Liquid Biopsies Help Personalize Cancer Therapy 

Nearly every patient with suspected cancer will undergo a tumor biopsy. In fact, tumor biopsy is the main way physicians diagnose most types of cancer and determine their grade or stage. In addition, biopsies can also be used to make treatment decisions. By analyzing the genetic material in the tumor specimen, physicians may uncover genetic changes that can be matched to specific targeted therapies. However, although tumor biopsy has been a critical part of cancer care for decades, depending on the location of the tumor and the patient’s general health, performing a tumor biopsy may not always be feasible or safe.

Physicians have followed circulating tumor biomarkers to monitor patient status for decades, including carcinoembryonic antigen (CEA), cancer antigen 125 (CA-125), CA 15-3/CA 27.29, CA 19-9, and PSA for colorectal, ovarian, breast, pancreatic, and prostate cancers, respectively. Over the last 15 years, strategies to capture and enumerate circulating tumor cells have also been reported. More recently, several investigators have reported the ability to purify and characterize circulating, cell-free tumor DNA. These approaches have been dubbed liquid biopsies. They offer the opportunity to easily and conveniently determine changes in both the amount of tumor burden and the genotype and phenotype of the cancer over time.

In a liquid biopsy, circulating tumor DNA is collected from bodily fluids and analyzed, providing what seems to be representative information about genetic changes in the tumor. Because genetic changes evolve as cancers grow and spread, this information can be used to stop a treatment to which resistance is emerging, as has been done with circulating proteins and tumor cells for years, or, perhaps more exciting, to switch to a different treatment that is tailored to a different mutation as it appears.

Even for patients who are able to undergo a traditional tissue biopsy, a liquid biopsy may be safer, quicker, and more convenient—and perhaps even more informative. For example, a biopsy only represents a single site of disease, and studies of tumor heterogeneity tell us that different tumor sites in the same patient may have different genotypes and phenotypes. Thus, a liquid biopsy may provide a snapshot of the tumor makeup of the entire body, not just that of the biopsied site.

Another advantage of a liquid biopsy is its potential to provide a snapshot of the full landscape of genetic changes present in a tumor. Different parts of the tumor often have genetically distinct groups of cells. Because a tissue biopsy takes only a small piece of the tumor, some key mutations may be missed. Nonetheless, research also shows that liquid biopsies sometimes fail to detect key mutations that are revealed by tissue biopsy tests.

Liquid biopsy informs lung cancer treatment decisions. 

One liquid biopsy test has already become part of routine care for patients with advanced lung cancer, and others are being developed using a variety of technologies. The test screens circulating tumor DNA from the blood for a specific mutation in the EGFR gene: T790M. This mutation occurs in approximately 60% of patients who develop resistance to epidermal growth factor receptor (EGFR)-targeted drugs, afatinib, gefitinib, and erlotinib.

It is important to know whether a patient has the T790M mutation because new treatments that specifically target this genetic change are available (eg, osimertinib and rociletinib). However, patients who do not have the T790M mutation should not receive such treatments, because they are less effective against T790M-negative tumors.

Tumor testing for T790M is now recommended for all patients with EGFR-positive NSCLC that worsens despite EGFR-targeted therapy. However, many patients are not able to have the test done; the tumor may be in an inaccessible location, there may be insufficient tissue available, or a biopsy may not be safe because the patient is in poor health. For such patients, a liquid biopsy test is now available. The blood test, known as cobas EGFR Mutation Test v2, was FDA approved in 2015 to identify patients who may benefit from osimertinib.87 In 2016, the test was also approved for use as a companion diagnostic to help identify patients with a different type of EGFR mutation who may benefit from initial treatment with erlotinib.88 In an early study, the liquid biopsy test identified six in 10 patients who had T790M-positive tumors.89 This is good news for patients who are unable to undergo a traditional tissue biopsy.

Meanwhile, several other promising liquid biopsy tests for patients with lung cancer are being explored. A blood test using a technique known as BEAMing identified seven of 10 patients with T790M mutations in their tumors (this study was funded in part by a grant from the NIH).90 A different test that uses so-called droplet digital polymerase chain reaction identified eight of 10 patients with T790M-positive tumors (this study was funded by a grant from the NCI).91 The latter test can also screen for other EGFR as well as KRAS mutations.

Finally, another early clinical trial found that response to the EGFR-targeted therapy rociletinib was similar irrespective of whether T790M status was determined through traditional tissue biopsy or liquid biopsy of urine or blood. The researchers used BEAMing technology for blood mutation analysis and a technique known as short footprinting for urine. Blood and urine testing identified several T790M-positive cases that were missed by tissue biopsy.92,93

These studies confirm that the accuracy of molecular testing using either blood or urine samples is high and that such testing predicts outcomes from EGFR therapy similar to those predicted by traditional tumor biopsy.90,94 Moreover, early findings show that regardless of how the T790M mutation is detected (liquid or traditional tumor biopsy), patients respond to osimertinib and rociletinib equally well.

However, a negative liquid biopsy test is not as reliable as a negative tumor biopsy test. Therefore, whenever possible, patients with a negative blood or urine test should have tumor tissue tested for confirmation.

Liquid biopsy may open new targeted treatment options. 

Another liquid biopsy test was reported last year that could rapidly and accurately screen blood samples for a broad panel of genetic changes, including EGFR T790M.95 An analysis of blood samples from 15,000 patients with 50 different types of cancer showed that the patterns of genetic changes in circulating tumor DNA were similar to those in the tumor.

The blood test detected 94% to 100% of changes in EGFR, BRAF, KRAS, ALK, RET, and ROS1 genes that had been found previously in tumor biopsy analyses from the same patients. It also provided leads for targeted therapy that could be matched to the genetic changes found in the circulating tumor DNA. The researchers identified such additional treatment opportunities for approximately two-thirds of patients who had insufficient tissue available for a biopsy.

Liquid biopsy predicts colon cancer recurrence. 

In 2016, researchers proposed an entirely different use for liquid biopsies. According to a large study, measuring circulating tumor DNA from the blood can accurately predict which patients with stage II colon cancer are at risk for recurrence (this study was funded in part by a grant from the NIH).96 Detection of circulating tumor DNA after colon cancer surgery is a sign that some cancer cells have been left behind, and this puts the patient at higher risk of recurrence.

Overall, patients with stage II colon cancer have a low risk of recurrence, and four of five are cured with surgery alone. Patients who are at high risk of recurrence may need additional treatment after surgery to lower the chances of recurrence. This new blood test may help identify more patients who might benefit from receiving chemotherapy after surgery.

In the study, nearly 80% of patients who had circulating tumor DNA detected in the blood after surgery experienced a recurrence of colon cancer. In contrast, only 10% of patients who tested negative for circulating tumor DNA experienced a recurrence. These findings are relevant to more than 300,000 people around the world who are diagnosed with stage II colon cancer each year.

Expanding Targeted Therapy Options for Ovarian Cancer

Worldwide, more women die from ovarian cancer than from any other gynecologic cancer. Although initial treatment of ovarian cancer with chemotherapy is usually effective, most patients will eventually experience a recurrence. Patients with recurrent ovarian cancer have limited treatment options, and median survival is generally reported as between 1 and 2 years from diagnosis.

Standard treatments for recurrent ovarian cancer include bevacizumab, which halts cancer growth for approximately 3 months, and the novel targeted treatment olaparib. Olaparib was the first treatment in a new class of targeted therapies that block PARP, a protein that repairs damaged DNA. Although olaparib is more effective than bevacizumab, it is only approved for use in patients with BRCA gene mutations, who account for just 10% to 15% of all women with ovarian cancers.

In 2016, researchers reported that a different PARP inhibitor, niraparib, is effective in a broader range of patients with advanced, recurrent ovarian cancer.97 The late-stage clinical trial included two groups of patients: women with germline (heritable) BRCA mutations and those without such mutations. Within the group lacking a BRCA mutation, there was a subset of patients with another defect in DNA repair processes called homologous recombination DNA repair deficiency (HRD). All patients had ovarian cancer that responded to platinum-containing chemotherapy.

The patients were randomly assigned to receive niraparib or placebo. Niraparib slowed cancer growth in all patient groups, but it was most effective in patients with BRCA mutations. In this group, the median time until the cancer worsened was 21 months with niraparib and 5.5 months with placebo. Among patients without BRCA mutations, cancer worsened after a median period of 9.3 months with niraparib, compared with 3.9 months with placebo. In the subset of patients with HRD, the median time to cancer progression was 12.9 months with niraparib and 3.8 months with placebo.

The most common severe adverse effects related to niraparib included low blood counts and anemia. Patients who received niraparib reported a quality of life comparable to that reported by those who received placebo.

These findings suggest that the benefit of niraparib is not restricted to patients with a known germline BRCA mutation, expanding access to PARP inhibitors. However, further work is needed to determine the most appropriate strategy for use of PARP inhibitors in this population.

Cancer Moonshot: Galvanizing a Renewed Commitment to Conquering Cancer

Joe Biden speaking at a podium Every year, thousands of oncologists and millions of patients all over the world await the news coming from [the ASCO Annual Meeting] ... new breakthroughs, new therapies, new promises of cure, hope….  I know of no cadre of people in the world more desperately in need of hope than the 16 million people with cancer. 

Joe Biden,
Former US Vice President

During his final State of the Union address, President Obama launched the Cancer Moonshot to renew the nation’s commitment to conquering cancer. Led by Vice President Joe Biden, the National Cancer Moonshot Initiative aligned the resources of the federal government to accelerate progress in cancer research and encouraged greater collaboration within the entire cancer research community.

Throughout 2016, Biden met with a wide range of stakeholders to better understand the current cancer research and cancer clinical practice environment—both opportunities in and barriers to providing cancer care and conducting cancer research in the United States. Working with the Cancer Moonshot Task Force (which included representatives from all federal agencies involved in cancer clinical care and research), Biden made a series of announcements to take immediate action to improve cancer research.

ASCO worked closely with Biden’s Moonshot team, submitting recommendations to Biden, the Task Force, and NCI Blue Ribbon Panel; speaking at public forums; engaging in strategic discussions; and welcoming Biden to address the world’s cancer leaders who convened at the ASCO Annual Meeting in Chicago in June 2016.

The Cancer Moonshot rightly called for patients with cancer to become our shared and primary focus. President Obama and Biden challenged the cancer community to unite and work together in recognition that the whole will be far greater than the sum of its parts. The Cancer Moonshot also addressed the entire continuum of cancer care to speed advances in cancer prevention, diagnosis, treatment, supportive care, survivorship, and end-of-life care. Biden made an important decision to include all types of cancer.

The Cancer Moonshot Initiative spurred public and private sector organizations into action and jumpstarted collaborations to accelerate the nation’s progress in fighting life-threatening cancers that affect so many. To continue the momentum in our work to conquer cancer, ASCO has urged Congress and the new Administration to take the following steps:

  • Advance initiatives to improve interoperability of health care information, which will help improve patient care and support quality measurement and research.
  • Identify ways to streamline regulatory and reporting requirements so researchers can spend less time on administrative tasks and more time on developing new ideas and conducting research.
  • Provide federal funding for the Cancer Moonshot Initiative and other translational and clinical research efforts.

ASCO is particularly pleased that the Cancer Moonshot Task Force highlighted the continuing work of the FDA with ASCO and Friends of Cancer Research to evaluate clinical trial entrance criteria that may unnecessarily restrict clinical trial access, such as such as brain metastases, HIV status, organ dysfunction, and age restrictions.

With the backing of the new Congress and Administration, we can build on the progress of the Cancer Moonshot and make gains in our fight against cancer.

View References.


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