Neoadjuvant Endocrine Treatment Research Articles

Monocyte subsets in breast cancer patients under treatment with aromatase inhibitor and mucin-1 cancer vaccine

BackgroundMonocytes comprise subsets of classical, intermediate and non-classical monocytes with distinct anti- or pro-tumor effects in breast cancer (BC). They are modulated by estrogen, and can contribute to BC control by endocrine therapy in preclinical models.MethodsTo elucidate whether changes in monocyte subsets are associated with treatment and response, we investigated peripheral blood samples of 73 postmenopausal women with estrogen receptor (ER) positive BC, who received aromatase inhibitor therapy with or without the mucin-1 vaccine tecemotide in the ABCSG34 trial. Blood was retrieved at baseline, midterm and end of therapy, and was analyzed for the distribution and ER expression of monocyte subsets by flow cytometry.ResultsWhen 40 healthy, age-matched women were compared with BC patients before treatment start, ER levels of monocytes did not differ, yet patients presented with a higher frequency of classical and fewer non-classical monocytes. Endocrine therapy triggered a significant increase in ER levels in all monocyte subsets, without affecting subset distribution. Vaccination had no overall impact on subset frequency and ER expression. Yet, a shift from intermediate to classical monocytes during therapy correlated with changes in plasma cytokines and chemokines and was significantly associated with low residual cancer burden in vaccinated patients. Without tecemotide, baseline ER levels in classical monocytes were significantly higher in women with good response to endocrine therapy.ConclusionsThis study identified classical monocytes to be associated with ER positive BC and with patient response to neoadjuvant endocrine treatment and cancer vaccination.

Surgical outcomes of neoadjuvant endocrine treatment in early breast cancer: meta-analysis.

Neoadjuvant endocrine therapy presents an important downstaging option with lower toxicity than neoadjuvant chemotherapy in oestrogen receptor (ER)-positive early breast cancer. Meta-analysis of the effects of neoadjuvant endocrine therapy on surgical outcomes across randomized clinical trials (RCTs) and cohort studies has not previously been performed. A systematic review and meta-analysis was performed to evaluate the effect of neoadjuvant endocrine therapy on surgical outcomes (PROSPERO (international prospective register of systematic reviews, 2020)) compared with surgery followed by adjuvant endocrine therapy. PubMed and EMBASE were searched to identify RCT and cohort studies between 1946 and 27 March 2024. Two independent reviewers manually screened the identified records and extracted the data. Risk of bias was assessed using the Cochrane Collaboration tools and random-effects meta-analysis was done with ReviewManager. The search identified 2390 articles eligible for screening. The review included 20 studies (12 cohort and 8 RCTs); 19 were included in the meta-analysis with a total of 6382 patients. Overall, neoadjuvant endocrine therapy was associated with a lower mastectomy rate compared with surgery first (risk ratio (RR) 0.53, 95% c.i. 0.44 to 0.64). Subgroup analysis showed similar improvement in the mastectomy rate in the neoadjuvant endocrine therapy group versus control group irrespective of study type (RCT: RR 0.58, 95% c.i. 0.50 to 0.66; cohorts: RR 0.48, 95% c.i. 0.33 to 0.70). There was no difference in the mastectomy rate by duration of neoadjuvant endocrine therapy (more than 4 months: RR 0.57, 95% c.i. 0.42 to 0.78; 4 months or less than 4 months: RR 0.52, 95% c.i. 0.43 to 0.64). Most of the studies were characterized by moderate-quality evidence with significant heterogeneity. Neoadjuvant endocrine therapy is associated with a reduction in mastectomy rate. Given the moderate methodological quality of previous studies, further RCTs are required. CRD42020209257.

Neoadjuvant endocrine treatment: Precious but insufficiently discovered issue

We would like to emphazise the importance of neoadjuvant endocrine treatment which is overshadowed by neoadjuvant chemotherapy for breast cancer patients. Missing knowledge is evaluation in terms of conventional notion of neoadjuvant chemotherapy that is it better to complete before surgery at least for some selected patients? Another point is, since it is a long term treatment, may be it will be a way give patients the chance to follow up without surgery. So this correspondence tries to ask two questions; shall we think about lengthening the duration of neoadjuvant endocrine treatment in selected patients and who are these patients?

Favorable outcome of neoadjuvant endocrine treatment than surgery-first in female HR-positive/HER2-negative breast cancer patients-A NCDB analysis (2010-2016).

To assess the efficacy of neoadjuvant endocrine therapy in female HR-positive/HER2-negative breast cancer patients. We identified female patients aged ≥18 years with cT1-4N0-XM0, HR(+), and HER2(-) breast cancer from the National Cancer Database. The patients who underwent surgery first were categorized as "surgery-first," while those who received NET before surgery were classified as "NET." Propensity score-matching, Cox proportional-hazard model, variance inflation factors, and interaction analysis were employed to estimate the correlation between NET and survival outcomes. Among 432,387 cases, 2914 NET patients and 2914 surgery-first patients were matched. Compared with the surgery-first group, the NET group received less adjuvant chemotherapy (p < 0.001). Furthermore, the NET group exhibited higher survival probabilities compared with the surgery-first group (3 years: 91.4% vs. 82.1%; 5 years: 82.1% vs. 66.8%). Multivariate Cox analysis indicated that NET was associated with improved OS (surgery-first vs. NET: HR 2.17, 95% CI: 1.93-2.44). Age over 55 years old, having public insurance, higher CDCC score, higher NSBR grade, ER(+)PR(-), and advanced clinical stage were related to worse OS (all p < 0.05). There was an interaction between age, race, income, and home and treatment regimen (all p < 0.05). NET may be a more effective treatment procedure than surgery-first in female HR-positive/HER2-negative, non-metastatic breast cancer patients. Future clinical studies with more detailed data will provide higher-level evidence-based data.

Neoadjuvant endocrine treatment in hormone receptor-positive breast cancer: Does it result in more breast-conserving surgery?

Patients with locally advanced endocrine positive tumors who will not benefit from chemotherapy can be treated by either primary surgery or neoadjuvant endocrine therapy (NET). How often does NET result in breast-conserving surgery (BCS)? We conducted a literature search in PubMed and Embase, to identify articles on surgical treatment after NET. In 19 studies the pathological complete response (pCR) rate was reported after NET; an overall pCR rate of 1% was found. Compared with neoadjuvant chemotherapy (NCT), the BCS rate was significantly higher after NET (OR 0.60; 95% CI, 0.51-0.69; P < 0.00001). The surgical conversion rate was reported in eight studies [4-75.9%], with a mean of 30.2%. This review found that one out of three patients becomes eligible for BCS after treatment with NET.

Informative tools to optimize neoadjuvant therapy in ER positive, HER2 negative breast cancers.

e12595 Background: Neoadjuvant therapy (NAT) in HR+/HER2- tumors is often disputable. While the role of Oncotype DX has been well established in adjuvant settings, its clinical utility and potential implementation for prediction of NAT benefit requires further study. This ongoing study aims to report the feasibility of Oncotype DX testing on core biopsy specimens prior to NAT in patients with operable HR+/HER2- breast cancer. The effect of the recurrence score (RS) on systemic treatment recommendations and its correlation to dynamic markers of proliferation and NAT response will be evaluated. Methods: Participants with clinical T2-T4 and/or node positive HR+/HER2- breast cancer had Oncotype DX testing done prior to NAT. Clinico-pathological information, treatment regimens, clinical, radiologic, and pathological responses were recorded. Results: Of the 48 patients with HR+/HER2- breast cancer referred to BC Cancer Vancouver for consideration of NAT between September 2021 and January 2023, 26 were eligible and enrolled in the study. The success rate of the Oncotype DX on core biopsy samples was 96%. The mean turnaround time from patient consent to RS report was 19 calendar days. Approximately 32% of tumors had a RS equal or higher than 26 while 4% had a score less than 10. Nearly 25% of neoadjuvant treatment recommendations were changed based on the RS. Overall, 33% of patients received neoadjuvant chemotherapy, 54% received neoadjuvant endocrine treatment, and 12.5% proceeded with upfront surgery. Conclusions: The success rate of Oncotype DX testing on core biopsy samples was excellent. There were multiple factors that influenced trial enrollment, highlighting the low uptake and equipoise of NAT use in HR+/HER2- tumors. The Oncotype DX testing resulted in a change in systemic treatment plan in 25% of patients. Analyses are ongoing to correlate the recurrence score to NAT response, dynamic Ki-67 changes and breast MRI changes. Clinical trial information: NCT03790813 .

Abstract P5-09-03: Real World Data on Neoadjuvant Endocrine Treatment and Ki67 Assessment in ER+/HER2- Breast Cancer. Results from a Single-Institution Prospective Cohort Study

Abstract Purpose: Neoadjuvant endocrine treatment (NET) has become a useful tool for the downstaging of luminal-like breast cancers in postmenopausal patients. It enables us to increase breast conserving surgery (BCS) rates and provides an opportunity for assessing in vivo NET effectiveness and studying any biological changes that may act as valid biomarkers. The purpose of this study was to evaluate the effectiveness of NET as well as to assess the role of Ki67 proliferation rate changes as an indicator of endocrine responsiveness. Methods: From June 2016 to January 2022, a single-institution cohort of patients treated with NET and further surgery was evaluated. In patients with Ki67≥10%, a second core biopsy was performed after four weeks. Information regarding histopathological and clinical changes, as well as surgical management, was gathered. Results: A total of 168 estrogen receptor positive (ER+)/HER2 negative patients were included. The median age at diagnosis was 69.5 years old (IQR: 16.0). The median treatment duration was 5.0 months (IQR: 4.0). Median maximum size in the surgical sample was 44.0% smaller than pretreatment size measured by ultrasound (p&amp;lt;.0001), showing an inverse linear relationship with treatment duration. Median pretreatment Ki67 expression was 20.0% (IQR: 18.0) and was reduced to 5.0% (IQR: 8.0) after four weeks, and to 2.0% (IQR: 7.25) in the surgical sample (p&amp;lt; 0.0001). Other significant downgrading changes were observed with respect to tumor grade (p&amp;lt; 0.0001) and progesterone receptor (PR) expression (p&amp;lt; 0.0001). BCS was performed on 145 patients (86.3%). One case of pathological complete response was recorded. A larger Ki67 fold-change after four weeks was significantly related to a PEPI score of 0 (p&amp;lt; 0.002). No differences were observed between luminal A- and B-like tumors with regard to fold-change and PEPI score. No treatment abandonment was produced during the study. Conclusions: In our cohort, NET has proven effective for tumor size and Ki67 downstaging. This results in a higher rate of conservative surgery, aids in therapeutic decision-making, provides prognostic information, and constitutes a safe and well-tolerated approach Biological changes after NET Patient and tumor characteristics Citation Format: Covadonga Marti, Laura Frias, Adolfo Loayza, Elisa Moreno, Marcos Meléndez, Jose Ignacio Sanchez-Mendez. Real World Data on Neoadjuvant Endocrine Treatment and Ki67 Assessment in ER+/HER2- Breast Cancer. Results from a Single-Institution Prospective Cohort Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-09-03.

Abstract P2-11-27: Peritumoral desmoplasia in breast cancer – does it matter?

Abstract Background: The peritumoral deposition of collagen is termed desmoplasia. It is characterized by the formation of new extracellular matrix, resulting from activation of tumor-associated fibroblasts. In other cancer entities (e.g. pancreatic and thyroid cancer), the presence of desmoplasia has significant prognostic impact. Furthermore, in preclinical models, targeting desmoplasia therapeutically to normalize the microenvironment has shown promising results. Yet, the role of desmoplasia in breast cancer is still unclear and data regarding this topic is rare. The aim of this study is to investigate whether desmoplasia is present in breast cancer and whether it is associated with other prognostic factors. Methods: We retrospectively analyzed 361 patients with breast cancer who had oncologic surgery at the University Hospital Leipzig, Germany between 2015 and 2018. Patients underwent operation without any preoperative therapy, after neoadjuvant chemotherapy, or after neoadjuvant endocrine treatment. One patient had had radiation in the past. Information regarding desmoplastic tumor reaction and other pathologic characteristics were retrospectively retrieved from the pathology reports. Results: Overall, data regarding desmoplasia was available for 197 patients. Median patient age was 61 years [IQR 50-73] with the most frequent tumor entity (62.9%) being invasive carcinoma of no special type (NST). 184 (93.4%) patients had either a T1 or T2 stadium. Patients had no preoperative therapy, neoadjuvant chemotherapy, or neoadjuvant endocrine treatment in 131 (66.5%), 36 (18.3%) and 29 (14.7%) cases, respectively. Desmoplasia was present in 151 cases. 46 cases showed no evidence for desmoplasia. Median age was almost similar in both groups (60.5 years vs. 61 years). Presence of desmoplasia was not associated with lymph node metastasis (pN1: 26.1% in patients with desmoplasia vs. 31.1% in patients without desmoplasia). Furthermore, there were only small differences in tumor grade between the two groups (G1: 45.7%, G2: 37.8%, G3: 15.9% [patients with desmoplasia] vs. G1: 39.1%, G2: 43.5%, G3: 17.4% [patients with no desmoplasia]. Tumor stages pT1 and pT2 were approximately equal in the two groups (pT1: 66.2% vs. 65.2%, pT2: 29.1% vs. 21.7%). There was a slight trend towards a higher (pT3) tumor stage in patients with desmoplasia (13%) compared to the patients with no desmoplasia (2.7%). Interestingly, the presence of desmoplasia was significantly associated with a higher number of Luminal A subtypes (64.2% vs. 47.8%, p-value: 0.047) and a lower number of triple negative carcinoma (10.6% vs. 17.4%. p-value: 0.22). Conclusions: In our analysis, the presence of desmoplasia is not associated with a more aggressive phenotype of breast cancer. There are hints for an association with a favorable subtype. Larger studies are necessary to validate these data and gain further information. Citation Format: Laura Weydandt, Benjamin Wolf, Lars-Christian Horn, Bahriye Aktas. Peritumoral desmoplasia in breast cancer – does it matter? [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-27.

Abstract PD9-03: Breast Cancer Microenvironment Change After Neoadjuvant Endocrine Treatment Breast Cancer Microenvironment Change After Neoadjuvant Endocrine Treatment

Abstract Background: Estrogen receptor positive (ER+)/HER-2 negative breast cancer (BC) is considered to be an immunologically cold tumor compared to triple negative breast cancer. Therefore, the tumor microenvironment (TME) of ER+/HER-2 negative BC is understudied. The receptor activator of nuclear factor-kB ligand (RANKL)-RANK pathway was first identified, as mediator of T and dendritic cells interaction, but it is mostly known for its role as key regulator of bone remodeling and pathophysiology of bone metastases. RANK is a member of the tumor necrosis factor receptor (TNFR) superfamily that is activated upon RANKL binding, promoting cell proliferation, survival and differentiation. The RANKL-RANK pathway also emerged as a major mediator of hormone-driven breast carcinogenesis. The aim of this study is to investigate the TME and the immune response during neoadjuvant endocrine therapy (NET) and to correlate this with the treatment response in a real life setting. Methods: Expressions of immune checkpoint receptors and immune cells were examined immunohistochemically in pre- and post- NET on a cohort of 44 ER+/HER-2 negative BC patients. They were treated with tamoxifen (N=8), an aromatase inhibitor (N=36) or a combination of an aromatase inhibitor with a PI3K inhibitor (N= 7) for a median duration of 6 months (range 1-32) months. Monoclonal antibodies for PDL-1, PD-1, TIM-3, LAG-3, CTLA-4, CD4, CD68, FOXP3, RANK and RANKL were used. All staining were done according to validated protocols and scoring was done by a pathologist specialized in breast cancer. Positivity was defined as staining &amp;gt; 1% on TILs. Response to NET was evaluated according to tumor size change on imaging and Ki-67 change. Results: The median age was 62.5 (44–90.3) years. Diameter of tumor size decreased with a mean of 7.818 mm (p &amp;lt; 0.0001) during NET and the value of Ki-67 value decreased significantly after NET (value, p&amp;lt; 0.0004). An increase in PD-L1 expression after NET showed a trend towards significant (p= 0.088) and RANK expression on TILs significantly decreased with a median of 30% (range= -70 to 85) (p= 0.0007) after NET. A good response to NET defined as a decrease in tumor size and/or decrease of Ki-67 was found to be associated with a longer duration of NET, a change of CD4+ T-cells, a change of RANK expression on TILs and a higher number of CD68+ tumor-associated macrophages before the start of NET and also RANK expression on TILs before the start of NET. Conclusion: The immune micro-environment plays an important role in ER+/HER-2 negative BC. NET influences the composition and/or functional state of the infiltrating immune cells. Furthermore, changes in the immune micro-environment are also associated with treatment response. Breast Cancer Microenvironment Change After Neoadjuvant Endocrine Treatment Comparison of continuous and categorical parameters before and after NET. Comparison of the continuous parameters was done using Wilcoxon signed rank test. Comparison of the categorical parameters was done using a Chi-square test. sTIL: stromal tumour infiltrating lymphocytes and NET: neoadjuvant endocrine therapy. Bold values denote statistical significance at the p &amp;lt; 0.05 level. Citation Format: Gizem Oner, Glenn Broeckx, Christophe Van Berckelaer, Sevilay Altintas, Zafer Canturk, Wiebren Tjalma, Karen Zwaenepoel, Zwi Berneman, Marc Peeters, Patrick Pauwels, Peter A van Dam. Breast Cancer Microenvironment Change After Neoadjuvant Endocrine Treatment Breast Cancer Microenvironment Change After Neoadjuvant Endocrine Treatment [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD9-03.

Abstract P2-21-02: Longitudinal tumor-immune microenvironment changes in patients with clinical luminal A early breast cancer treated with neoadjuvant palbociclib and endocrine therapy: results from the Swedish randomized PREDIX Luminal A trial

Abstract Introduction: The use of preoperative CDK4/6 inhibitors combined with endocrine treatment remains investigational in breast cancer (BC), while their effect on tumor-immune microenvironment (TIME) in luminal BC is the subject of few published studies. The aim of this study was to characterize the treatment-induced changes of TIME at a spatial proteomic and bulk tumor transcriptomic level in clinical luminal A BC patients treated with neoadjuvant palbociclib and endocrine treatment. Methods: The PREDIX Luminal A phase II randomized clinical trial (NCT02592083) included patients with stage 2-3 BC and IHC-defined luminal A biology (ER+ and PR+, HER2-, low proliferation) treated with preoperative ET (tamoxifen or aromatase inhibitor) with or without the addition of CDK4/6i palbociclib, based on the early change of Ki67 levels. A core biopsy was obtained at baseline, after 10 weeks of treatment (on-treatment) and at surgery. The study was closed after the inclusion of 10 patients due to slow accrual. By using formalin-fixed paraffin-embedded tissue from all timepoints, we performed the GeoMx® Digital Spatial Profiling (DSP, NanoString, Seattle, WA, USA) for the spatial profiling of 27 immune cell and tumor markers (immune cell profiling core and pan-tumor panels) both at intra-epithelial and stromal tissue segments. Upon data normalization, a linear mixed model was adopted for differential marker expression assessment between the different timepoints and treatment arms, using the DSP Suite® software. RNA was also extracted from fresh-frozen biopsies and the nCounter® Breast Cancer 360™ panel (NanoString) was used for gene expression profiling of 776 targets and data analysis was performed using the nSolver® software. Results: A total of 7 patients received palbociclib + ET and 3 were treated with ET only. All patients experienced an on-treatment radiological partial response while no patient achieved pathological complete response. While ET suppressed the ER axis in both palbociclib-treated and untreated patients, treatment with palbociclib additionally led to cell-cycle arrest as evidenced by a decrease in proliferation and downregulation of cell-cycle gene pathways. Immune-related protein markers were enriched in the stroma segments and pan-tumor markers were enriched in the intra-epithelial segments at all timepoints. In palbociclib-treated patients, immune cell markers (e.g. CD45, CD68, CD20, CD4, HLA-DR) were significantly enriched in on-treatment samples (n=3) both in tumor and stromal segments, while these expression changes were reversed between on-treatment and surgery. In the ET-treated patients immune markers reflecting e.g. T-, B- and/or antigen-presenting-cells were significantly enriched at the operation samples (n=2), in the intra-epithelial but not in the stromal areas. This finding was confirmed also at the gene level, where immune-related pathways (e.g. chemokine and cytokine activity and receptor binding) were upregulated in the palbociclib-treated patients on-treatment but they were partially abrogated at surgery. The ET-only treated patients presented with enhanced immune activation gene sets at both on- and post-treatment timepoints Conclusion: The findings of this small hypothesis-generating study indicate an upregulation of immune function during treatment with palbociclib and ET and an altered tumor microenvironment. The prognostic and potential therapeutic implications of sensitizing tumors to subsequent chemotherapy and immunotherapy need to be further investigated in larger studies. Citation Format: Ioannis Zerdes, Dimitrios Salgkamis, Alexios Matikas, Lars Selander, Kang Wang, Evangelos Tzoras, Emmanouil Sifakis, Susanne Agartz, Xinsong Chen, Mats Hellström, Johan Hartman, Jonas Bergh, Theodoros Foukakis, Thomas Hatschek. Longitudinal tumor-immune microenvironment changes in patients with clinical luminal A early breast cancer treated with neoadjuvant palbociclib and endocrine therapy: results from the Swedish randomized PREDIX Luminal A trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-21-02.

Abstract 1233: A novel 14-gene signature to predict response to neoadjuvant chemotherapy and endocrine treatment in breast cancer patients

Abstract mRNA transcriptomic markers have become a key tool in the classification of breast cancer and deciding treatment regimens for patients. However, limited studies have evaluated markers that might be predictive of response to neoadjuvant treatment (chemotherapy and endocrine treatment). Defining such key markers that are associated with treatment response could offer new insights on the relative molecular mechanisms and provide more tailored treatment regimens to target pathways that might be over-represented. We aimed to identify mRNA expression markers associated with breast cancer patients’ response to neoadjuvant treatment from a pool of studies in which tumor samples were collected at pre-treatment and on-treatment timepoints. We collated 1194 pre- and on-treatment samples (721 unique patients) from 9 publicly available gene expression datasets that met our inclusion criteria. The standardized gene expression values from each study were merged in a global matrix of 1551 genes and 1194 samples. Differential Gene Expression Analysis adjusted for timepoint, pam50 subtype (as predicted by the genefu package in R), treatment and batch effects was conducted. 14 significantly (FDR = 0.05) differentially expressed were identified (CCNA2, RFC3, VRK1, PSMB2, ALDH7A1, RRM2, ADRM1, TSPAN4, ZNF473, RNH1, HDAC1, CDK1, SMC1A and TOR1AIP1) when responders and non-responders were compared, some of which are known drug targets (e.g. PSMB2/carfilzomib). Using the set of identified genes we performed Monte-Carlo consensus clustering on the full set (optimal number of clusters: 6). Clusters were significantly associated with response (p = 2·10-8), timepoint (p &amp;lt; 10-15) and pam50 subtype (p &amp;lt; 10-15), but not treatment (p = 0.35). We then split our data into a training, a validation and a test set (776, 299, 119 samples respectively) and used the 14 genes (alone or in combination with metadata) as predictors to fit three types of machine learning models (lasso-regularized Logistic Regression, Decision Trees and Support Vector Machines). Support Vector Machines demonstrated the best classification performance on the validation set (75% classification accuracy) and achieved accuracy of 80% on the test set. Pathway analysis based on the identified genes revealed enriched nuclear membrane organization, protein deubiquitination, DNA replication and histone modification pathways. Prediction of response to treatment at baseline or mid-treatment can aid in patient stratification in the neoadjuvant setting and separate patients who would benefit from treatment the most and could undergo a less extensive surgical operation from patients who are unlikely to respond and should be scheduled for surgery sooner. This kind of early intervention has the potential to lead to improved patient outcomes and reduced side effects from unnecessary treatment administration. Citation Format: Aristeidis Sionakidis, Jonine D. Figueroa, Timothy I. Cannings. A novel 14-gene signature to predict response to neoadjuvant chemotherapy and endocrine treatment in breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1233.

Altered breast cancer management due to COVID-19 during first lockdown and the follow up results

Introduction: The COVID-19 pandemic has significantly impacted healthcare delivery and has led to alterations in cancer care. From 16th March to 8th May 2020 lockdown was imposed with alert level-4. The objective of our study was to determine the alteration in breast cancer management and the final outcome of those alterations in our hospital.Methods: All patients who were discussed in MDT for surgical treatment during the 1st lockdown were included in the study and were followed prospectively till November 2021. Patient demographics, standard and altered surgical management of these patients and final treatment outcomes were recorded.Results: A total of 91 patients were treated during this period of which 20 were diagnosed by screening and 71 were symptomatic. The median age was 62 years (range 28-98). Forty-six patients (50.55%) had altered management due to COVID. Among them, neoadjuvant chemotherapy was omitted in 4 patients where it was standard, 32 had bridging neoadjuvant endocrine treatment (NET), 1 had mastectomy when she was eligible for breast conserving surgery and 9 patients couldn't have immediate reconstruction after mastectomy. Twenty-eight patients (87.5%) had surgery after NET and remaining 4 patients were converted to primary endocrine treatment. Of the 9 patients who couldn't have immediate reconstruction two patients are waiting for delayed DIEP, 2 patients decided not to have any reconstruction, 1 patient is still undergoing adjuvant treatment, one patient was not suitable for any reconstruction due to smoking and increased BMI and 3 patients are yet to be seen in the clinic.Conclusion: COVID-19 has significantly impacted the breast cancer services and is having repercussions on follow-up treatment as well. Introduction: The COVID-19 pandemic has significantly impacted healthcare delivery and has led to alterations in cancer care. From 16th March to 8th May 2020 lockdown was imposed with alert level-4. The objective of our study was to determine the alteration in breast cancer management and the final outcome of those alterations in our hospital. Methods: All patients who were discussed in MDT for surgical treatment during the 1st lockdown were included in the study and were followed prospectively till November 2021. Patient demographics, standard and altered surgical management of these patients and final treatment outcomes were recorded. Results: A total of 91 patients were treated during this period of which 20 were diagnosed by screening and 71 were symptomatic. The median age was 62 years (range 28-98). Forty-six patients (50.55%) had altered management due to COVID. Among them, neoadjuvant chemotherapy was omitted in 4 patients where it was standard, 32 had bridging neoadjuvant endocrine treatment (NET), 1 had mastectomy when she was eligible for breast conserving surgery and 9 patients couldn't have immediate reconstruction after mastectomy. Twenty-eight patients (87.5%) had surgery after NET and remaining 4 patients were converted to primary endocrine treatment. Of the 9 patients who couldn't have immediate reconstruction two patients are waiting for delayed DIEP, 2 patients decided not to have any reconstruction, 1 patient is still undergoing adjuvant treatment, one patient was not suitable for any reconstruction due to smoking and increased BMI and 3 patients are yet to be seen in the clinic. Conclusion: COVID-19 has significantly impacted the breast cancer services and is having repercussions on follow-up treatment as well.

The Clinical Impact of Neoadjuvant Endocrine Treatment on Luminal-like Breast Cancers and Its Prognostic Significance: Results from a Single-Institution Prospective Cohort Study.

Purpose: Neoadjuvant endocrine treatment (NET) has become a useful tool for the downstaging of luminal-like breast cancers in postmenopausal patients. It enables us to increase breast- conserving surgery (BCS) rates, provides an opportunity for us to assess in vivo NET effectiveness, and allows us to study any biological changes that may act as valid biomarkers. The purpose of this study was to evaluate the safety and effectiveness of NET, and to assess the role of Ki67 proliferation rate changes as an indicator of endocrine responsiveness. Methods: From 2016 to 2020, a single-institution cohort of patients, treated with NET and further surgery, was evaluated. In patients with Ki67 ≥ 10%, a second core biopsy was performed after four weeks. Information regarding histopathological and clinical changes was gathered. Results: A total of 115 estrogen receptor-positive (ER+)/HER2-negative patients were included. The median treatment duration was 5.0 months (IQR: 2.0–6.0). The median maximum size in the surgical sample was 40% smaller than the pretreatment size measured by ultrasound (p < 0.0001). The median pretreatment Ki67 expression was 20.0% (IQR: 12.0–30.0), and was reduced to 5.0% (IQR: 1.8–10.0) after four weeks, and to 2.0% (IQR: 1.0–8.0) in the surgical sample (p < 0.0001). BCS was performed on 98 patients (85.2%). No pathological complete responses were recorded. A larger Ki67 fold change after four weeks was significantly related to a PEPI score of zero (p < 0.002). No differences were observed between luminal A- and B-like tumors, with regard to fold change and PEPI score. Conclusions: In our cohort, NET was proven to be effective for tumor size and Ki67 downstaging. This resulted in a higher rate of conservative surgery, aided in therapeutic decision making, provided prognostic information, and constituted a safe and well-tolerated approach.

Cyclin-dependent kinase 4 and 6 inhibitors in combination with neoadjuvant endocrine therapy in estrogen receptor-positive early breast cancer: a systematic review and meta-analysis.

The combination of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors and endocrine treatment has benefited patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER + /HER2-) metastatic breast cancer; however, its effects in the neoadjuvant setting for ER + /HER2- early breast cancer (EBC) are unclear. Systematic searches were performed in PubMed, Embase, Cochrane Library, and major oncological meetings for trials of CDK4/6 inhibitors plus neoadjuvant endocrine treatment (NET) vs. NET/neoadjuvant chemotherapy (NACT) alone up to January 30, 2021. We assessed the efficacy of CDK4/6 inhibitors plus NET vs. NET/NACT alone in ER + /HER2- EBC. Six studies that included 803 patients treated with CDK4/6 inhibitors plus NET vs. NET/NACT alone were used. Compared with NET/NACT alone, CDK4/6 inhibitors plus NET increased the complete cell cycle arrest (CCCA) rate (OR, 9.00; 95% CI, 5.42-14.96; P < 0.001). Nonsignificant differences between CDK4/6 inhibitors and NET/NACT alone occurred in the preoperative endocrine prognostic index (PEPI)-0 rate (OR, 1.13; 95% CI, 0.59-2.18; P = 0.71), pathological complete response (pCR) rate (OR, 0.75; 95% CI, 0.13-4.29; P = 0.74), objective response rate (ORR) (OR, 0.70; 95% CI, 0.21-2.29; P = 0.55), and disease control rate (DCR) (OR, 1.16; 95% CI, 0.47-2.89; P = 0.74). CDK4/6 inhibitors plus NET indicated a high risk of neutropenia (OR, 56.43; 95% CI, 15.76-202.11; P < 0.001) as an adverse effect (AE) and elevated alanine aminotransferase (ALT) level (OR, 15.30; 95% CI, 2.02-115.98; P = 0.008) as grade 3/4 AEs. Compared with NET/NACT alone, CDK4/6 inhibitors plus NET increased CCCA rate in ER + /HER2- EBC patients. CDK4/6 inhibitors plus NET did not substantially improve the PEPI-0 rate, pCR rate, ORR, or DCR. The combination increased the risk of neutropenia and elevated ALT levels. In the neoadjuvant setting, addition of CDK4/6 inhibitors to NET may be an option for treating ER + /HER2- EBC.

Abstract P4-02-02: The association between adiposity and anti-proliferative response to neoadjuvant endocrine therapy with letrozole in post-menopausal patients with estrogen receptor positive breast cancer

Abstract Background: The impact of obesity on the efficacy of endocrine treatment (ET) in patients with estrogen receptor positive (ER+) breast cancer (BC) is poorly investigated. Several neoadjuvant trials, using changes in Ki67 as biomarker of anti-proliferative response, have demonstrated that neoadjuvant ET improves surgical and clinical outcomes. A recent study has shown that the subgroup of patients with an anti-proliferative response to neoadjuvant aromatase inhibition has a better prognosis as compared to the other patients (Smith et al., The Lancet 2020). However, it is unclear if obesity, and mammary adiposity are associated with anti-proliferative response. Material and Methods: We included 56 post-menopausal patients with ER+ BC that were treated with 4 months of neoadjuvant letrozole in a single institution. Body mass index (BMI) was categorized according to the WHO criteria and considered both as categorical and continuous variable. Centralized Ki67 assessment was performed as per study protocol. Consistently with previous neoadjuvant clinical trials, Ki67 index was dichotomized (&amp;lt;14% and ≥14%) identifying three groups of patients according to Ki67 at baseline (Ki67bl) - Ki67 at surgery (Ki67srg) (“high - high”, “high - low”, “low - low”). Anti-proliferative response was defined as “high - low”, absence of response as “high - high” while “low - low” were excluded from the response analysis. Digital assessment of mammary adipocytes (distant from the tumor and cancer-associated adipocytes - CAAs) and assessment of tumor infiltrating lymphocytes (TILs) were performed on scanned H&amp;E BC slides, derived from surgical specimens. We performed univariate and multivariable logistic regressions adjusted for Ki67bl to evaluate the association of BMI, adipocyte size, TILs (dichotomized at 10%) with response to ET. The Wilcoxon rank-sum test was performed to evaluate the association between adipocyte size and histology. Results: 13 (23.2%), 20 (35.7%), and 23 (41.1%) patients were lean, overweight and obese, respectively. BMI did not show any significant association with the standard clinico-pathological characteristics. A significantly higher proportion of tumors with an anti-proliferative response was observed in obese patients as compared to lean and overweight patients (86%, 25%, 80% respectively, p = 0.03). A significant association between BMI (obese vs lean) and anti-proliferative response, was observed by the multivariable analysis (odds ratio (OR): 13.76, 95% Confidence Interval : 95%CI: 1.48 - 207.63, p = 0.02). A similar trend was observed when considering BMI as a continuous variable (OR: 1.19, 95%CI: 1.00 - 1.50, p = 0.04). Larger distant adipocyte size (diameter and area) was further identified as an independent predictor of anti-proliferative response (OR: 11.75, 95%CI: 10.02 - 17.02, p = 0.04, OR: 100.15, 95%CI: 100.01 - 100.55, p = 0.02). At the exploratory level, we showed an association between low TILs (&amp;lt; 10%) and anti-proliferative response, although not significantly (OR: 0.16, 95%CI: 0.01 - 1.20, p = 0.06). Finally, we showed that lobular BC patients (n = 10) had smaller CAAs diameter and area compared to ductal BC patients (n = 25; median diameter 44.00 µm and 49.32 µm; median area 1681 µm2 and 2122 µm2; respectively, p = 0.04) reflecting a possible differential tumor cell/adipocyte interaction according to the BC histology. Conclusions: This study suggests that anti-proliferative response to neoadjuvant aromatase inhibition might be more frequent in patients with increased adiposity as compared to lean patients. These observations, which need to be confirmed in larger series of patients, highlight the need of investigating treatment efficacy and BC biology according to the adiposity of the patient. Citation Format: Edoardo Isnaldi, François Richard, Maxim De Schepper, Sophia Leduc, Marion Maetens, Tatjana Geukens, Karen Van Baelen, Ha-Linh Nguyen, Ghizlane Rouas, Gabriele Zoppoli, Fatima Cardoso, Christos Sotiriou, Denis Larsimont, Giuseppe Floris, Elia Biganzoli, Christine Desmedt. The association between adiposity and anti-proliferative response to neoadjuvant endocrine therapy with letrozole in post-menopausal patients with estrogen receptor positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-02-02.

Neoadjuvant Endocrine Therapy (NET) in breast cancer – COVID setting

Introduction: During the height of the COVID-19 pandemic, breast cancer surgery advisory body guidance was issued in the UK prioritising ER negative or node positive patients for surgery. This necessitated the use of neoadjuvant endocrine treatment (NET) in deferring surgery for node negative, hormone receptor positive patients. Previous studies looking at the risk of conversion to node positive status during the surgical deferment time are few.

The Present and Future of Neoadjuvant Endocrine Therapy for Breast Cancer Treatment.

Simple SummaryThe treatment of breast cancer has evolved considerably over the last two decades, leading toward individualized disease management. Hormone-sensitive breast cancers constitute the vast majority of cases and endocrine therapy is the mainstay of their treatment. On the other hand, neoadjuvant or pre-surgical treatments provide a number of advantages for tumor management. In this review we will discuss the existing evidence on neoadjuvant endocrine therapy, as well as its possible future indications.Endocrine therapy (ET) has established itself as an efficacious treatment for estrogen receptor-positive (ER+) breast cancers, with a reduction in recurrence rates and increased survival rates. The pre-surgical approach with chemotherapy (NCT) has become a common form of management for large, locally advanced, or high-risk tumors. However, a good response to NCT is not usually expected in ER+ tumors. Good results with primary ET, mainly in elderly women, have encouraged studies in other stages of life, and nowadays neoadjuvant endocrine treatment (NET) has become a useful approach to many ER+ breast cancers. The aim of this review is to provide an update on the current state of art regarding the present and the future role of NET.

Rate and predictors of nodal pathological complete response following neoadjuvant endocrine treatment in clinically biopsy-proven node-positive breast cancer patients

BackgroundData on effectiveness and optimal use of neoadjuvant endocrine therapy (NET) in clinically biopsy-proven node-positive breast cancer is lacking. This study examined the incidence of axillary pathological complete response (pCR) on NET in clinically biopsy-proven node-positive breast cancer patients. Secondary, patient and tumour characteristics, as well as the optimal duration of NET in relation to the occurrence of axillary pCR were investigated. Material and methodsPatients diagnosed with primary hormone receptor positive, HER2 negative breast cancer between 2014 and 2019, with at least one positive axillary lymph node (pathologically proven), treated with NET were selected from the Netherlands Cancer Registry. The incidence of axillary pCR in combination with patient, tumour and treatment characteristics was analysed. ResultsIn a population of 561 patients, an axillary pCR of 7.3% on NET was observed. Median length of treatment was 8.1 months in the patients without vs. 8.8 months in those with axillary pCR, with no statistically significant difference. A p-value <0.30 was found for age, histologic type, clinical tumour status, hormone receptor status and the type of NET in univariable analysis. After multivariable logistic regression analyses, none of these variables were independently associated with the likelihood of an axillary pCR. ConclusionThe rate of axillary pCR after NET in HR + HER2-clinically biopsy-proven node-positive breast cancer patients is low. Factors independently associated with the likelihood of an axillary pCR could not be identified. More research is warranted regarding optimizing the duration of NET and the prognostic value of residual disease in the axilla after NET.

Abstract PS5-14: Gene-expression profiling and response to neoadjuvant endocrine treatment in the phase II LETLOB trial

Abstract Background: Hormone receptor positive (HR+)/HER2- breast cancer (BC) is a clinically and biologically heterogeneous disease, encompassing all BC molecular intrinsic subtypes. We here explore the association between gene-expression profiles and response to neoadjuvant endocrine-based treatment in early HR+/HER2- BC. Methods: The LETLOB phase II trial randomized 92 postmenopausal women with clinical stage II-IIIA HR+/HER2- BC to receive neoadjuvant letrozole + lapatinib or letrozole + placebo for 6 months. Objective response was the primary endpoint, as defined by study protocol and previously published (Guarneri, JCO 2014). Gene-expression data (Affymetrix platform) from pre-treatment frozen core-biopsies was available for 66 pts. Intrinsic subtype was assigned using a research-based PAM50 subtype predictor. The PAM50 based chemo-endocrine score (CES) was calculated using published definition (Prat, CCR 2017). Higher values of CES indicate increased endocrine sensitivity, while lower values indicate higher chemosensitivity. Results: Intrinsic subtype distribution was as follows: Luminal A 39% (N=25), Luminal B 36% (N=24), HER2-enriched 8% (N=5), basal-like 18% (N=12). Non-luminal tumors (basal-like and HER2-enriched) were characterized by less differentiated histological grades (Grade 3 65% vs 33%, p=0.037) and higher Ki67 expression at baseline as compared to luminal tumors (median 20% vs 15%, p=0.013). Considering both treatment arms combined, non-luminal tumors showed a significantly lower objective response rate as compared to luminal tumors (47% vs 78%, p=0.031). This difference was statistically significant in the lapatinib arm (43% vs 90%, p=0.021), but not in the placebo arm (50% vs 68%, p=0.449; interaction test p=0.169). After treatment, non-luminal tumors had significantly higher Ki67 levels than luminal ones (post-treatment median 10% and 7%, respectively, p=0.004). Median CES level at baseline was -0.03 (range: -1.11, +1.12). Each unit increase in CES levels at baseline was numerically associated with higher probability of achieving an objective response (Odds Ratio 1.95, 95% CI 0.74-5.18, p=0.178, both arms combined). Conclusions: In HR+/HER2- early BC patients enrolled in the LET-LOB trial, patients with non-luminal tumor or low CES score showed reduced sensitivity to endocrine-based treatment. The highest response rate (90%) was observed in luminal patients treated with letrozole + lapatinib. Gene-expression profiling could potentially be used to identify patients with low sensitivity to endocrine treatment for which neoadjuvant chemotherapy should be preferred. Citation Format: Gaia Griguolo, Maria Vittoria Dieci, Daniele Giulio Generali, Laia Paré, Antonio Frassoldati, Luigi Cavanna, Enrico Tagliafico, Katia Cagossi, Giancarlo Bisagni, Federico Piacentini, Federica Miglietta, Guido Ficarra, Aleix Prat, PierFranco Conte, Valentina Guarneri. Gene-expression profiling and response to neoadjuvant endocrine treatment in the phase II LETLOB trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-14.

Outcome Of Elective Nodal Radiation In Elderly Patients With High Risk Prostate Cancer

The role of pelvic lymph-node irradiation in prostate cancer remains controversial. Nevertheless, it is agreed that for ‘high-risk’ disease standard therapy should remain prostate and pelvic radiotherapy with extended period of androgen suppression. In the UK there is some reluctance to using pelvic irradiation due to the risk of acute and late bowel toxicities. In clinical practice patients are often older with comorbidities which may impact treatment outcome quality of life. Retrospective analyses of all patients aged 70 years or older treated with pelvic nodal irritation at our institute between January 2015 to September 2018. iSOFT manager for used for clinical data and MOSAIQ for radiotherapy parameters. Statistical analysis was performed using Stata version 11.2 72 patients were identified. Median age was 73.6 years (range of 70 to 83). 88% have pT3 or grater disease. Median PSA was 78.4 (IQ range 2.4 – 209). 51% had node positive disease. All patients were treated with at least 3 months of neoadjuvant endocrine treatment before starting radiotherapy (range 3-8 months). All patients were treated with 74 Gy in 37 fractions using IMRT technique .84% patients were given 55 Gy to pelvic nodes and remaining 16% were given nodal dose up to 64 Gy( 10% received 60 Gy and 6% 64 Gy respectively).After median follow up of 27 months( IQ range 14-58 months), 12% had biochemical recurrence and 2 patients had metastatic disease. Grade 3 bowel toxicities were documented in 5% cases and 18% patients had grade 2 or above urinary toxicities. No grade 4 gastrointestinal (GI) and genitourinary (GU) toxicity was observed. Our study demonstrates that elective IMRT of the pelvic nodes for elderly patients with a high-risk of lymphatic spread is safe and shows an excellent clinical outcome without compromising the quality of life.