By Dorys Lopez
The ESMO Breast Cancer 2022 took place in Berlin on May 3 – 5. A well-attended conference covering a broad range of breast cancer topics. Our team was there to present three posters.
Here are our takeaway messages from the conference.
Escalation and de-escalation of therapy
Escalation and de-escalation of care was thoroughly discussed by Drs. Giuseppe Curigliano, Peter Schmid and Javier Cortes during a session focused on systemic therapy for early triple negative breast cancer (TNBC).
Dr. Giuseppe Curigliano focused more on the chemotherapy for TNBC. He went back to the ABC trials explaining that for early TNBC there is little chance to leave anthracyclines out from the neoadjuvant therapy (NAT) regimens, as they are the basis for systemic therapy along with taxanes. One option is adding platinum therapy in high risk, node-positive patients and capecitabine in patients with residual disease with wild type BRCA. He reminded the audience that TNBC patients that achieved a pathological complete response (pCR) have better event free survival (EFS), regardless of germline BRCA (gBRCA) status. He talked about tailored chemotherapy escalation in patients with residual disease, and de-escalation in low-risk patients. However, he emphasized the need to generate a framework to understand when to escalate or de-escalate treatment in TNBC patients.
Dr. Peter Schmid talked about the incorporation of novel agents into early TNBC. TNBC is a very heterogeneous disease, however, he explained that TNBC subtyping provides a better understanding of the disease, but that it has low clinical relevance, at least until now. He talked about antibody drug conjugates (ADCs) and how there is no longer a need to target oncogenic drivers of the disease. Thus, it is possible to generate ADCs for TNBC, characterized by the absence of molecular targets. In regards of immunotherapy (IO), nodal status makes no difference for patient response, contrary to what is seen for chemotherapy. Subgroups with PD-L1+ and PD-L1- have similar EFS and pCR when treated with immune checkpoint inhibitors (ICI). He reasoned that early disease tumors are still plastic and that allows them to change since the beginning of chemotherapy, and with that the PD-L1 status can change. For immunotherapy clinical trials he recommended dual endpoints: pCR and EFS. He finalized by saying that in TNBC stage it is still unclear how aggressive the treatment should be. He posed the questions: Can we de-escalate? Can we give low risk patients chemo free therapy, ADCs alone? Salvage them with chemo when they have residual disease? Finally, he underscored the need to identify optimal responders, not only to IO, but also to chemotherapy.
Dr. Javier Cortes explained escalation strategies in human epidermal growth factor receptor 2-positive (HER2+) and TNBC patients. First, he talked about escalation of therapy and gave a brief overview of the Keynote-522 and NeoSphere trials as an example of escalation of therapy. Keynotte-522 added pembrolizumab to the therapy of TNBC patients while NeoSphere added pertuzumab to the therapy of HER2+ patients, which increased the EFS and the progression free survival (PFS) respectively. More escalation examples included the CREATE-X trial for TNBC, where the addition of capecitabine increased disease-free survival (DFS). In the Katherine trial for HER2+ patients, the addition of trastuzumab emtansine (TDM1) increased invasive-DFS rate. His overview of de-escalation included the APT trial, which evaluated shorter trastuzumab duration, while the ATEMPT trial evaluated TDM1 vs. TH (paclitaxel + trastuzumab). He suggested similar strategies should be followed for TNBC de-escalation.
Dr. Cortes also talked about platinum compounds adding benefit to chemotherapy with paclitaxel. Tumor infiltrating lymphocytes (TILs) came up as well, where data suggests that having more TILs translates to a better outcome for the patient. Of note, during Dr. Curigliano’s talk, he mentioned that TILs are prognostic but not predictive. Dr. Cortes further discussed the prognostic impact of pCR and PD1 status. He said for patients with lower pCR additional chemo might improve outcome.
Towards the end of his talk, he asked – can we de-escalate treatment on Monday Morning in the neo/adjuvant setting? – the answer was no. There is need for better strategies based on response to therapy. He also reminded the audience that de-escalation of treatment includes de-escalation of surgery and radiation therapy. So far, the biomarkers that might be correlated to a better pCR are not ready to be implemented in the clinic.
Our technology provides precisely what the three speakers emphasized is needed, a framework that can be used to evaluate various therapies and support the physician’s decision to escalate or de-escalate therapy. In an abstract/poster “Prediction of Response to Neoadjuvant Therapy in Early-Stage Breast Cancer using a Biophysical Simulation Platform” we described how our platform can accurately predict response to standard-of-care therapy, not only for TNBC, but in all breast cancer subtypes. The results presented are part of a broader push to validate the technology across multiple institutions.
There was a special focus on HER2-low breast cancer. Dr. Frederique Penault Llorca talked about HER2-low breast cancer, asking whether it can be considered a real entity. HER2-low is a subset of HER2 expressing breast cancer (approximately 40 to 55% of all breast cancers are HER2-low – IHC 2+ non amplified and IHC 1+). She highlighted the need for more and better efforts to standardize the scoring of HER2-low disease and potentially implement new and more sensitive assays that can help to better discriminate HER2 levels within HER2-negative breast cancer.
Dr. Paolo Tarantino talked about the prognostic and biologic significance of HER2-low expression in early breast cancer. HER2-low breast cancers are currently classified as either HR+/HER2- or TNBC. Anti-HER2 ADCs have shown activity in HER2-low metastatic breast cancer reaching objective response rates (ORR) between 32% – 39% with trastuzumab deruxtecan, trastuzumab duocarmazine and disitamab vedotin. However, it remains unclear whether HER2 low expression is associated with a distinct biology or prognosis or as Dr. Penault Llorca pointed out, if it is a real entity. Dr. Tarantino and his group performed a large retrospective analysis to characterize HER2-low early breast cancer including over 5,000 patients. Fifty-five percent of patients were HER2-low and 45% HER2-zero. Further classification, according to hormone receptor (HR) status, showed that HR+ tumors were 58% HER2-low, while in TNBC 39% tumors were HER2-low. In the analysis they observed that estrogen receptor (ER) expression was positively associated with HER2-low and that pCR rates were different between HER2-low and HER2-zero, with HER2-low having lower pCR rates than HER2- zero. However, once the data was adjusted for HR expression, pCR rates were the same (after removing ER-low cases). In the unadjusted analysis, HER2-low tumors had more favorable survival than HER2- zero, again this difference was gone after adjusting for ER expression. Dr. Tarantino concluded that there are clinicopathologic differences that distinguish HER2-low from HER2-zero tumors, but that the differences observed are mostly due to ER expression. While these results do not support HER2-low as a distinct biologic subtype of breast cancer, Dr. Penault Llorca’s conclusion was somewhat different, where she said that it is very likely that HER2-low is a real entity. However, better standardized HER2 testing practices are needed to clinically distinguish HER2-low from HER2-zero. Perhaps prospective studies with standardize HER2 testing assays would solve the question of whether HER2-low is a real clinical entity. It is also possible that we are not seeing the full picture of HER2 when it is being evaluated; indeed, a biopsy is only taken from a single point in a tumor. In one of our studies presented at the conference, “Spatially-resolved single-cell HER2 tumor heterogeneity captured by biophysical modeling”, our goal was to visualize HER2 heterogeneity within tumors using 3D maps of HER2 expression. We integrated single cell RNA-seq data with patient-specific tumor morphology using a biophysical modeling platform. Our approach could potentially provide clarity to the clinical differences between HER2-low and HER2-zero breast cancers.
During a chemotherapy and immunotherapy in TNBC session, Dr. Nadia Harbeck explained that ESMO guidelines list NAT as standard-of-care. She highlighted again that for TNBC and HER2+ breast cancer reaching pCR is very important as it leads to better long-term outcomes.
In terms of the optimal chemotherapy backbone, she mentioned that in Germany platinums have been incorporated for quite some time, as they increase the probability of pCR, and there is always the option to change to anthracyclines and/or taxanes if needed. Platinum treatment works better in patients with wtBRCA, although BRCA status is not predictive of platinum benefit, and both wtBRCA and mutBRCA cohorts show numerical benefit. Regarding immunotherapy, she mentioned that PD-L1 status is not predictive, but pembrolizumab improves pCR and patient outcome. She pointed to the IMpassion studies where atezolizumab seemed to improve pCR. These studies were expanded on by the next speaker in the session. Dr. Harbeck closed by reminding the audience that there are still many open questions about optimal patient cohort, chemotherapy backbone, neoadjuvant vs. adjuvant, etc.
Dr. Peter Fasching continued the discussion talking about the advancements in immuno-oncology for early and metastatic breast cancer. He first discussed the IMpassion trials. The IMpassion 130 trial assessed nab-paclitaxel vs nab-paclitaxel + atezolizumab, the results were promising with an improved PFS observed in the study arm. However, the follow-up trial IMpassion 131 could not confirm the results obtained in the IMpassion 130 trial. Atezolizumab was withdrawn as a treatment option for metastatic TNBC in 2021. He next discussed the Keynote-355 trial that assessed the efficacy of pembrolizumab and chemotherapy in comparison to solely chemotherapy treatment of patients with metastatic TNBC. This trial achieved all prespecified study aims for the subgroup of patients with a PD-L1 score (CPS) higher than 10. Patients with a PD-L1 score higher than 10 seem to have higher efficacy than patients with a PD-L1 score lower than 10, who showed lower efficacy to the combination of pembrolizumab and chemotherapy. Dr. Fasching explained that checkpoint inhibitors and chemotherapy are just the beginning, there are more therapeutic options in the pipeline.
After Dr. Fasching spoke an expert pathologist, Dr. Vicente Peg Camara, discussed PD-L1 testing in TNBC. While explaining how PD-L1 assessment is done, he said that it varies depending on the drug that the patients will receive. If the patients receive atezolizumab the SP142 antibody is used with a specific assay. If patients receive pembrolizumab the antibody 22C3 is used to evaluate PD-L1 with a different assay than the one for the SP142 antibody. He asked the audience how many knew what assay was used to evaluate PD-L1 at their institution. As he expected, few oncologists were aware of that difference or what antibodies their pathologists employed. He also underscored the unlikeliness of finding both techniques at the same institution.
At the conference we presented a “Novel platform combines pathology and transcriptomics for a multi-scale analysis and visualization of the breast tumor heterogeneity.” This technology, PhenoScope, integrates cancer data across scales to extract cross modality trends that drive cancer invasion. This analysis of breast cancer pathology slides in three different scales could potentially aid in the identification of more robust biomarkers that could better classify patients that could benefit from immunotherapy, or even better classify HER2 patients.
Antibody Drug Conjugates
There is also a growing interest in developing more targeted therapies, mainly ADCs, not only for tumors with an existing molecular marker such as HER2, but also for TNBC that has long been characterized by absence of targetable molecules. As Dr. Peter Schmid mentioned in his talk, there is no longer the need for an oncogenic driver to be targeted. For TNBC and HER2-negative breast cancers one such promising drugs is the sacituzumab govitecan-hziy. This ADC, which targets the protein Trop 2, showed improved overall survival in heavily pretreated and chemotherapy refractory TNBC and showed activity in HR+/HER2-negative metastatic breast cancer. On April 2020, the FDA granted this ADC accelerated approval as a treatment for metastatic TNBC patients that received at least two prior therapies for metastatic disease.
Dr. Frederik Marmé presented the safety interim analysis (SIA) of the SASCIA phase III trial focused on studying the efficacy of sacitumab govitecan-hziy vs. TPC (capecitabine or platinum based) in HER2-negative breast cancer. While the study arm presented higher rates of AEs, these are manageable, and the study continues as expected. At the time of the analysis 142 patients had been randomized and 88 patients were included in the SIA.
Another promising ADC is being evaluated in the SOLTI TOT-HER3 study designed to evaluate the activity of HER3-DXd. This is a HER3-directed antibody drug conjugate for HR+/HER2- operable breast cancer. At the time of the conference 77 patients had been enrolled. In untreated early HR+/HER2- BC, a single dose of HER3-DXd improved response and increased immune infiltration. The overall response rate observed in the study arm was 45%.
Overall, it was a very exciting conference demonstrating the pace of innovation in breast cancer care, and the challenges and opportunities to come.