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.

Adjuvant chemotherapy recommendations for ER+/HER2− early-stage breast cancers (eBC) involve integrating prognostic and predictive information which rely on physician judgment; this can lead to discordant recommendations. In this study we aim to evaluate whether Oncotype DX improves confidence and agreement among oncologists in adjuvant chemotherapy recommendations. We randomly select 30 patients with ER+/HER2− eBC and recurrence score (RS) available from an institutional database. We ask 16 breast oncologists with varying years of clinical practice in Italy and the US to provide recommendation for the addition of chemotherapy to endocrine therapy and their degree of confidence in the recommendation twice; first, based on clinicopathologic features only (pre-RS), and then with RS result (post-RS). Pre-RS, the average rate of chemotherapy recommendation is 50.8% and is higher among junior (62% vs 44%; p < 0.001), but similar by country. Oncologists are uncertain in 39% of cases and recommendations are discordant in 27% of cases (interobserver agreement K 0.47). Post-RS, 30% of physicians change recommendation, uncertainty in recommendation decreases to 5.6%, and discordance decreases to 7% (interobserver agreement K 0.85). Interpretation of clinicopathologic features alone to recommend adjuvant chemotherapy results in 1 out of 4 discordant recommendations and relatively high physician uncertainty. Oncotype DX results decrease discordancy to 1 out of 15, and reduce physician uncertainty. Genomic assay results reduce subjectivity in adjuvant chemotherapy recommendations for ER +/HER2− eBC.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy and now represent the mainstay of treatment for many tumor types, including triple-negative breast cancer and two agnostic registrations. However, despite impressive durable responses suggestive of an even curative potential in some cases, most patients receiving ICIs do not derive a substantial benefit, highlighting the need for more precise patient selection and stratification. The identification of predictive biomarkers of response to ICIs may play a pivotal role in optimizing the therapeutic use of such compounds. In this Review, we describe the current landscape of tissue and blood biomarkers that could serve as predictive factors for ICI treatment in breast cancer. The integration of these biomarkers in a "holistic" perspective aimed at developing comprehensive panels of multiple predictive factors will be a major step forward towards precision immune-oncology.

Background: Nausea and vomiting are common side effects of Trastuzumab Deruxtecan (T-DXd), but guidelines for optimal management were not initially available. This retrospective single-center study aimed at evaluating the efficacy of two antiemetic regimens in patients receiving T-DXd.Methods: Data from metastatic breast cancer patients receiving T-DXd were collected. Two groups were defined: patients treated with 5-HT3 receptor antagonists (RA) ± dexamethasone (5-HT3-group) and patients treated with a fixed oral combination of netupitant (NK1RA) and palonosetron ± dexamethasone (NK1 group). Physicians preferentially offered the NK1 regimen to patients at higher risk of nausea and vomiting based on internal recommendations. Only nausea and vomiting during cycles 1 and 2 were considered. Comparisons of nausea and vomiting by the antiemetic prophylaxis group were assessed using chi-square.Results: A total of 53 patients were included in the analysis. At cycle 1, 72% and 28% of patients received the 5-HT3 and NK1 prophylaxis, respectively. Overall, 58% reported nausea, with no differences between groups (58% vs. 60%; p = 0.832), but with a trend for lower grade in the NK1 group (33.3% G1; 26.7% G2) compared to the 5-HT3 group (23.7% G1; 31.6% G2; 2.6% G3). Vomiting was reported by 21% and 0% of patients in the 5-HT3 and the NK1 group, respectively (p = 0.054). Among the 15 patients in the 5-HT3 group with nausea at cycle 1 who escalated to NK1 at cycle 2, nausea decreased from 100% to 53% (p = 0.022) and vomiting decreased from 47% to 13% (p = 0.046).Conclusions: The NK1 regimen improved vomiting control at cycle 1 and, when introduced at cycle 2, significantly improved both nausea and vomiting. The biased NK1 selection for higher-risk patients may have dampened the differences between groups at cycle 1. These findings support enhanced control of T-DXd-related nausea and vomiting with NK1RA.

Purpose: In Italy, Lombardy was the first region to reimburse multigene assays (MGAs) for patients otherwise candidates for chemotherapy. This is a real-world experience of MGAs usage in six referral cancer centers in Lombardy. Methods: Among MGAs, Oncotype DX (RS) was used in 97% of cases. Consecutive patients tested with Oncotype DX from July 2020 to July 2022 were selected. The distribution of clinicopathologic features by RS groups (low RS: 0–25, high RS: 26–100) was assessed using chi-square and compared with those of the TAILORx and RxPONDER trials. Results: Out of 1,098 patients identified, 73% had low RS. Grade and Ki67 were associated with RS (p < 0.001). In patients with both G3 and Ki67 > 30%, 39% had low RS, while in patients with both G1 and Ki67 < 20%, 7% had high RS. The proportion of low RS in node-positive patients was similar to that in RxPONDER (82% vs 83%), while node-negative patients with low RS were significantly less than in TAILORx (66% vs 86%, p < 0.001). The distribution of Grade was different from registration trials, with more G3 and fewer G1 (38% and 3%) than in TAILORx (18% and 27%) and RxPONDER (10% and 24%) (p < 0.001). Patients ≤ 50 years were overrepresented in this series (41%) than in TAILORx and RxPONDER (31% and 24%, respectively) (p < 0.001) and, among them, 42% were node positive. Conclusions: In this real-world series, Oncotype DX was the test almost exclusively used. Despite reimbursement being linked to pre-test chemotherapy recommendation, almost 3/4 patients resulted in the low-RS group. The significant proportion of node-positive patients ≤ 50 years tested indicates that oncologists considered Oncotype DX informative also in this population.

Background: Luminal breast cancers with high proliferation (MKS^hi) and low ER-related signalling (ERS^lo) have a poor prognosis. We investigated treatment responses and molecular features of MKS^hi/ERS^lo tumours to inform potential therapies. Methods: 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. Results: Compared to MKS^hi/ERS^hi tumours, MKS^hi/ERS^lo 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^hi/ERS^lo 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^hi/ERS^lo 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). Conclusions: MKS^hi/ERS^lo 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.