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Role of Genomic Profiling in Younger Patients With Cancer

A Conversation With Timothy Triche, MD, PhD


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Although overall cancer survival rates continue to improve among all age groups in the United States—there are currently an estimated 15.5 million cancer survivors, and that number is expected to increase to 20.3 million by 20261—survival rates for adolescents and young adults with cancer (AYAs) still lag behind those for children and older adults with the disease. According to one study, between 2002 and 2006, the 5-year relative survival rate for all invasive cancers diagnosed in AYAs, those between the ages of 15 and 39, was 82.5%.2 However, survival is worse in AYAs with specific cancers, such as acute myeloid leukemia (AML) and medulloblastoma, compared with children with those cancers; it also is worse in AYAs than in older adults who have hepatic carcinoma, AML, high-grade astrocytoma, acute lymphoblastic leukemia (ALL), pancreatic carcinoma, low-grade astrocytoma, gastric carcinoma, renal carcinoma, cancer of the oral cavity and pharynx, Hodgkin lymphoma, ovarian cancer, fibromatous sarcoma, other soft-tissue sarcoma, and thyroid carcinoma.2 In addition, compared with older women, women younger than age 40 are generally diagnosed with more aggressive breast cancers and tend to have lower survival rates.3

The variations in survival among the three age groups are multifactorial and include delays in diagnosis and treatment, a lack of treatment guidelines and clinical trials specifically for teenagers and young adults, and differences in the biology of some cancers.

Timothy Triche, MD, PhD

Over the past decade, Timothy Triche, MD, PhD, Co-Director of the Center for Personalized Medicine Program and Professor of Pathology at the Keck School of Medicine at the University of Southern California Children’s Hospital Los Angeles, has focused his research on understanding the genetic mechanisms underlying cancers that are commonly found in children and adolescents and young adults, especially sarcomas, and in developing genomics-based biomarker profiles to predict outcomes and identify patients for risk-stratified therapies and potential therapeutic targets.

The ASCO Post talked with Dr. Triche about his research in the biologic features of cancer in adolescents and young adults and the role of precision medicine in determining potential therapeutic targets to improve survival outcomes.

Reasons for Survival Disparity

What are you learning from your research about the biologic features of cancer in AYAs compared with younger children and older adults? What are the factors contributing to the survival disparity among these age groups?

Although adolescents and young adults are sometimes diagnosed with cancers typically found in older adults, such as breast and colon cancers, they are more commonly diagnosed with cancers found in children, for example, leukemia and sarcoma. Those cancers have been successfully treated in children younger than age 16 because of standardized, national clinical trials, most notably those developed by the Children’s Oncology Group (COG), which investigate new therapies and treatment protocols that have dramatically improved outcomes for young patients.

Many efforts have been made by the COG and others to expand the upper age limit for its clinical trials to include the AYA age group to offer the benefits of childhood cancer protocols for the same tumor type in older patients. And these efforts have resulted in some success with tumors such as osteosarcoma and soft-tissue sarcoma. In contrast, leukemia spans all age groups, but the types that occur in younger patients are very different, lacking the mutations common in older patients with the cancer, but marked by a far higher incidence of so-called gene fusions that drive the tumor process. For example, ALL or AML is not the same disease in young adult patients, and it is better treated in most cases like leukemia in children. Treatment tailored to the unique features of cancer biology in a young adult leads to better outcomes.

At least two issues help to explain the survival disparity in AYAs: one is the lack of ready access to standardized treatment protocols such as those established years ago for children; and two is the likely acquisition of additional genetic drivers in AYAs, which often make their tumors more aggressive.

Age is often a prognostic factor in children with cancers, such as sarcomas and leukemia, and this factor likely extends to the AYA age group as well. A surprising finding from our research on all types of childhood cancer is that at least 15% of pediatric and AYA patients, and perhaps as high as 30% of these patients, have an inherited predisposition to cancer; they, and potentially their siblings, are likely to develop many types of cancer, including adult-type cancers, earlier in life. For example, when a woman in her 20s is diagnosed with breast cancer, it is a red flag that there is a very good chance she has an inherited predisposition factor and suggests a very different approach to treatment than breast cancer in older women.

In these cases, genetic counseling and germline testing for family members are often warranted, as well as close surveillance of the patient over time due to the propensity for the development of second malignancies.

“AYA patients and their family members should be screened for inherited risk factors if there is a strong family history of cancer and offered genetic counseling.”
— Timothy Triche, MD, PhD

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Identifying Genetic Risk Factors for Developing Cancer

Since AYAs diagnosed with cancer may have germline variants associated with cancer predisposition, should they automatically be offered genetic testing and counseling?

I would argue that all childhood cancers, including those that affect AYAs, by definition have an increased incidence of inherited risk factors. After all, these tumors occur in the very young, in whom mutational burden, environmental exposure, and lifestyle are unlikely to be factors in the development of their cancer. However, we do not yet know what all those risk factors are. We know that mutations in BRCA1/2 genes and in the P53 gene increase the risk for cancer, but it’s now clear that many other genes contribute to the likelihood of developing cancer. And that list is likely to grow as we learn the significance of a variety of inherited gene differences.

Since documented inherited cancers such as Li-Fraumeni syndrome, in which patients inherit a defective copy of the P53 gene, are often diagnosed in adolescence or young adulthood, AYA patients and their family members should be screened for inherited risk factors if there is a strong family history of cancer and offered genetic counseling. The problem is that we really don’t know all the gene mutations that may increase the risk for cancer, and that may be a good argument for standardizing genetic profiling of AYAs with cancer. If we do it uniformly for all patients with a strong family history of cancer, we’re going to learn a great deal more about which genes actually matter in increasing cancer risk and which ones do not.

Improving Models of Circulating Cell Detection

Genomic tumor testing is becoming more commonly used in adults with advanced-staged cancer to inform treatment decisions. What is the role of genomic profiling in AYAs with cancer? Are precision medicine approaches being used in the treatment of these younger patients?

Brandon Hayes-Lattin, MD, FACP

Brandon Hayes-Lattin, MD, FACP

A major success of the early clinical trials for children is the effective chemotherapy protocols that were developed for childhood cancers. However, those trials also led to a one-size-fits-all approach to treatment, and we’ve since learned that a uniform approach to cancer treatment does not optimize outcomes for all patients, because some are likely to be undertreated or overtreated or may require different therapy altogether. Genomic profiling has moved from simply giving us information on the potential aggressiveness of the tumor to giving us information about potential therapeutic targets. It can also tell us whether a patient has developed resistance to a specific therapy and what new treatment susceptibility features might be in the recurrent tumor. We know that the tumor a patient walks into our office with is not the same tumor he or she has after relapse.

GUEST EDITOR

Adolescent and Young Adult Oncology explores the unique physical, psychosocial, social, emotional, sexual, and financial challenges adolescents and young adults with cancer face. The column is guest edited by Brandon Hayes-Lattin, MD, FACP, Associate Professor of Medicine and Medical Director of the Adolescent and Young Adult Oncology Program at the Knight Cancer Institute at Oregon Health and Science University in Portland, Oregon.

There is increasing interest in developing biomarker profiles as part of genomic screening for all patients with cancer, including AYAs, to look for both favorable and unfavorable prognostic markers to determine risk status and treatment strategy. The problem is that, generally, the AYA patient population has different tumor types than those found in older adult patients; thus, many of the detection technologies we currently use to isolate circulating tumor cells, for example, from adult patients are ineffective in younger patients.

Specifically, adult cancers are usually carcinomas, and they express an epithelial membrane antigen, which is used to isolate circulating tumor cells for analysis. Cancers in young patients are rarely carcinomas and so cannot be isolated using this technology. We are attempting to identify alternate cell-surface markers or even alternative methods that do not require a cell-surface marker to isolate circulating tumor cells. Once these methods are developed, it will be possible to follow the evolution of recurrent pediatric and AYA cancers as effectively as adult cancers.

Predicting More Effective Cancer Care

What is the future of precision medicine for AYAs with cancer?

All of the clinical trials sponsored by the National Cancer Institute (NCI) have integrated translational science centers, which are tasked with developing genetic profiling technologies, such as tumor panels and circulating tumor cell detection technologies. One such clinical trial underway, the NCI-COG Pediatric MATCH trial, is attempting to develop these technologies for targeted therapy focused on the initial treatment of high-risk cancers.

It is all but certain that this approach will become standard of care over time to achieve better outcomes with fewer toxic side effects. Of particular interest will be the concordant development of clinical trials for patients with relapsed disease, in which liquid biopsy–based tumor profiling will be required to guide therapy.

COMPARING SURVIVAL IN AYAS WITH THOSE IN CHILDREN AND OLDER ADULTS

Tumor Types Linked to Worse 5-Year Survival in AYAs Than in Children
  • Acute myeloid leukemia (AML)
  • Medulloblastoma
Tumor Types Linked to Worse 5-Year Survival in AYAs Than in Older Adults
  • Hepatic carcinoma
  • AML
  • High-grade astrocytoma
  • Acute lymphoblastic leukemia
  • Pancreatic carcinoma
  • Low-grade astrocytoma
  • Gastric carcinoma
  • Renal carcinoma
  • Cancer of the oral cavity and pharynx
  • Hodgkin lymphoma
  • Ovarian cancer
  • Fibromatous sarcoma
  • Other soft-tissue sarcoma
  • Thyroid carcinoma
Source: Keegan TH, et al.2

Certainly, the cell-free liquid biopsy approach is reasonable right now. All patients shed both normal and tumor RNA and DNA into their blood circulation, which can be harvested and sequenced, and tumor-associated genetic defects that may match one or more targeted therapeutics can be identified. The problem is we don’t yet know whether we will get enough information from the cell-free approach as opposed to information we get from individual circulating tumor cells in patients with solid tumors to enable the accurate detection of treatable genetic defects. That is why we are taking a two-pronged approach with liquid biopsy. By looking at both the cell-free nucleic acid and isolated circulating tumor cells from the same blood sample, we will be able to compare the results with the clinical evolution of the patient to decide which (or both) to further develop for clinical use.

We know the information is there, but the technology has to become more sophisticated to help us identify how cell-free DNA and RNA or individual circulating tumor cells relate to tumor evolution and the development of treatment resistance in children and in AYAs, compared with cancers in older adults, in which a great deal more of this information is already available. The use of liquid biopsy in young adult patients is just beginning.

If we can accurately use cell-free and circulating tumor cell technologies to frequently monitor young adult patients over time to identify their mutational burden and whether their tumor cells are developing treatment-resistant or treatment-sensitive features, we will be better able to realize the true potential of precision oncology in the treatment of these patients.With this knowledge, we will be able to stop a treatment that isn’t working and move to an alternate, often targeted therapy, that is more likely to be beneficial. If we can do that, we will improve outcomes for these AYA patients as well as children and older adults with cancer. This is our hope and expectation.

DISCLOSURE: Dr. Triche reported no conflicts of interest.

REFERENCES

1. National Cancer Institute: Cancer statistics. Available at www.cancer.gov/about-cancer/understanding/statistics. Accessed November 20, 2018.

2. Keegan TH, Ries LA, Barr RD, et al: Comparison of cancer survival trends in the United States of adolescents and young adults with those in children and older adults. Cancer 122:1009-1016, 2016.

3. Young Survival Coalition: Breast cancer in young women: Statistics and disparities. Available at www.youngsurvival.org/learn/ about-breast-cancer/statistics. Accessed November 20, 2018.


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