Antibody-drug conjugates (ADCs) provide specificity for cytotoxic drugs as well as monoclonal antibodies (mAbs) and represent an important step in the treatment of breast cancer. This review summarizes the current status, efficacy, safety, and future prospects of ADCs in the treatment of breast cancer. mAbs enable drug delivery by detecting specific antigens on cancer cells. Cytotoxic payloads cause cell death upon internalization. The linker binds the mAb to the payload and influences drug release. All three components together form an ADC. Transtuzumab Emtansine 1 (T-DM1) (Kadcyla) targets human epidermal growth factor receptor 2 (HER2)-positive breast cancer and has shown activity against both metastatic and early disease. Fam-trastuzumab deruxtecan (T-DXd; Enhertu) has shown improved progression-free survival and overall survival for T-DM1 in HER2-positive metastatic breast cancer. Sacituzumab govitecan (SG) targets the Trophoblast Antigen 2 (TROP2) receptor and has been shown to be effective in triple-negative breast cancer and hormone receptor-positive, HER2-negative advanced breast cancer. Fatigue, nausea, and diarrhea are the most common. Some ADCs have their own side effects. T-DXd, which can cause interstitial lung disease, and SG, which increases the risk of diarrhea. Monitoring and controlling these adverse events is important to achieve good patient outcomes. There are ongoing issues with ADC use including drug-related and other issues. The drug-related issues include side effects and ADCs drug resistance. This resistance can be due to a variety of reasons including downregulation of the target antigen, reduced internalization, increased drug efflux, and reduced burden. Strategies to reduce resistance include the use of combination therapies, early detection of resistance, and the development of more effective products. Second-generation ADCs with improved structure and potency are under development. There is ongoing research focusing on novel targets beyond HER2, such as Trop-2 and Claudin-18.2. Non-drug-related issues include tumor heterogeneity, patient selection, manufacturing issues, and increased costs. In conclusion, ADCs are a huge improvement over conventional chemotherapy for breast cancer treatment. The importance and use of ADCs in cancer treatment is bound to increase. The future of ADCs in breast cancer treatment looks promising with ongoing research into new targets, new therapeutic agents, and advances in drug resistance leading to mediated and effective methods.

Background – The inverse association between high mammographic breast density (MBD) and pathologic complete response (pCR), following neoadjuvant chemotherapy (NAC) for early breast cancer (BC), implicates high MBD in chemotherapy resistance. However, no trial has extended the relationship beyond pCR to overall survival. Aim - To validate the relationship between MBD and pCR in patients undergoing NAC for early BC. To assess the relation of MBD with clinical complete response (cCR), relapse-free (RFS) and BC-specific survival (BCSS). Methods – MBD was measured in contralateral mammograms in 127 women before NAC, using Cumulus software. Percent dense area (PDA) was correlated with patient and tumour characteristics, short-term (pCR/cCR incidences), and long-term chemotherapy outcomes (RFS and BCSS). Results - Overall rates of cCR and pCR of 49% and 21% were observed. Mean MBD was higher in those not undergoing cCR (p = 0.041) and relapsing patients (p = 0.041) but did not vary by pCR or BC-deaths. As a dichotomous variable, high MBD corresponded to lower cCR (40 v 58%, p = 0.027). No difference was seen between high and low MBD cohorts for pCR (17.5 v 25.0%, p = 0.15), BC relapse (38 v 30%, p = 0.15) or BC-death (32 v 25%, p = 0.20). A planned analysis in obese patients demonstrated high MBD was associated with lower pCR (0% v 28.1%, p = 0.036) and higher relapse rates (56% v 28%, p = 0.063). No such relationship was observed in non-obese patients. Conclusion – high MBD associated with lower cCR and higher relapse but not with pCR or BC death. Further analysis, including by body mass index, is warranted.

Introduction: An inverse association between high mammographic breast density (MBD) and pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC) for early breast cancer (EBC) has been reported. However, the relationship of MBD to relapse-free (RFS) and breast cancer-specific survival (BCSS) is unexplored. This study aims to validate the relationship between MBD and NAC pCR in EBC and to assess correlations with RFS and BCSS. Materials & Methods: MBD was measured on contralateral mammograms in 127 women before NAC using Cumulus software. The percent dense area was correlated with patient and tumour characteristics, pCR, RFS and BCSS. Results: Mean MBD was higher in relapsing patients (p = 0.041) but did not vary by pCR or BC-deaths. As a dichotomous variable, no difference was seen between high and low MBD cohorts for pCR (17.5 vs. 25.0%, p = 0.15), BC relapse (38 vs. 30%, p = 0.15) or BC death (32 vs. 25%, p = 0.20). A planned analysis by body mass index (BMI) demonstrated high MBD associated with lower pCR (0% vs. 28.1%, p = 0.036) and trends for higher relapse (56% vs. 28%, p = 0.063) and BC deaths (56 vs. 28%, (p = 0.071)) in obese patients. No relationship was observed in non-obese patients. Conclusions: Obesity and high MBD may interact to cause chemoresistance. Further research in these patients is warranted.

Background: The cytotoxic agent eribulin has been shown to promote EMT reversion, reduce treatment resistance, and potentially enhance responses to a range of therapeutic agents. Methods: We examined the effects of eribulin in patient-derived breast cancer tissues and a phenotypically heterogeneous breast cancer cell line to assess EMT and chemotherapy response. Results: Nanostring-based analysis of EMT-associated gene expression in breast cancers from patients receiving standard-of-care TAC neoadjuvant chemotherapy compared to a cohort receiving neoadjuvant eribulin (NeoEribulin trial) showed markedly reduced expression of EMT markers in cancers treated with eribulin versus TAC. Through single-cell immunofluorescent imaging and analysis, we identified that HCC38 triple-negative breast cancer (TNBC) cells exhibited a shift towards an epithelial-like state marked by E-cadherin upregulation following acute eribulin exposure, but not with other chemotherapeutic agents. Investigation of primary breast cancer cultures derived from pre-neoadjuvant biopsies also revealed that HER2-enriched primary breast cancer cells displayed heightened chemosensitisation to doxorubicin (Adriamycin), which was not recapitulated in TNBC cultures. Conclusions: Our data highlight the presence of contextual parameters which govern the degree of EMT regulation by eribulin.