Luminal breast cancers with high proliferation (MKS
) and low ER-related signalling (ERS
) have a poor prognosis. We investigated treatment responses and molecular features of MKS
/ERS
tumours to ...inform potential therapies.
Gene expression data from patients who received neoadjuvant chemotherapy (NAC) without (MDACC, N = 199) or with pembrolizumab (I-SPY2, N = 40), or endocrine therapy (NET) without (POETIC, N = 172) or with palbociclib (NeoPalAna, N = 32) were analyzed to assess treatment response by MKS/ERS-subgroups. TCGA was used to assess the mutational landscape and biomarkers associated with palbociclib-resistance (Cyclin-E, RBsig, IRPR) and immunotherapy-response (TMB, TILs, T-cell inflamed) by MKS/ERS-subgroups.
Compared to MKS
/ERS
tumours, MKS
/ERS
tumours had higher pathological response rates to NAC (22% vs 8%, p = 0.06) but a higher recurrence risk (4-year metastasis-free survival 70% vs 94%, p = 0.01). MKS
/ERS
tumours frequently harboured TP53 (34%) and PIK3CA (33%) mutations, and showed high expression of Cyclin-E, RBsig and IRPR, high TMB and elevated TIL and T-cell inflamed metagene expression. MKS
/ERS
tumours retained high proliferation after NET with or without palbociclib but had higher pathological complete response rates when pembrolizumab was added to NAC (42% vs 21%, p = 0.07).
MKS
/ERS
tumours have dismal outcomes and are enriched in chemotherapy-sensitive but ET- and palbociclib-resistant tumours. Biomarker analysis and clinical data suggest a potential role for immunotherapy in this group.
Abstract
Background: In HER2-positive (HER2+) early breast cancer (eBC) treated with neoadjuvant therapy (NAT), HER2 loss on residual disease (RD) might be correlated with a dampen survival. Recent ...data from the KATHERINE trial showed a maintained benefit from post-neoadjuvant trastuzumab emtansine (T-DM1) in patients with HER2 loss on RD, even if clinicopathological variables associated with HER2 loss have not been reported. We aimed to characterize the clinicopathological variables and clinical outcomes associated with HER2 loss after NAT in patients with HER2+ eBC.Methods: We retrieved data from a prospectively collected database including all consecutive HER2+ eBC patients treated with NAT at European Institute of Oncology from September 1999 to May 2018. We collected data on age, menopausal status, NAT regimen, clinical and pathological stage, as well as histological subtype and grade, hormone receptor (HR), HER2, and Ki67 status before and after NAT. HR and HER2 status were re-assessed according to the latest ASCO/CAP guidelines. Invasive disease-free survival (IDFS), distant relapse-free survival (DRFS), and overall survival (OS) were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariate (UVA) and multivariate analyses (MVA) were performed to identify variables associated with survival outcomes. Variables considered in UVA included: clinical tumor stage (cT: 1-2 vs 3-4) and nodal status (cN: 0 vs 1-2-3), pre-and post-NAT HR status (neg vs pos), NAT (anti-HER2 agents: yes vs no; endocrine therapy: yes vs no), pathological tumor stage (ypT: is-0-1-2 vs 3-4) and nodal status (ypN: 0 vs 1-2-3). Variables with a p value<0.1 were included in the MVA. Results: Of 920 patients with HER2+ eBC who had received NAT, 106 (11.5%) had RD with HER2 loss and were included in the analysis. Median age was 49 yrs (range 29-76). 55 (51.9%), 48 (45.3%) and 3 (2.8%) patients were post-, pre- and peri-menopausal, respectively. Most patients had cT2 tumors (44.3%, vs cT1 3.8%, cT3 20.8%, cT4 31.1%) and cN+ disease (81% vs 19% N0). 84 patients (79.2%) were HR-pos at diagnosis. All patients received neoadjuvant chemotherapy; 73 patients (69.5%) received also anti-HER2 agents. Pathologic staging was: ypT0-is 9.4%, ypT1 47.2%, ypT2 24.5%, ypT3 17%, ypT4 1.9%; ypN0 42.5%, ypN1 27.4%, ypN2 14.2%, ypN3 16.0%. At a median follow-up of 80.8 months (interquartile range, 43.5-159.4), median IDFS, DRFS, and OS were 100 (95% CI, 61-NA), 183 (95% CI, 157-NA), and 197 months (95% CI, 130-NA), respectively. At UVA, pre-NAT HR status (p=0.088) along with cT (p=0.008) and ypN (p=0.016) status were significantly associated with IDFS. At MVA, only HR status retained significance (HR 0.48, 95% CI 0.24-0.94, p=0.032). Median IDFS in HR-pos and HR-neg patients was 109 (95% CI 68.8-NR) and 61 (95% CI 20.9-NR) months, respectively. None of the considered variables was significantly correlated with DRFS at MVA. cT (p=0.006) and ypN (p=0.003) status were also associated with OS at UVA, with ypN that remained independently associated with OS at MVA (HR 3.6, 95% CI, 1.18-11.3, p=0.025). Median OS in ypN0 vs ypN+ patients was 122 (95% CI, 84-NR) vs NR (95% CI, 213-NR), respectively. Conclusions: HER2 loss on RD can be found in ~10% of HER2+ eBCs treated with NAT. In this subset of patients, HR-negative tumors are associated with worse IDFS, warranting the investigation of escalation treatment strategies. Node-negative disease at surgery was instead associated with a significantly longer OS.
Citation Format: Stefania Morganti, Antonio Marra, Giulia Viale, Paola Zagami, Elham Sajjadi, Chiara Corti, Giuseppe Curigliano, Nicola Fusco, Carmen Criscitiello. Loss of HER2 on residual disease after neoadjuvant therapy in HER2-positive early breast cancer: Clinicopathological characteristics and association with outcomes 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 P4-07-01.
We performed a multi-parametric analysis investigating the association between adiposity (as measured using body mass index BMI and computed tomography CT-based body composition), tumour infiltrating ...lymphocytes (TILs) and clinical outcomes in patients with advanced-stage cancer treated with immunotherapy in phase I clinical trials.
All consecutive patients (N = 153) with metastatic solid tumours treated within immunotherapy-based phase I clinical trials between August 2014 and May 2019 at our institution were included. Baseline characteristics, BMI, TILs value and CT-assessed fat indices (total fat area TFA, subcutaneous fat area SFA and visceral fat VFA) were collected. The primary endpoints were to evaluate the impact of these parameters on overall survival (OS) and progression-free survival (PFS). Kaplan–Meier method and Cox proportional-hazards model were used for survival analyses.
At both univariate and multivariate analyses, BMI was not associated with PFS neither when considered as continuous variable (HR 0.90, 95% CI 0.74–1.09, P = 0.28) nor as dichotomous variable (underweight/normal versus overweight/obese) (HR 0.79, 95% CI 0.55–1.14, P = 0.21). Interestingly, patients diagnosed with ‘immunogenic’ tumours and higher VFA/SFA ratio (1st and 2nd tertile versus 3rd tertile) presented an increased OS (HR 0.88, 95% CI 0.78–1.00, P = 0.047).
Our analysis showed that patients with tumours that are already known as responsive to ICIs with higher VFA/SFA ratio presented an increased OS. Further studies are needed to elucidate the effect of adiposity on the host immune response to immunotherapy.
•No association links adiposity and outcome in patients treated with immunotherapy.•Patients responsive to immunotherapy with a higher VFA/SFA ratio have a better OS.•The results of our analysis need to be confirmed in subsequent prospective studies.
Abstract
Background - Chemotherapy is the current backbone of immune checkpoint inhibitors (ICIs) for approved indications in triple negative breast cancer (TNBC). While it is expected that different ...chemotherapeutic agents might have distinct immunomodulatory effects, data in patients is scarce. Here we compared the early modulation of molecular pathways and immune-related features in TNBC patients receiving neoadjuvant doxorubicin/cyclophosphamide (AC) or nab-paclitaxel/carboplatin (nab/C). Methods - Two cohorts of TNBC patients with available RNA-seq for paired core biopsies obtained before (baseline) and after the first cycle of neoadjuvant chemotherapy (day 21, D1C2) were selected: i) 84 patients treated with nab/C from the control arm of the NeoTRIPaPDL1 trial (Gianni L SABCS 2019, Bianchini G ESMO 2021); ii) 22 patients treated with AC from a publicly available dataset (Park Nat Comms 2020). Presence of immune cell populations was estimated by gene expression profile deconvolution using ConsensusTME R package (n=19). Hallmark gene set collection and custom signature activation status were estimated in each sample using singscore R package (n=63). We also assessed modulation of PD-L1 gene expression and selected immune-related genes. To minimize batch effects between the two cohorts, in each dataset, median score expression at baseline was subtracted from all samples. Continuous scores were compared by 2-sided t-test. Results - Thirty-nine pathways were significantly and similarly modulated in both cohorts (all p<0.01) at D1C2 compared to baseline. They included upregulation of all immune cell related signatures (e.g. T cells, dendritic cells, monocytes and macrophages, B cells and NK), immune function-related signatures and apoptosis, and downregulation of proliferation related signatures. PD-L1 gene expression was upregulated in both cohorts (p<0.001). A comparison between D1C2 of the two cohorts was performed to evaluate whether chemotherapies differently modulated gene signatures. Nab/C more strongly downregulated signatures of G2M checkpoint, mitotic spindle, DNA repair, MYC targets and oxidative phosphorylation. AC more strongly upregulated some immune-related signatures (e.g. cytotoxic cells, CD4+ T-cells, regulatory T cells, IL2/STAT5 and JAK/STAT3) and apoptosis. PD-L1 was more upregulated in AC cohort (p=0.006). For each signature, we identified, in each cohort, patients ‘signature high’ and ‘signature low’ using the median value at baseline as a threshold. We then investigated whether signature modulation at D1C2 was different in the two groups. In ‘signature high’ patients, immune-related signatures were similarly upregulated, whereas nab/C showed downregulation of proliferation related markers. In ‘signature low’ patients, a more robust upregulation of all immune-related signatures was observed in both cohorts (all p<0.0001), but it was quantitatively stronger in AC arm for several immune signatures (e.g. cytotoxic cells, gamma/delta T cells, CD4+ T-cells, regulatory T cells, NK) (p<0.01). PD-L1 was significantly upregulated at D1C2 only in PD-L1 low group in both cohorts (p<0.0001), but the effect was stronger in AC (p=0.014). Chemotherapy induced modulation of other individual genes will be presented at the meeting. Conclusions - The two investigated chemotherapy regimens had a strong early immunomodulatory and chemoattractant effect, which confirms the rationale for combination with ICIs. Anthracyclines elicit a quantitatively stronger immune modulatory effect compared to nab/C, which is particularly evident in. “immune low” tumors. These observations can have clinical implications for the selection of the ideal chemotherapy partner to ICIs in not-inflamed/PD-L1 negative tumors.
Citation Format: Maurizio Callari, Marco Barreca, Matteo Dugo, Barbara Galbardi, Lucia Viganò, Alberta Locatelli, Luca Licata, Giulia Viale, Pinuccia Valagussa, Giuseppe Viale, Luca Gianni, Giampaolo Bianchini. Comparison of early modulation of biological pathways and immune microenvironment by anthracyclines- or taxane-based treatment 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 PD10-09.
Antibody-drug conjugates (ADCs) are a rapidly expanding class of compounds in oncology. Our goal was to assess the expression of ADC targets and potential downstream determining factors of activity ...across pan-cancer and normal tissues.
ADCs in clinical trials (n = 121) were identified through ClinicalTrials.gov, corresponding to 54 targets. Genes potentially implicated in treatment response were identified in the literature. Gene expression from The Cancer Genome Atlas (9000+ cancers of 31 cancer types), the Genotype-Tissue Expression database (n = 19,000 samples from 31 normal tissue types), and the TNMplot.com (n = 12,494 unmatched primary and metastatic samples) were used in this analysis. To compare relative expression across and within tumour types we used pooled normal tissues as reference.
For most ADC targets, mRNA levels correlated with protein expression. Pan-cancer target expression distributions identified appealing cancer types for each ADC development. Co-expression of multiple targets was common and suggested opportunities for ADC combinations. Expression levels of genes potentially implicated in ADC response downstream of the target might provide additional information (e.g. TOP1 was highly expressed in many tumour types, including breast and lung cancers). Metastatic compared to primary tissues overexpressed some ADCs targets. Single sample "targetgram" plots were generated to visualise the expression of potentially competing ADC targets and resistance/sensitivity markers highlighting high inter-patient heterogeneity. Off-cancer target expression only partially explains adverse events, while expression of determinants of payload activity explained more of the observed toxicities.
Our findings draw attention to new therapeutic opportunities for ADCs that can be tested in the clinic and our web platform (https://tnmplot.com) can assist in prioritising upcoming ADC targets for clinical development.
Highlights • Osteoimmunology studies the crosstalk between skeletal and immune systems. • RANK/RANKL/OPG signaling is essential for osteoclastogenesis, bone remodeling, immune system development and ...regulation. • Cancer cells evade immunosurveillance and the bone often harbors DTCs against anticancer therapy and immune response. • Besides being effective in preventing and treating SREs, bisphosphonates exert direct anti-tumor effects. • The molecular crosstalk between immune and skeletal systems could be targeted with new therapeutic strategies.
Northern Italy has been one of the European regions reporting the highest number of COVID‐19 cases and deaths. The pandemic spread has challenged the National Health System, requiring reallocation of ...most of the available health care resources to treat COVID‐19‐positive patients, generating a competition with other health care needs, including cancer. Patients with cancer are at higher risk of developing critical illness after COVID‐19 infection. Thus, mitigation strategies should be adopted to reduce the likelihood of infection in all patients with cancer. At the same time, suboptimal care and treatments may result in worse cancer‐related outcome. In this article, we attempt to estimate the individual risk–benefit balance to define personalized strategies for optimal breast cancer management, avoiding as much as possible a general untailored approach. We discuss and report the strategies our Breast Unit adopted from the beginning of the COVID‐19 outbreak to ensure the continuum of the best possible cancer care for our patients while mitigating the risk of infection, despite limited health care resources.
Implications for Practice
Managing patients with breast cancer during the COVID‐19 outbreak is challenging. The present work highlights the need to estimate the individual patient risk of infection, which depends on both epidemiological considerations and individual clinical characteristics. The management of patients with breast cancer should be adapted and personalized according to the balance between COVID‐19‐related risk and the expected benefit of treatments. This work also provides useful suggestions on the modality of patient triage, the conduct of clinical trials, the management of an oncologic team, and the approach to patients’ and health workers’ psychological distress.
This article discusses strategies employed by an institution in Northern Italy to ensure the continuum of the best possible cancer care during the COVID‐19 pandemic for breast cancer patients while mitigating the risk of infection, despite limited healthcare resources.
Inflammatory breast cancer (IBC) is an aggressive, although infrequent form of invasive breast cancer. Despite some advances in systemic treatment, even in the early setting, with combined-modality ...approach being the current recommended standard of care, the prognosis of IBC still remains unfavorable and has not significantly improved over time. Thus, a better understanding of the biology of IBC is eagerly awaited in order to identify possible targets for new drug development. This paper aims to provide an overview on recent data on the molecular and biological features of IBC and on possible targetable pathways. Molecular subtypes of IBC, similarly to other forms of breast cancer, have both therapeutic and prognostic implications. Moreover, few activated pathways have been described in IBC, including angiogenesis, epidermal growth factor receptor (EGFR), Janus kinase/signal transducer of activation (JAK/STAT) signaling and phosphoinositide 3-kinase/Akt/mTOR (PI3K/AKT/mTOR) pathways. However, when tested in clinical trials, agents targeting these pathways have provided only small benefit. Several clinical trials are currently ongoing investigating combination of standard chemotherapeutics, new targeted agents and immunotherapy. Moreover, tumor microenvironment (TME) is likely to play a central role in the disease; targeting the components of the tumor stroma may represent an interesting therapeutic strategy.
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