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Oncologists’ Guide to Genomics

Stay current on the latest trends in genomics and molecular diagnostics for oncology.

Wednesday, August 23, 2023

Sacituzumab Govitecan Shows Survival Benefit in Metastatic Breast Cancer

​By Dibash Kumar Das, PhD

The latest analysis of the Phase III TROPiCS-02 study (NCT03901339), investigating the use of sacituzumab govitecan in hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer, has revealed promising results. The study, which focused on patients with pretreated, endocrine-resistant, HR+/HER2- metastatic breast cancer, demonstrated a significant overall survival advantage for sacituzumab govitecan compared to treatment of physician's choice. The research was presented at the 2023 ASCO Annual Meeting (Abstract 1003).

The trial enrolled eligible patients with HR+/HER2- metastatic breast cancer who had previously received taxane, endocrine therapy, CDK4/6 inhibitors, and 2-4 lines of chemotherapy. The participants were randomly assigned to receive either sacituzumab govitecan (10 mg/kg IV on Day 1 and 8, every 21 days) or treatment of physician's choice until disease progression or unacceptable toxicity.

The primary endpoint was progression-free survival, while key secondary endpoints included overall survival and safety. Additionally, an exploratory analysis assessed overall survival based on HER2 immunohistochemistry (IHC).

Study Details
In the study, a cohort of 543 patients was enrolled with 272 individuals assigned to receive sacituzumab govitecan and 271 patients assigned to receive treatment of physician's choice. After a median follow-up of 12.75 months, a total of 437 overall survival events were recorded.

The extended follow-up analysis reaffirmed the superior overall survival outcomes associated with sacituzumab govitecan compared to treatment of physician's choice, with a median overall survival of 14.5 months for sacituzumab govitecan versus 11.2 months for treatment of physician's choice (HR: 0.79; 95% CI: 0.65-0.95; nominal P=0.01).

At the 12-month mark, the overall survival rates for sacituzumab govitecan and treatment of physician's choice were 60.9 percent and 47.1 percent, respectively, providing further evidence of the survival benefits conferred by sacituzumab govitecan in this specific patient population. Remarkably, regardless of HER2 status, the analysis demonstrated that sacituzumab govitecan improved overall survival, with both the HER2 IHC0 and HER2-low groups exhibiting prolonged survival rates when compared to treatment of physician's choice.

In an interview with Oncology Times, study author Sara Tolaney, MD, MPH, revealed the impact of their research on treatment approaches for patients diagnosed with HR+/HER2– metastatic breast cancer. Tolaney is Associate Professor of Medicine at Harvard Medical School and Chief of the Division of Breast Oncology in the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute.
 
Oncology Times: How do the results of this trial impact the treatment landscape for HR+/HER2- metastatic breast cancer, and what are the potential implications for clinical practice?
Tolaney: “Data from TROPiCS-02 demonstrate that sacituzumab govitecan results in improved progression-free survival and overall survival compared to standard chemotherapy in patients with metastatic HR+ breast cancer who have progressed on endocrine therapy and prior chemotherapy in the metastatic setting. These data confirm the benefits of sacituzumab govitecan and it is important as it adds an effective treatment option for patients with metastatic HR+ disease."

Oncology Times: What were the most common adverse events observed with sacituzumab govitecan in the TROPiCS-02 trial and how were they managed?
Tolaney: “Common adverse events with sacituzumab govitecan include neutropenia, diarrhea, and fatigue. About half of the patients in the trial used growth factor support to help with the neutropenia, and loperamide, as needed, is very effective for patients with diarrhea."

Oncology Times: What are the next steps for research in this area, and how do you envision future treatment options for patients with HR+/HER2- metastatic breast cancer evolving in light of these findings?
Tolaney: “There is interest in seeing if sacituzumab govitecan could be used in an earlier line setting for metastatic HR+ breast cancer. The ASCENT-07 trial (NCT02574455) is looking at sacituzumab compared to standard chemotherapy in patients who have progressed on endocrine therapy in the metastatic setting, but had not received any chemotherapy for their metastatic disease."

Dibash Kumar Das is a contributing writer. ​

Monday, July 24, 2023

New Discovery Highlights Why Kidney Cancers Become Metastatic

​Researchers at The University of Texas MD Anderson Cancer have engineered a new model of aggressive renal cell carcinoma (RCC), highlighting molecular targets and genomic events that trigger chromosomal instability and drive metastatic progression. The study, published in Nature Cancer, demonstrates that the loss of a cluster of interferon receptor (IFNR) genes plays a pivotal role in allowing cancer cells to become tolerant of chromosomal instability (2023; https://doi.org/10.1038/s43018-023-00584-1). This genomic feature may be used to help clinicians predict a tumor's potential to become metastatic and treatment-resistant.

Researchers led by Luigi Perelli, MD, PhD, postdoctoral fellow of Genitourinary Medical Oncology, and Giannicola Genovese, MD, PhD, Professor of Genitourinary Medical Oncology, used CRISPR/Cas9 gene editing to create a model that faithfully represents RCC in humans, using cross-species analyses to provide further insights into the mechanisms involved in aggressive kidney cancer evolution.

“Until now, there haven't been effective experimental models for metastatic renal cancer progression, but we introduced specific mutations that closely mimic the early stages of human cancers to see how tumors evolve and metastasize," Genovese said. “These tumors become extremely genomically unstable and, to tolerate this instability, they tend to lose genetic material at a specific site where the interferon genes are located. These insights can help clinicians identify tumors that have the genomic potential to become aggressive."

Renal cell carcinoma is the most common type of kidney cancer, and patients often are treated effectively with surgery, targeted therapy, immunotherapy, or a combination of these treatments. However, up to one-third of these patients will have aggressive disease progression, highlighting a need to understand specific mechanisms that drive metastasis in order to identify more effective therapeutic strategies and predict treatment responses.

One hallmark of cancer is chromosomal instability, which is associated with resistance to many types of therapy and a poor prognosis. However, it is unclear if specific types of chromosomal abnormalities are involved in driving metastasis and how tumors are able to tolerate them.

The researchers used CRISPR/Cas 9-based genome editing to generate RCC models lacking common tumor suppressor genes. They then targeted cell cycle regulator genes to mimic common chromosomal abnormality associated with metastatic RCC in humans, leading to a phenotype consistent with the human disease. This is the first immunocompetent somatic mosaic model for metastatic RCC, meaning the model has an accumulation of different mutations that result in uncontrolled cell growth but still maintains a functional immune system.   

Using genome sequencing and single-cell RNA sequencing to further examine these models, the researchers uncovered molecular drivers of RCC and gained a new understanding of the evolution of chromosomal instability. Their single-cell analyses revealed that a cluster of highly conserved IFNR genes was suppressed in the model and it normally functions as a critical gatekeeper, or tumor suppressor, of renal cancer progression.

IFNR gene clusters normally are involved in the immune response. After analyzing various data sets from both mice and humans, the researchers discovered an inverse correlation between the loss of these IFNR genes and aneuploidy, a condition marked by having an abnormal number of chromosomes.

This study suggests that the tumors adapt to high levels of chromosomal instability through the disruption of the IFNR pathway and this is likely a major biomarker of metastatic potential. It also highlights how renal cancers in different species have followed similar evolutionary patterns that converge around chromosomal instability, which in turn may explain the heterogeneity of these tumors.

In the future, the researchers plan to test drug combinations in these newly generated models to determine how the tumors adapt to various therapies with the goal of rapidly translating these studies into clinical trials that can help predict treatment response in patients with RCC.​

Thursday, April 20, 2023

Liquid Biopsy Assay for Accurate Detection of Pediatric Solid Tumors

​By Dibash Kumar Das, PhD

Pediatric solid tumors make up around 40 percent of all childhood cancers and they can occur in many areas of the body. Genomic profiling has been used to aid in diagnosis and determine the progno​sis for pediatric cancers and guide treatment in some cases. However, pediatric tumors have different genetic characteristics compared to adult tumors, which means that specific tests are needed to diagnose and treat them.

While adult tumors are often caused by mutations, pediatric tumors are more frequently characterized by copy number alterations (CNAs), gene fusions, and other large-scale genetic rearrangements. Recent studies have shown that using cell-free DNA (cfDNA) from plasma can help detect genetic changes in pediatric tumors (Cancer Discov 2022; https://doi.org/10.1158/2159-8290.CD-21-1136), but more research is needed to develop clinical tests to diagnose and monitor a variety of pediatric solid tumors.

Now, scientists at Children's Hospital Los Angeles (CHLA) have created a liquid biopsy (LB) for pediatric solid tumors that can help diagnose specific types of cancer when traditional biopsies are not feasible (npj Precis Onc 2023: https://doi.org/10.1038/s41698-023-00357-0). The study will investigate whether plasma-based LB and low-pass whole genome sequencing (LP-WGS) might support the clinical diagnosis and prognosis of pediatric solid tumors, monitor therapy response, and detect early evidence for relapse. The researchers combined LP-WGS with targeted sequencing of cfDNA from plasma to identify CNAs, mutations, and gene fusions linked with pediatric solid tumors.

A significant aspect of this study was that the amount of sample required for testing was much smaller than that required for LB studies in adults, since infants and young children have smaller blood volumes, and the assays were scaled down to adjust for this. With LP-WGS, many samples can be loaded onto a sequencer at once, allowing for low-cost testing. Moreover, the assay could be used across pediatric tumors and use different sources for LB samples, such as aqueous humor, cerebral spinal fluid, and blood samples.

A total of 143 plasma samples were analyzed, including 73 from patients with newly diagnosed or recurrent malignant bone or soft tissue sarcomas, as well as germ cell, hepatic, thyroid, or renal tumors, and 19 from non-cancer control patients. Researchers collected cfDNA at diagnosis, during and after therapy, and/or at relapse, which was isolated from plasma samples.

Specifically, the assay detected that 70 percent (26 out of 37) of patients had circulating tumor DNA (ctDNA) in the diagnostic samples and 43 percent (10 of 19) in relapse samples. The LP-WGS test also detected CNAs in 67 percent (18 of 27) of patients with localized disease and 80 percent (8 of 10) of patients with metastatic disease. This data shows that, even with previous therapy, patients could still have enough ctDNA in their plasma to be found by LP-WGS. The control group did not have detectable somatic CNAs. Notably, this study is one of the few to demonstrate the applicability of ctDNA detection in pediatric solid tumor patients with localized disease.

Next, the researchers investigated whether the test could identify CNAs associated with specific types of tumors. In osteosarcoma patients, the assay identified genomic instability, a hallmark of the disease, in 53 percent of patients out of 17 tested. Among 13 Ewing sarcoma patients, nine patients had detectable CNAs with seven patients showing a gain of chromosome 8, an abnormality frequently observed in this cancer type. The assay also detected CNAs in 75 percent of newly diagnosed renal tumor patients and in all five relapsed renal tumor patients.

Next, mutations identified in tumor samples using a next-generation sequencing (NGS) panel, OncoKids, were also observed in 14 out of 26 plasma samples through the analysis of ctDNA using LP-WGS. A total of 16 hotspot mutations in 14 patients were detected, including alterations in PIK3CA, TP53, and CTNNB1, demonstrating the sensitivity of LP-WGS, the low but significant number of mutations present in pediatric solid tumors. Lastly, the researchers developed a hybridization-based capture panel to detect EWSR1 and FOXO1 fusions, which were detected in 10 out of 12 patients with Ewing sarcoma and 2 out of 2 patients with alveolar rhabdomyosarcoma.

The researchers suggest that a larger cohort size is needed to confirm the applicability of fragment size analysis in detecting ctDNA and distinguishing tumor types in pediatric cancers. They also propose that validating the use of LB assays in larger cohorts of patients with pediatric solid tumors, combined with clinical biomarkers such as alpha-fetoprotein, could lead to a non-invasive means of molecular diagnosis and monitoring patients from diagnosis through treatment and recurrence. Serial studies using NGS-based LB assays could help in understanding how they can be employed for this purpose.

For more insights into the study, Oncology Times connected with Jaclyn Biegel, PhD, FACMG, senior author and Division Chief of Genomic Medicine and Director of the Center for Personalized Medicine at Children's Hospital Los Angeles, as well as Professor of Clinical Pathology in the Keck School of Medicine at the University of Southern California.
 
Oncology Times: Can you elaborate on the potential clinical applicability of your LB platform to evaluate pediatric patients with a variety of solid tumors, and how it differs from other LB assays available on the market?
Biegel: “The majority of LB assays available on the market today target the most frequent DNA alterations observed in tumors in adults, for example activating mutations in oncogenes in colon cancer and lung cancer. The cfDNA yield from 20 mLs of blood in an adult is more than adequate to perform those assays, but it is not feasible in pediatric patients. Pediatric tumors are more often characterized by tumor-associated patterns of CNAs and gene fusions, and very few mutations. The LB assays we have developed require an input of only 1-5 ng of cfDNA isolated from 50 μL of aqueous humor from patients with eye tumors, or 2-4 μL of cerebrospinal fluid (CSF) or blood from patients with brain or solid tumors. The first clinically validated LB assay at Children's Hospital Los Angeles employs low-pass WGS to detect copy number changes in newly diagnosed patients, as well as patients with recurrent or metastatic disease. Subsequent versions of the assay will employ targeted sequencing to detect mutations and gene fusions."
 
Oncology Times: How do you ensure that you are accurately distinguishing ctDNA from cfDNA, given the challenge of cfDNA being derived predominantly from hematopoietic cells?
Biegel: “The use of low-pass WGS allows us to identify CNAs in ctDNA that are not seen in the germline (normal cells). The challenge arises when the tumor has a normal copy number profile; for example, in Ewing sarcomas with balanced translocations that result in EWSR1 gene fusions. Targeted sequencing to detect specific gene fusions or mutations will result in higher sensitivity and specificity to detect ctDNA in LB specimens. ctDNA fragments are shorter than fragments derived from normal cells and thus we also used in-silico approaches to enrich for ctDNA content in our analyses."

Oncology Times: The study mentions that the incidence of pediatric solid tumors is low, and the number of histologic, genomic, and clinical subtypes is large. How do you account for this heterogeneity when developing a pan-cancer assay for LB?
Biegel: “The utility of WGS as a basis for the assay ensures that we will capture the majority of CNAs across the entire tumor genome in the same way that we currently employ chromosomal microarray analysis of bone marrow aspirates or tumor tissue to aid in the diagnosis of hematologic malignancies, and brain and solid tumors. In contrast, most of the currently available LB-based tests focus on particular regions in the adult cancer genomes that are likely to demonstrate mutations or specific gains or losses of a particular target gene. To complement the copy number aspect of the LB assay for pediatric cancer, we will develop targeted sequencing approaches that can be used for multiple tumor types and expand the feasibility studies described in the paper for clinical validation with a larger cohort of patients."
 
Oncology Times: How do you see the use of LBs for pediatric patients with solid tumors evolving in the next 5-10 years? What challenges need to be addressed to make this a widespread clinical tool?
Biegel: “We expect to see rapid growth in the development of LB assays for pediatric cancer over the next several years. We have already demonstrated the utility of our assay as an aid in diagnosis when a tumor biopsy is not feasible, for detection of high-risk genetic features that may guide therapy, and for early detection of relapse prior to the presence of tumor visualized by imaging. Larger studies across the spectrum of tumor types are required to demonstrate the use of LB assays for surveillance in patients who are at risk for the development of cancer due to genetic predisposition factors or who may relapse after treatment. This will be challenging because many of the subtypes of pediatric cancer are, fortunately, very rare and specimens may still be limited.

“We know very little about the factors that influence the yield of ctDNA in plasma and CSF and are, therefore, being conservative in using the total amount of ctDNA isolated from plasma or CSF as a specific biomarker. Clinical assays based on tumor-associated methylation profiles of ctDNA, non-coding RNAs, mitochondrial DNA variants, and proteins are all in development and will allow us to use LBs for a larger number of applications than we have available at present. The relatively rare nature of pediatric cancer may be an advantage as we aim to develop patient-specific assays for clinical use."

Dibash Kumar Das is a contributing writer.​

Monday, March 20, 2023

Distinct Metastatic Signature Predicts Survival in Renal Cell Carcinoma

By Dibash Kumar Das, PhD

Renal cell carcinoma (RCC) has been noted as the seventh most common type of neoplasm in the developed world. The clear cell subtype of RCC (ccRCC) makes up 75-85 percent of all cases. When ccRCC is confined to the kidneys, the prognosis is often positive and surgical resection or thermal ablation of the tumor is frequently curative.

However, approximately 25 percent of patients present with metastatic disease. In the metastatic setting, ccRCC continues to be a lethal disease having a 5-year survival rate of under 10 percent. To improve the avenues of therapeutic intervention for metastatic RCC, a careful dissection of the complex relationship between stromal cells and tumor cells within the ecosystem of the tumor microenvironment (TME) is required.

Now, novel research reveals that, among patients with ccRCC, the activity of four specific genes seems to reveal a distinct transcriptional signature that is predictive of metastatic potential and the patient's chances of survival. The preclinical study was published in Nature Communications (2022; https://doi.org/10.1038/s41467-022-33375-w).

Study Details
The current study consists of researchers at Karolinska Institutet in Sweden; clinicians at Massachusetts General Hospital, where the patients were recruited; and computational scientists from Harvard Medical School in Boston. The coordinated surgical and research teams profiled fresh patient samples from nine patients, which included human ccRCC tumors and their matched normal control kidney tissue from treatment-naïve patients. In two patients, the investigators also compared primary tumor tissue from the kidney with tissue from skeletal metastases.

A single-cell transcriptomic analysis of treatment-naïve ccRCC primary tumors and adjacent normal kidney tissue with a focus on the TME was performed. The analysis revealed the following observations:

  • Tumor cells are transcriptionally similar to a proximal tubule cell population subset, which potentially represents ccRCC cell of origin.
  • The synchronous assessment of primary tumor and bone-metastatic tumor tissues from two patients presenting with de novo metastases uncovered a specific metastatic signature linked with poor prognosis.
  • Stromal cells found in RCC tumors revealed the highest transcriptional variation of analyzed cell types compared to adjacent normal kidney.
  • Additional components of the TME were identified. They included a cellular map of the stromal cell compartment and of cell-to-cell interactions in the tumor that are perhaps vulnerable to therapeutic targeting.

Importantly, the study revealed that a genetic signature of four specific genes is predictive of tumor metastasis to the skeleton and whether it can predict survival. Simultaneous upregulation of SAA1, SAA2, and APOL1 in high-grade ccRCC, and MET as a tyrosine kinase receptor involved in tumor cell proliferation, survival, and migration as a therapeutic target of cabozantinib, indicate the patient has a greater risk of developing a tumor that spreads and a poorer survival outcome.

"This could potentially become a tool to gain a better understanding of the course of the disease at an early stage. Patients with a cancer profile with a high probability of spreading could then be monitored more closely to quickly detect and treat any growth of the tumor," noted senior study author, Ninib Baryawno, PhD, a researcher and team leader at the Department of Women's and Children's Health, Karolinska Institutet.

Additionally, within the complex immune microenvironment, TREM2 was discovered to be elevated in the TME myeloid cells. This finding elevated the receptor's prospect as a prognostic marker in ccRCC and as a biomarker for detecting patients who could benefit from checkpoint blockade immunotherapy.

Researchers identified the CD70-CD27 relationship as potentially important with regard to cell-cell interactions. An in silico cell-to-cell interaction analysis showed that the CXCL9/CXCL10-CXCR3 axis and CD70-CD27 axis were possible therapeutic targets that could provide further promise in preclinical models. Researchers noted CD70-CD27 interactions could cause immune evasion by the tumor.

Overall, these findings reveal biological insights on interactions between tumor cells and the ccRCC microenvironment.

"We hope that our results will contribute to further investigations of factors that affect the tumor microenvironment, which can ultimately provide new ways to treat relapse and the spread of cancer. For us, the next step is to study how metastases in the bone marrow and the skeleton differ from the local tumor in the kidney, but also how the bone marrow in patients with kidney cancer metastases in the skeleton differs from healthy bone marrow. We hope that it can help us answer the question as to why immunotherapy does not work in some kidney cancer patients," concluded study author, Adele Alchahin, a PhD student at the Department of Women's and Children's Health at the Karolinska Institutet.

Dibash Kumar Das is a contributing writer.​

Monday, February 20, 2023

Enzyme Linked to Mutational Signatures in Small Intestine Cancers

​The first comprehensive study of somatic mutations in normal human small intestine has been conducted by researchers at the Wellcome Sanger Institute and their collaborators. The findings revealed that an enzyme named APOBEC1 is likely responsible for two mutational signatures found in many cancers, SBS2 and SBS13, in the small intestine.

Published in Nature Genetics, the research expands the members of the APOBEC family linked to SBS2 and SBS13 (2023; https://doi.org/10.1038/s41588-022-01296-5). Because APOBEC1 performs a vital role in nutrient absorption in the small intestine, it is possible that high levels of SBS2 and SBS13 in the small intestine may be “collateral damage" caused by the normal functioning of cells.

Somatic mutations accumulate in cells during life. Though the majority of these mutations are harmless, some are known to be involved in diseases such as cancer. The biological processes that create mutations in normal cells, and the rate at which mutations occur, are not well understood.

But in recent years, researchers have taken advantage of technological advances to begin characterizing the landscape of somatic mutations in normal human cells across many tissue types. These studies have identified patterns of mutation, known as “mutational signatures," which provide insights into what “normal" somatic mutation looks like in different parts of the body and how they can lead to disease.

APOBEC is a family of enzymes that edit DNA or RNA. Mutations caused by the activity of these enzymes are common in many human cancers. Previous studies had focused on APOBEC3A and APOBEC3B as the primary generators of the mutational signatures SBS2 and SBS13 in human cancers.

Study Details
In this new study, researchers set out to characterize the mutational landscape of the small intestine for the first time. A total of 342 individual small intestine crypts from 39 individuals were whole genome sequenced at the Wellcome Sanger Institute.

Analysis of somatic mutations in these tissues identified three mutational signatures found in most normal human cells: SBS1, SBS5, and SBS18. More surprisingly, it revealed that mutational signatures SBS2 and SBS13 were also common, which are rare in the large intestine and most other normal tissues.

“Previous research on the SBS2 and SBS13 mutational signatures in humans has generally focused on APOBEC3A and APOBEC3B," noted Yichen Wang, BS, first author of the study from the Wellcome Sanger Institute. “However, our findings show that, in normal small intestine epithelium, APOBEC1 is the likely culprit. It could be that the high levels of SBS2 and SBS13 in this organ are 'collateral damage' caused by the high levels of APOBEC1 present, which are needed for the small intestine to do its normal job of absorbing and transporting nutrients."

By retracing how each intestinal crypt developed from a single cell into several thousand, the researchers discovered fundamental information about somatic mutation in the small intestine.

“Our analysis reveals that APOBEC mutations occur in small bursts, with a single or very small number of episodes during the lifetime of an individual," stated Philip Robinson, PhD, a co-author of the study from the Wellcome Sanger Institute and the University of Cambridge. “The earliest instance we found was 4 years of age. The likely cause of APOBEC mutations in the small intestine seems to be due to circumstances within the cell itself, rather than as a result of an external factor such as genotoxic metabolites produced by bacteria."

Despite clear links between APOBEC mutations and cancer, the precise role that these enzymes play and the causal mechanism by which cancer begins to develop remain unclear. The concept of “collateral damage" resulting from normal cell functioning is something that merits further exploration. One way to do this would be to inactivate the APOBEC1 enzyme in experimental models and observe whether SBS2 and SBS13 developed or not.

“Though we have been studying somatic mutation in normal human cells for several years now, we continue to be surprised by what 'normal' looks like in the different tissues of the body," stated Sir Mike Stratton, PhD, a senior author of the study from the Wellcome Sanger Institute. “The discovery that APOBEC1 lies behind two important mutational signatures in the small intestine, rather than its better-studied cousins, gives us cause to reevaluate our understanding of APOBEC mutations more widely. Sometimes science throws up more questions than answers, but with each question we are one step closer to the truth."​