Principal Investigator: Dr. Christina Curtis, PhD, MSc
Associate Professor of Medicine and Genetics
Co-director, Molecular Tumor Board, Stanford Cancer Institute
Director, Breast Cancer Translational Research
Personalized Treatment and Monitoring for High-risk of Recurrence in ER-positive Breast Cancer
Background: By harnessing advanced genomic technologies and computation, Dr. Christina Curtis has redefined the molecular map of breast cancer, resulting in the identification of 11 subgroups of breast cancer, each with distinct prognoses and ‘drivers’. These subgroups include two groups of triple-negative breast cancer -- one with an elevated risk of relapse beyond 5 years as well as four estrogen receptor (ER)-positive subgroups with a persistent risk of relapse up to 20 years post-diagnosis. Collectively, these four subgroups account for one quarter of ER-positive patients (80% of all breast cancers) and the vast majority of relapses. This new “integrated” molecular classification system not only identifies which breast cancer patients are at high risk of relapse, but provides information about genetic alterations that confer this high risk and how to therapeutically target them. Accordingly, this approach has revolutionized the ability to identify patients with high risk of recurrence who require more aggressive monitoring and therapy.
Research strategy: While generally viewed as a less aggressive subtype, it is apparent that new therapeutic strategies are urgently required to prevent and treat recurrence in high-risk ER-positive breast cancer patients. To tackle this open challenge, Dr. Curtis and her team proposed and received federal funding for two first ever biomarker-guided clinical trials to target the specific alterations in tumors from these high-risk patient populations. The goals of these studies are:
Consenting of patients onto the first of these trials has begun and it is anticipated that the second trial will open in the Spring of 2021. For both of these trials, patients consent to donate blood and tumor biopsies during the course of therapy, providing an unparalleled opportunity to learn why therapies are successful in some patients and not in others.
In particular, Dr. Curtis and her team have established a powerful technique to generate organoids (organ-like) cultures of breast cancer patient biopsies that can be studied in the laboratory. These tiny mini-breast tumors capture the heterogeneity of disease and represent patient ‘avatars’ that can be used to determine whether an individual patient will respond to a given therapy. Accordingly, this approach can inform the development of new treatment strategies.
Additionally, blood will be collected from patients enrolled on trial at the time of diagnosis, during treatment and beyond and use genome techniques to search for the presence of tiny amounts of tumor DNA in the blood. Importantly, the presence of tiny fragments of tumor DNA in the blood is indicative of residual tumor and an elevated risk of recurrence. Such non-invasive strategies to detect residual cancer cells are far more sensitive than conventional approaches, potentially providing an opportunity to pursue more aggressive treatment courses when needed. However, the optimal strategies for monitoring high-risk patient for evidence of residual tumor following treatment is not yet known and is particularly complex in the setting of ER-positive disease.
Funding need: While federal funding has been secured to cover the majority of patient-care related costs for these investigator-initiated clinical trials, we are now at a critical juncture where seed funding is necessary to support correlative research on the precious specimens obtained from patients enrolled on these studies. These funds will enable the detailed molecular characterization of patient tissues and blood to define features associated with treatment response and to identify patients with continued risk of relapse following therapy by generating organoids and looking for DNA in the blood. Importantly, Dr. Curtis and her colleagues have already established the infrastructure and expertise to support this work and are prepared to begin immediately towards the goal of translating these findings to the clinic.
The trial for patients who have already recurred is open and we plan to enroll 12-16 patients. We have generated two organoids so far, and expect to generate eight more knowing that some of the tissue will have too few cells to make viable organoids. We will also profile plasma to look for a drop in tumor burden on treatment indicating response to the new drugs. Because these patients should have large amounts of circulating tumor DNA this also serves as a control (relative to early stage patients of the same subgroups in the Phase II trial). Specifically, we will investigate whether the alterations that confer a high risk of relapse are detectable and at what levels. This allows us to improve the approach in patients with early disease and less tumor shed.
The trial for early stage patients at high risk for recurrence should open in the middle of 2021, and our target enrollment is 200 patients. In year 1, we aim to generate organoids for eight of these patients. We will collect plasma at six time point and follow patients for as many years as they are willing in order to monitor their risk of recurrence over the time following their initial therapy. These approaches leverage bleeding edge technologies and encompass new paradigms that are unlikely to be funded by conventional means until this initial work is published.
$250,000 will provide 12-18 months of partial salary support of a clinical research coordinator and a postdoctoral researcher; reagents for organoid culture, characterization and drug studies; and blood (plasma) ctDNA genomic profiling at multiple time points. We will seek additional funding from multiple sources based on results of this portion of the study.
Impact: These transformative studies will lead to the development of genome-informed, risk stratified treatment and monitoring approaches for ER-positive breast cancer and have significant potential to transform outcomes for the subset of patients in greatest risk of recurrence. With initial trials underway, Dr. Curtis anticipates the near-term translation of these findings (within the next 3-5 years). These “bench to the bedside” studies represent an exemplar of precision medicine that pave the way to circumvent and ultimately prevent breast cancer recurrence across all patient subgroups.
Associate Professor of Medicine and Genetics
Co-director, Molecular Tumor Board, Stanford Cancer Institute
Director, Breast Cancer Translational Research
Personalized Treatment and Monitoring for High-risk of Recurrence in ER-positive Breast Cancer
Background: By harnessing advanced genomic technologies and computation, Dr. Christina Curtis has redefined the molecular map of breast cancer, resulting in the identification of 11 subgroups of breast cancer, each with distinct prognoses and ‘drivers’. These subgroups include two groups of triple-negative breast cancer -- one with an elevated risk of relapse beyond 5 years as well as four estrogen receptor (ER)-positive subgroups with a persistent risk of relapse up to 20 years post-diagnosis. Collectively, these four subgroups account for one quarter of ER-positive patients (80% of all breast cancers) and the vast majority of relapses. This new “integrated” molecular classification system not only identifies which breast cancer patients are at high risk of relapse, but provides information about genetic alterations that confer this high risk and how to therapeutically target them. Accordingly, this approach has revolutionized the ability to identify patients with high risk of recurrence who require more aggressive monitoring and therapy.
Research strategy: While generally viewed as a less aggressive subtype, it is apparent that new therapeutic strategies are urgently required to prevent and treat recurrence in high-risk ER-positive breast cancer patients. To tackle this open challenge, Dr. Curtis and her team proposed and received federal funding for two first ever biomarker-guided clinical trials to target the specific alterations in tumors from these high-risk patient populations. The goals of these studies are:
- Provide targeted therapy to patients who have already recurred, thereby improving survival.
- Prevent lethal recurrence in early-stage patients at high-risk of recurrence.
- Develop strategies to monitor risk or recurrence following initial therapy.
Consenting of patients onto the first of these trials has begun and it is anticipated that the second trial will open in the Spring of 2021. For both of these trials, patients consent to donate blood and tumor biopsies during the course of therapy, providing an unparalleled opportunity to learn why therapies are successful in some patients and not in others.
In particular, Dr. Curtis and her team have established a powerful technique to generate organoids (organ-like) cultures of breast cancer patient biopsies that can be studied in the laboratory. These tiny mini-breast tumors capture the heterogeneity of disease and represent patient ‘avatars’ that can be used to determine whether an individual patient will respond to a given therapy. Accordingly, this approach can inform the development of new treatment strategies.
Additionally, blood will be collected from patients enrolled on trial at the time of diagnosis, during treatment and beyond and use genome techniques to search for the presence of tiny amounts of tumor DNA in the blood. Importantly, the presence of tiny fragments of tumor DNA in the blood is indicative of residual tumor and an elevated risk of recurrence. Such non-invasive strategies to detect residual cancer cells are far more sensitive than conventional approaches, potentially providing an opportunity to pursue more aggressive treatment courses when needed. However, the optimal strategies for monitoring high-risk patient for evidence of residual tumor following treatment is not yet known and is particularly complex in the setting of ER-positive disease.
Funding need: While federal funding has been secured to cover the majority of patient-care related costs for these investigator-initiated clinical trials, we are now at a critical juncture where seed funding is necessary to support correlative research on the precious specimens obtained from patients enrolled on these studies. These funds will enable the detailed molecular characterization of patient tissues and blood to define features associated with treatment response and to identify patients with continued risk of relapse following therapy by generating organoids and looking for DNA in the blood. Importantly, Dr. Curtis and her colleagues have already established the infrastructure and expertise to support this work and are prepared to begin immediately towards the goal of translating these findings to the clinic.
The trial for patients who have already recurred is open and we plan to enroll 12-16 patients. We have generated two organoids so far, and expect to generate eight more knowing that some of the tissue will have too few cells to make viable organoids. We will also profile plasma to look for a drop in tumor burden on treatment indicating response to the new drugs. Because these patients should have large amounts of circulating tumor DNA this also serves as a control (relative to early stage patients of the same subgroups in the Phase II trial). Specifically, we will investigate whether the alterations that confer a high risk of relapse are detectable and at what levels. This allows us to improve the approach in patients with early disease and less tumor shed.
The trial for early stage patients at high risk for recurrence should open in the middle of 2021, and our target enrollment is 200 patients. In year 1, we aim to generate organoids for eight of these patients. We will collect plasma at six time point and follow patients for as many years as they are willing in order to monitor their risk of recurrence over the time following their initial therapy. These approaches leverage bleeding edge technologies and encompass new paradigms that are unlikely to be funded by conventional means until this initial work is published.
$250,000 will provide 12-18 months of partial salary support of a clinical research coordinator and a postdoctoral researcher; reagents for organoid culture, characterization and drug studies; and blood (plasma) ctDNA genomic profiling at multiple time points. We will seek additional funding from multiple sources based on results of this portion of the study.
Impact: These transformative studies will lead to the development of genome-informed, risk stratified treatment and monitoring approaches for ER-positive breast cancer and have significant potential to transform outcomes for the subset of patients in greatest risk of recurrence. With initial trials underway, Dr. Curtis anticipates the near-term translation of these findings (within the next 3-5 years). These “bench to the bedside” studies represent an exemplar of precision medicine that pave the way to circumvent and ultimately prevent breast cancer recurrence across all patient subgroups.
