Highlights from ESMO Breast Cancer 2022

May 18, 2022

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.

HER2-Low treatment

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.

 

Immunotherapy

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.

To read the full SimBioSys’ abstracts visit the ESMO Breast Cancer 2022 abstract book or our publications site.

 

TumorScope™ Breast

SimBioSys TumorScope™ currently aids the identification of the safest and most efficacious drug regimens for breast cancer patients.

It provides quantitative and qualitative analysis of a patient’s potential response to therapy, generated with a 3D computational model incorporating previously acquired diagnostic data.

The results from TumorScope™ are intended to be used in conjunction with the oncologist’s professional judgment, patient’s clinical history, symptoms, and other diagnostic tests.

With hundreds of retrospective patients validated, our results speak for themselves – a 95% correlation between simulated final volume and actual clinical volume post-therapy.

The Future
TumorScope™ Brain

Please Stay Tuned

The Future
TumorScope™ Mouth/Throat

Please Stay Tuned

TumorScope™ Lung

SimBioSys is developing TumorScope™ Lung, with the goal of having a positive impact on quality of life, clinical decision-making, and healthcare costs associated with lung cancer.


Though lung cancer is the leading cause of cancer-related deaths worldwide, it is amongst the few solid tumors for which immunotherapeutics have shown great promise.


The structure of lung tissue is dissimilar to that of other tissues we have studied, as the lungs are highly vascularized, oxygenated, and composed of numerous branching sets of airways.


These factors facilitate the need for accurate 3D models of the lung tumor microenvironment, and require nuanced optimization of our image analysis and segmentation methods.

The Future
TumorScope™ Bladder

Accounting for approximately 81,000 new cases in the US each year, bladder cancer is the sixth most-frequently diagnosed solid tumor.

The primary goal of neoadjuvant chemo for advanced bladder cancer is not to enable bladder-conserving treatment, but to downstage the tumor before radical cystectomy.

Bladder cancer staging is strongly dependent on the cancer’s invasion into the bladder wall and surrounding perivesical tissue.

Because of this, the SimBioSys TumorScope™ is poised to offer healthcare providers new methods to predict the degree of downstaging under different treatment regimens, and thereby optimize therapy for patients.

The Future
TumorScope™ Prostate

Affecting approximately 165,000 men in the United States each year, prostate cancers tend to occur in older men, and are often slow to progress.

As a result, management of the disease frequently includes watchful waiting and active surveillance.

SimBioSys TumorScope™ is capable of predicting tumor growth and progression, both with and without intervention.

There exists an obvious application in weighing the risks and benefits of less aggressive approaches to prostate cancer management.

The Future
TumorScope™ Ovary

The “silent killer”, early stage ovarian cancer often presents with symptoms similar to those of other common gynecological or gastroenterological issues.

Approximately 70% of epithelial ovarian cancers are not diagnosed until stage III or IV.

Ovarian cancer represents a natural next step for SimBioSys, allowing us to leverage the knowledge and modeling expertise we’ve accumulated.

This will allow us to target a cancer with high morbidity and mortality, for which neoadjuvant therapy is becoming an increasingly important option.

The Future
TumorScope™ Colon

Please Stay Tuned

The Future
TumorScope™ Skin

Please Stay Tuned

The Future
TumorScope™ Kidney

Please Stay Tuned

The Future
TumorScope™ Liver

Please Stay Tuned

The Future
TumorScope™ Uterus

Please Stay Tuned

The Future
TumorScope™ Thyroid

Please Stay Tuned

The Future
TumorScope™ Pancreas

Please Stay Tuned

The Future
TumorScope™ Esophagus

Please Stay Tuned

Tumor Microenvironment
Modeling

The tumor microenvironment is understood as a complex space where cancer cells adapt their metabolic behavior, competing and cooperating with nearby healthy cells in order to grow.

Understanding the complex ways in which cancer cells interact with other nearby cell types—competing for some resources, sharing others, and eliciting molecular signals that reshape their surroundings—is critical for understanding tumor progression and response to therapy.

SimBioSys TumorScope™ offers a computational window to these interactions, enabling patients and healthcare providers to explore how different treatment regimens can influence tumor response, and ultimately, patient survival.

Virtual Trials

The logistical and financial requirements of clinical drug trials are burdensome in the context of developing novel cancer therapeutics.

Additionally, there is inherent risk for the participants of these trials, both human and animal.

Building on the aforementioned technology, SimBioSys plans to create software to virtually test the efficacy of a drug on our library of patients.

The goal is to use this technology for planning and selecting the most appropriate cohorts, using computational methods, before a trial begins.

Additionally, this technology will be used for testing the effects of various forms of a drug on virtual patients, as opposed to humans or animals.

This technology will provide a deeper understanding of the mechanisms underlying treatment non-response, and will aid in drug development efforts.

Drug Delivery Modeling

After the SimBioSys platform has been extended to nearly the full range of solid mass tumors, pharmaceutical companies will be able to test their numerous therapies against a range of simulated tumors to discover new uses and delivery methods for drugs.

Studies show a salient relationship between sub-optimal drug delivery and acquired drug-resistance, leading to increased risk of mortality.

TumorScope™ provides an opportunity to reduce the likelihood of this occurrence.

Tushar Pandey
Chief Executive Officer MBA University of Chicago, BS Engineering University of Illinois at Urbana-Champaign

With a passion to support the fight against cancer, Tushar’s focus is to ensure the company delivers on its mission to empower precision medicine. In his prior role as VP of Decision Support at Strata Decision Technology, he worked
with over 150 health systems across the country including Kaiser Permanente, Cleveland Clinic, MD Anderson, Intermountain Healthcare, Dana Farber among others. Under his leadership, Strata Decision received the prestigious “Best in
KLAS” recognition for five consecutive years. With over a decade of healthcare experience, Tushar has been one of the key thought leaders in the healthcare analytics and cost of care space.

Joseph R. Peterson
Chief Technical Officer PhD Chemistry University of Illinois at Urbana-Champaign

Driven by an interest in computing, Joseph’s 10 years of scientific research has spanned investigating combustion and explosion, to analyzing the role of the environment on microbes’ behavior, to examining individual differences in
breast tumors. He is passionate about developing software for the health and scientific R&D sectors. His goal as Chief Technical Officer at SimBioSys, Inc. is not merely to develop enterprise technologies that enable new
clinical action, but to foster lasting relationships between key players in cancer treatment.

John A. Cole, Jr.
Chief Scientific Officer PhD Physics University of Illinois at Urbana-Champaign

John is a biophysicist specializing in stochastic models and systems biology. Equally comfortable with pencil-and-paper mathematical modeling and high-performance computational simulation, John’s “whatever works” approach to problem
solving and friendly, collaborative demeanor has allowed him to contribute significantly to a range of projects in basic science and health. As Chief Science Officer of SimBioSys, Inc., he is excited to extend this line of research
to enable transformative cancer treatment.

Tyler Earnest
Director of Computational Medicine PhD Physics University of Illinois at Urbana-Champaign

Tyler has a long history of mathematical modeling as applied to biological systems. He is also well-versed in software development, 3D visualization, and GPU programming as applied to computational biology. His primary focus is on
conceiving, constructing, and validating new cancer and drug models.

Michael Hallock
Director of Technology Development MS Bioinformatics University of Illinois Urbana-Champaign

Michael has more than 10 years of experience in the software development and information technology fields. He has extensive experience developing software for scientific computing, high performance computing, and cloud computing.
He applies his extensive knowledge to work on advanced analytics software, focusing on back-end (database, server/client communication, database development, IT infrastructure, etc.) technologies, as well as working closely with
full stack developers. Additionally, he will provide software support for scientific development.

Anu Antony,
MD, MPH, MBA, FACS
Chief Medical Officer MBA Kellogg School of Management at Northwestern University, MPH Harvard School of Public Health, MD University of North
Carolina- Chapel Hill School of Medicine, Stanford University Medical Center, Memorial Sloan-Kettering Cancer

Dr. Antony is a Harvard, Stanford, and Memorial-Sloan Kettering Cancer Center-trained surgeon with 20 years of experience in breast cancer, including multiple leadership positions in Chicago as Professor and Vice-Chair of the Department of Surgery at Rush University, Co-Director of the Breast Cancer Service Line, and Chief of Breast Reconstruction at the Rush University Cancer Center, and Vice-Chair of the Breast Cancer Center at the University of Illinois at Chicago Hospital and Health Services. She is passionate about innovation in precision oncology and commercializing cutting-edge technology to bring it directly into the hands of physicians and patients. Her interest in science and medicine began at UNC-Chapel Hill where she graduated with distinction in Chemistry. After graduating with honors at UNC-Chapel Hill School of Medicine, she became intrigued with medical device innovation during her general surgery and plastic surgery training in silicon valley at Stanford University Medical Center. She furthered her education and training during an oncologic reconstructive surgery fellowship at Memorial Sloan-Kettering Cancer Center, a Masters in Biostatistics and Clinical Outcomes at the Harvard School of Public Health, and an additional research fellowship training at Massachusetts General Hospital/Harvard Medical School. Recognizing the benefits of dovetailing science, medicine, and business, she completed an MBA at the Northwestern-Kellogg School of Management. Dr. Antony has worked in government and private sectors where she actively treated cancer patients, co-led a multimillion dollar NIH program grant as co-PI studying stem cells in a primate model, actively publishes, lectures nationally and internationally, and has served as Chair and President of several regional and national professional societies and conferences.

Tim Foley
Vice President, Business Development MBA, Kellstadt Graduate School of Business at DePaul University with emphasis on Applied Economics and Strategy, Execution, and Valuation

Charged with partnering initiatives to further our mission of empowering precision cancer care, Tim has joined as our VP of Business Development and comes armed with over 20 years in healthcare BD having led transaction teams at both Takeda and Astellas. Tim’s most recent focus is on helping health tech startups navigate the partnering paradigm. Cancer has had a large impact on his personal life leaving him impassioned to unlock new-generation solutions aimed at radically improving outcomes for tomorrow’s patients.

Tricia Carrigan,
PhD SVP, Precision Medicine PhD

Dr. Tricia Carrigan is an accomplished Biopharmaceutical and Diagnostic Executive with over 24 years of experience across the biomarker discovery- companion diagnostic-drug development and commercialization spectrum. She specializes in Companion Diagnostics (CDx) Strategy & Commercialization, drug development programs, early and late stage drug licensing, Oncology, Women’s Health, Cardiovascular, and Hematology. She has an international experience in assay implementation/development for Phase I-III trials, external innovation and business development/partnering in EU and Asia- Pacific markets.

Eduardo Braun, MD
Head of Clinical Affairs
MD, Rio de Janeiro School of Medicine, RUSH University Medical Center
Eduardo Braun, MD earned his medical degree at the Federal University of Rio de Janeiro School of Medicine. He completed his Fellowship in Hematology/Oncology, and his Residency in Internal Medicine at RUSH University Medical Center in Chicago. He is board certified in internal medicine, medical oncology and hematology.
Dr. Braun actively participates in lung cancer, breast cancer and lymphoma research and his work has been published. He is an active member of the American Society of Clinical Oncology, American Society of Hematology and the International Association for the Study of Lung Cancer.
Dr. Braun practices in Valparaiso, Chesterton, Hobart and Westville, Indiana.

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