PMRT and 719 (75.0 %) not receiving PMRT. No statistically significant differences between the two patient groups in terms of neither breast cancer-specific (adjusted Hazard Ratio (HR): 0.49; 95 % Confidence Interval (CI): 0.14 – 1.73) nor overall survival (adjusted HR: 0.63; 95 % CI: 0.29 – 1.35) was found. In the pooled analyses after literature review, PMRT did not result in better breast cancer-specific (5 studies; pooled HR: 1.06; 95 % CI: 0.88–1.27; I2 = 1 %; low certainty of evidence) or overall survival (6 studies; pooled HR: 1.01; 95 % CI: 0.91–1.13; I2 = 10 %; low certainty of evidence). ConclusionPMRT does not seem to impact survival in patients with T1 or T2 breast cancer with micrometastatic disease in SLND. Considering the low level of evidence and the relatively short follow-up of included studies, caution in interpreting the results into clinical practice is suggested.

Abstract 22: Development and characterization of human tumor specific cytotoxic lymphocytes for preclinical drug development

Abstract Heterogeneity within a tumor allows it to better adapt to changing conditions and can have therefore a negative impact on a patient’s prognosis, response to treatment and overall health. Breast cancer is a highly heterogeneous disease caused by distinct genetic mutations in mammary epithelial cells, resulting in significantly different forms of the disease and a need for highly personalized treatment schemes for patients. Hence, it is important to develop and improve (immuno)therapies for breast cancer patients. Adoptive T-cell therapy with autologous CD8+ cytotoxic T cell lymphocytes (CTL) is a promising method that has already shown promising effects in melanoma patients. Unfortunately, there is almost no information about the use in breast cancer patients. We developed an in vitro protocol to generate tumor-specific CTLs by priming on HER2+ breast cancer cell lines JIMT-1 and SKBR-3. Subsequently, these primed CTLs were tested in 2D and 3D immune cell killing assays in a life cell imaging device in combination with an endpoint viability assay. The activity was compared with unspecific CD8+T cells activated by phytohemagglutinin (PHA) or αCD2/αCD3/αCD28, HER2-peptide specific T cells and HER2-CAR T cells serving as a positive control. We investigated the feasibility to freeze CTLs for use in subsequent studies and validated the relevance of HER2 as the main druggable target in the tumor lines using an siRNA approach. The CTLs were most effective on JIMT-1 in a 3D setting, whereas the SKBR-3 CTLs displayed similar activity in 2D and in 3D. The respective CTLs were tumor line specific, as SKBR-3 CTLs did not kill efficiently the JIMT-1 cells and vice versa. The same CTLs displayed the same efficacy pattern after thawing but less pronounced. Thus, within one experimental set-up it is recommended to use either one. The Her2 knockdown in the target cells reduced the killing activity of the CTLs slightly. However, this effect was not statistically significant proving the importance of CTLs as treatment option as well as neoantigens as targets in drug development. In summary, the CTLs proved to capture the respective tumor heterogeneity showing high killing rates in both SK-BR3 and JIMT-1 being more active than HER2-peptide specific T cells. The availability of CTLs in a preclinical setting facilitates screening approaches for combinational studies. Beyond that they can serve as starting material to develop cancer vaccines and identify highly immunogenic neoantigens. Citation Format: Ina Rohleff, Lea Gröne, Kanstantsin Lashuk, Julia B. Schueler. Development and characterization of human tumor specific cytotoxic lymphocytes for preclinical drug development [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 22.

Abstract 3972: Personalized immune-organoid co-culture system for modeling the anti-tumor immune response in breast cancer patients

Abstract Recent studies have reported the effectiveness of immune checkpoint blockade (ICB) therapy in breast cancer patients. However, only a subset of patients benefits from ICB therapy due to various immunosuppressive mechanisms. The development of personalized predictive models for the anti-tumor immune response is essential to broaden the indication of ICB therapy. Here, we suggest a novel model platform using a co-culture system with patient tumor-derived organoids and matched immune cells to predict the immune response of individual patients. We successfully established fifty-nine cases of patient-derived breast cancer organoids with matched peripheral blood mononuclear cells (PBMCs) (subtype: Luminal A, 18.6%; Luminal B, 28.8%; Triple-negative breast cancer, 35.6%; HER2-positive, 17.0%). Three rapidly proliferating organoids (one Luminal B and two TNBC organoids) were selected to develop an immune-organoid co-culture (IOC) system. To mimic the anti-tumor immune response, cytotoxic immune cells were expanded from PBMCs by modified cytokine-induced killer (CIK) cell expansion protocol utilizing IL-2/IL-15. The CIK cells were co-cultured with patient-derived tumor organoids for killing assay to enable the prediction of ICB responsiveness in vitro. The CIK cells were expanded in the IOC system by stimulation of PBMC with IL-2/IL-15 in the presence of matched tumor organoids for 11 to 14 days. The CIK cells exhibited tumor organoid-specific killing (measured by Caspase-3, 15.22% ± 8.58, mean ± SEM) on organoid co-culture and showed induction of CD107a and CD137 expression in CD8+ T cells and NK cells with the PD-1 blocking antibody. The CIK-mediated tumor organoid deaths and immune cell activation were reduced by HLA class I blocking antibody (W6/32) treatment, confirming HLA-TCR mediated immune response and killing of tumor organoids in the IOC system (-14.85% in organoid-specific lysis and -7.46% in CD107a expression). In the live cell imaging of the IOC system, the interaction between T cells and tumor organoid cells and subsequent induction of Caspase 3 was noted. Our IOC system could directly measure the immunogenic tumor organoid killing by immune cells on ICB treatment in individual breast cancer patients. Moreover, the analysis of immune receptor profiles may reveal immune modulating mechanisms in each patient. We expect the IOC system to serve as a useful platform for personalized immunotherapy and exploration of combinatory therapy to enhance the anti-tumor efficacy of ICB in breast cancer patients. Citation Format: Cheol-Hwa Hong, Won-Ji Ryu, Shinyoung Park, Tae Yeong Kim, Yumi Hwang, Hyunju Han, Seongyeon Jo, Taeyong Kweon, Gun Min Kim, Min Hwan Kim, Hyung Seok Park, Joo Hyuk Sohn. Personalized immune-organoid co-culture system for modeling the anti-tumor immune response in breast cancer patients [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 3972.

Abstract 2014: Tumor glycosylation impacts the efficacy of HER2 targeting therapies

Abstract Cancer progression remains a major obstacle to the successful treatment of cancer. In HER2+ breast cancer, targeting therapies against HER2 have revolutionized the treatment landscape. However, predictive factors for response are largely unknown and a significant number of patients develop resistance. An extensive body of work has revealed a plethora of mechanisms of resistance. However, a key aspect of cancer cells has been largely overlooked: their aberrant glycosylation profile. Aberrant glycosylation of proteins is a hallmark in cancer and has been linked to multiple processes such as invasion, angiogenesis and modulation of the immune response. Yet the influence of altered glycosylation on the efficacy of HER2-targeted therapies remains unknown. Therefore, here, we address this question using clinical data, 3D co-culture systems and advanced live microscopy. Bioinformatics analysis of SPY-2 clinical trial data reveals an association of specific glycogenes with response to HER2-targeting therapies in breast cancer patients. We validated these findings in resistance cell models generated in-vitro and in-vivo using gain and loss of function assays. Furthermore, to provide a more relevant cell model system, we implement the use of 3D co-cultures of cancer spheroids and immune cells. Thus, our research addresses a largely unexplored area in cancer biology combining clinical data from tumor biopsies, trastuzumab-resistant cancer cell models and, live imaging of 3D heterotypic cultures. This work holds the potential to identify new markers of response to therapies and highlights the importance of the interplay of cancer cells and their microenvironment on the efficacy of current treatments. Citation Format: Ana Ruiz-Saenz, Roos Vincken, Denise Wolf, Veronica Steri, Laura van't Veer, John Martens, Danny Huylebroeck, Mark M. Moasser. Tumor glycosylation impacts the efficacy of HER2 targeting therapies [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 2014.

Modeling of Mouse Experiments Suggests that Optimal Anti-Hormonal Treatment for Breast Cancer is Diet-Dependent

Estrogen receptor positive breast cancer is frequently treated with anti-hormonal treatment such as aromatase inhibitors (AI). Interestingly, a high body mass index has been shown to have a negative impact on AI efficacy, most likely due to disturbances in steroid metabolism and adipokine production. Here, we propose a mathematical model based on a system of ordinary differential equations to investigate the effect of high-fat diet on tumor growth. We inform the model with data from mouse experiments, where the animals are fed with high-fat or control (normal) diet. By incorporating AI treatment with drug resistance into the model and by solving optimal control problems we found differential responses for control and high-fat diet. To the best of our knowledge, this is the first attempt to model optimal anti-hormonal treatment for breast cancer in the presence of drug resistance. Our results underline the importance of considering high-fat diet and obesity as factors influencing clinical outcomes during anti-hormonal therapies in breast cancer patients.

Skin perfusion and oxygen saturation after mastectomy and radiation therapy in breast cancer patients

The pathophysiological mechanism behind complications associated with postmastectomy radiotherapy (PMRT) and subsequent implant-based breast reconstruction are not completely understood. The aim of this study was to examine if there is a relationship between PMRT and microvascular perfusion and saturation in the skin after mastectomy and assess if there is impaired responsiveness to a topically applied vasodilator (Methyl nicotinate – MN).Skin microvascular perfusion and oxygenation >2 years after PMRT were measured using white light diffuse reflectance spectroscopy (DRS) and laser Doppler flowmetry (LDF) in the irradiated chest wall of 31 women with the contralateral breast as a control. In the non-irradiated breast, the perfusion after application of MN (median 0.84, 25th–75th centile 0.59–1.02 % RBC × mm/s) was higher compared to the irradiated chest wall (median 0.51, 25th–75th centile 0.21–0.68 % RBC × mm/s, p < 0.001). The same phenomenon was noted for saturation (median 91 %, 25th–75th centile 89–94 % compared to 89 % 25th–75th centile 77–93 %, p = 0.001). Eight of the women (26%) had a ≥10 % difference in skin oxygenation between the non-irradiated breast and the irradiated chest wall.These results indicate that late microvascular changes caused by radiotherapy of the chest wall significantly affect skin perfusion and oxygenation.

273 (PB-089) Poster - Effect of pharmacogenomic polymorphism on hormone therapy for breast cancer patients: systematic review and meta-analysis

273 (PB-089) Poster - Effect of pharmacogenomic polymorphism on hormone therapy for breast cancer patients: systematic review and meta-analysis