Getting an accurate family history can be one of the most challenging things that nurses face, according to Suzanne Mahon, DNSc, a clinical nurse specialist at SLUCare physician group, St Louis, Missouri.

“Part of the issue is our electronic medical record which will phrase the question generally, like, ‘Does anyone in your family have health problems?’” Mahon said. “That does not dig deep enough.”

When discussing family history, Mahon recommended asking specifically about siblings, then parents, then grandparents, then aunts and uncles, nieces and nephews, and cousins. By asking about each, it forces the patient to think more granularly.

Different familial cancer syndromes can present differently in families. Someone may be diagnosed with ovarian cancer, and another family member may have had a history of melanoma, whereas another may have had prostate cancer. Although the patient may not think all of those are related, different syndromes can lead to different combinations of disease, Mahon said.

It is also important to review a family history each time you see a patient, she added. “I worked with a breast surgeon who sent a patient to see us who had surgery four or five years ago,” Mahon recalled. “Originally, there was no family history, but when the patient was seen later for follow-up and the surgeon asked again about her family history, her cousin and sister had both since been diagnosed. Family history should never be stagnant.”

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Getting an accurate family history can be one of the most challenging things that nurses face, according to Suzanne Mahon, DNSc, a clinical nurse specialist at SLUCare physician group, St Louis, Missouri.
 

Assessing Family History: A Moving Target

In her role as a genetic professional, Suzanne Mahon, DNSc, a clinical nurse specialist at SLUCare physician group in St Louis, Missouri, recently met with a 46-year-old single mother who had been diagnosed with metastatic triple-positive breast cancer and referred for genetic counseling and testing.

The woman had marketplace insurance and was denied coverage for genetic testing, but Mahon worked with the testing laboratory. Together with other compassionate care resources, the cost of testing was able to be covered. Testing revealed a CHEK2 mutation, a germline mutation that has been linked with up to a 37% lifetime risk for breast cancer.

“This information will guide her treatment decisions regarding use of bilateral mastectomies, as well as her long-term follow-up, such as more frequent colon, gynecologic, and thyroid screening,” Mahon said.

The patient had a 22-year-old daughter who was also concerned about her risk and sought genetic counseling. After 2 counseling sessions, the daughter decided to proceed with genetic counseling; however, she was uninsured. Again, compassionate care funding was used to cover the cost of her testing, which revealed she was negative for the CHEK2 mutation and at average risk for developing cancer. Now, Mahon said, the daughter can focus on her studies and caring for her mother.

Inherited genetic mutations play a role in between 5% to 10% of all cancers, according to the National Cancer Institute.

 Specific genetic mutations have now been associated with more than 50 hereditary cancer syndromes. The National Comprehensive Cancer Center (NCCN) offers guidelines on genetic testing organized by both disease and syndrome type.

More generally, though, nurses can look for several characteristics or situations that might point to genetic or familial high-risk situations, according to Mahon.

The first, and often easiest to spot, is the diagnosis of a cancer in a young person that typically occurs at an older age. For example, the diagnosis of breast or colon cancer at age 50 or younger. “Cancers that we usually see in 60- or 70 year-olds occurring in younger patients, that is always a red flag,” Mahon said.

Another group of people often flagged for possible genetic testing are those diagnosed with very rare tumors, such as male breast cancer, paragangliomas, or medullary thyroid cancer.

Specific characteristics of a cancer diagnosis might also point to the need for genetic testing. For example, people with colon cancers that show high microsatellite instability (MSI-high),3 a patient with more than 15 or 20 colon polyps in a lifetime, or a patient with a lot of atypical moles.

“These are not necessary malignant conditions, but when they occur they often can be the beginning of something or an indicator that something else is going on,” Mahon said.

Any or all of these factors might point to the need for genetic testing, and that is before even diving into a patient’s family history.

“This is the very first thing that nurses on the front line take in every type of medical practice,” said Wendy Brouwer, NP, of The University of Texas MD Anderson Cancer Center in Houston, who deals mostly with hereditary breast and ovarian cancers.

For example, the NCCN guidelines for high-penetrance breast cancers call for genetic testing among women aged 45 to 50 with one or more blood relatives with any breast, ovarian, or pancreatic high-grade prostate cancer. Testing is also indicated in those diagnosed at any age with one or more blood relatives diagnosed with breast cancer at age 50 or younger, or ovarian, pancreatic, or prostate cancer at any age, and in anyone with 3 or more breast cancer diagnoses in close blood relatives.

“These things do not always mean there is a mutation there, but it does mean that if there is one we don’t want to miss it,” Brouwer said.

Undergoing testing to look for genetic risk for cancer can be difficult, but there are ways in which nurses can help guide patients through the process.

One of the most important things to emphasize, according to Mahon, is that counseling is not testing.

“Counseling means that you are coming in to learn about your options,” she said. “We emphasize that the counseling appointment is not where testing is done.”

Mahon has seen a wide variety of outcomes after genetic counseling. Some patients who were intent on getting testing done decide to delay after exploring their options. Others who were set against testing learn more and ask for tests to be done immediately.

It is also important for nurses not to trivialize testing and what it could mean to the patient and their families. Explain that it is OK for them to be scared. It is ok for them to be hesitant. Those feelings are normal.

Nurses can also encourage patients to bring another family member to the genetic counseling and testing appointments. Sometimes dealing with a cancer diagnosis and the burden of having to share information about familial risk can be too much for the patient alone to take on, Mahon said.

Finally, Brouwer said, patients may respond to the information that the results of their genetic testing could not only affect treatment decisions for their care, but could help increase prevention of future cancers in themselves and their family members.

Mahon said that she will not conduct genetic testing for any mutations that are not considered “actionable,” meaning knowledge about the mutation can affect treatment decisions or future cancer prevention.

Women who have BRCA 1/2 mutations and are diagnosed with breast or ovarian cancer may qualify for treatment with PARP inhibitors.

Patients with Lynch syndrome, an inherited cancer syndrome associated with increased risk for colon and other cancers, tend to have higher rates of MSI-high tumors, which may respond to immunotherapy with pembrolizumab.

For prevention, knowledge of a BRCA 1/2 mutation in breast cancer can affect decisions made about choice of breast surgery, for example. Women with these mutations have a higher risk for a second breast cancer and may opt to undergo bilateral mastectomy rather than lumpectomy.

Genetic testing for Lynch syndrome could encourage people to undergo increased screening for colon cancer, endometrial cancer, ovarian cancer, and more. People found to have a genetic mutation for medullary thyroid cancer can encourage family members to undergo screening, as there is a nearly 100% lifetime risk for developing malignancy associated with these mtuations.

“Where you are really getting into some conundrums are testing in some hematologic malignancies,” Mahon said. “Identification of genetic mutations [is] not really actionable for family members, but [is] important to know if you need to select possible transplant donors.”

Nurses will play an important role in guiding patients through their testing results, and discussing sharing any positive results with family members.

“The HIPAA rules prohibit me from calling these family members,” Mahon said. “All I can do is tell the patient, ‘These are the family members at increased risk.’ [For] people with the greatest risk, like siblings and offspring, we make the biggest deal about offering the option of testing.”

Looking to the future, Mahon said she hopes to begin to see more oncology nurses specializing in genetic counseling.

“I do this and only this all day long,” Mahon said. “We have to have more training programs for nurses to learn this and devote their practice to it. That would allow for more excellent care for families across the board.”

Brouwer said she hopes that a focus on genetics spreads even further than just among oncology nurses. She belongs to the International Society of Nurses in Genetics (ISONG), a global nursing specialty organization dedicated to genomic health care, education, research, and scholarship.

“This organization represents a really up-and-coming field,” Brouwer said. “Oncology nurses are on the second line, when cancers have already started to happen. If nurses can all start to have a lot more knowledge about genetics, enough to pick up on risk in family history, we can start to play more of a role in the prevention side of things.”

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https://www.cancer.gov/about-cancer/causes-prevention/genetics

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https://www.cancer.org/cancer/colon-rectal-cancer/causes-risks-prevention/genetic-tests-screening-prevention.html

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https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf

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As genetics in cancer care grows, so will the role of the oncology nurse.

Nurses Unlock Role in Cancer Genetics

Women being screened for breast cancer using mammography, or who are undergoing diagnostic procedures, are often asked if they have a known history of breast or other cancers in a family member — on both maternal and paternal sides – and also if they have particular ancestry. This information becomes integrated into their family history and contributes to risk assessment related to breast cancer. A woman whose family has a significant history of breast, ovarian, prostate, and/or pancreatic cancer in addition to her personal diagnosis of breast cancer, may represent a good candidate for genetic testing and counseling, especially if hereditary cancer mutations have not already been found in the person’s relative(s).

All cancers develop as a result of genetic changes or mutations. Hereditary, or germline, mutations, can be inherited from other family members and also passed along to children.

 Germline mutations are relatively rare (<20% of cancers are thought to be due to inherited mutations) and can be found in any cell of the body, not just tumor cells. The most well-known hereditary mutations in breast cancer are BRCA1 and BRCA2. Since these germline mutations may be detected prior to the clinical diagnosis of a cancer, assessment of these mutations may be applied to primary prevention of breast cancer or altering the surveillance approach in order to detect a cancer at the earliest time possible.

Acquired mutations are much more common, and occur as a result of other genetic changes or exposures, e.g. tobacco, hormones, chemicals, adiposity, etc.

, and are found in tumor tissues. Thus, assessment of acquired mutations may help identify targets and treatments that might apply to prognosis or prediction of therapeutic effectiveness.

The National Comprehensive Cancer Network (NCCN)

, along with many other groups and agencies

, has established guidelines for genetic/familial high-risk assessment in multiple tumor types. For breast cancer, the NCCN currently recommends testing individuals that meet the following criteria:

With blood relatives who have known/likely pathogenic variants

45 years or diagnosed age 45-50 years with either unknown or limited family history

Diagnosed at any age with second breast primary OR if they are of Ashkenazi Jewish ancestry

Diagnosed with triple-negative (ER-, PR-, HER2-) breast cancer at 

In 2019, based on reports that documented patients who did not meet NCCN guidelines were found with similar mutation rates as those who did,

 the American Society of Breast Surgeons (ASBS) established consensus guidelines

 that recommend ALL patients with a personal history of breast cancer be considered for genetic testing for BRCA1, BRCA2, PALB2, and other genes. In addition, the ASBS recommended that patients who previously had genetic testing before 2014 be considered for repeat testing since current testing includes better technology as well as inclusion of other important genes, such as PALB2, that were not available earlier. The ASBS recommendations run counter to the U.S. Preventive Services Task Force recommendations, that indicate women with a, “personal or family history of breast, ovarian, tubal, or peritoneal cancer or an ancestry associated with BRCA1/2 gene mutation” should undergo genetic testing (Evidence Grade of B), whereas the USPSTF recommends against routine genetic counseling, testing or risk assessment in any women who do not meet these guidelines (Evidence Grade of D).

 looked at all women diagnosed at the Mayo Clinic from 2000-201 (N=3907) and were tested for germline pathogenic variants in nine breast cancer predisposition genes: BRCA1 and BRCA2, as well as PALB2, CDH1, CHEK2, NF1, PTEN, TP53 and ATM. Based on the NCCN guidelines, less than half of the sample (47.9%) met criteria for testing. However, of those women who did not meet NCCN criteria, 13.1% were found to have mutations in BRCA1 or BRCA2, and 29.9% were found to have variants in the nine-gene panel. However, no evaluation of cost-effectiveness of this broader-based testing was done.

Although the clinical and testing recommendations may differ, all of these groups are clear that breast cancer risk assessment is an important component of breast cancer diagnosis and care. In addition, if an institution/practice takes on genetic testing, they must have resources in place to provide such vital services as pre- and post-testing genetic counseling (which can be physicians, nurses, genetic counselors, or other professionals with the needed expertise), appropriate referral, support services for families who may be affected, and resources for preventive and/or surveillance if the testing demonstrates pathogenic variants.

 Lastly, not all insurance payors cover the costs of genetic testing

; thus, providers should check with the payor to understand what services will (or will not) be covered.

1. Mahdavi M, Nassiri M, Kooshyar MM, Vakili-Azghandi M, Avan A, Sandry R, Pillai S, Lam AK, Gopalan V. Hereditary breast cancer; Genetic penetrance and current status with BRCA. 

. 2019 May;234(5):5741-5750. doi:10.1002/jcp.27464. Epub 2018 Dec 14. Review. PubMed PMID: 30552672.

2. Zhang Y, Xiong S, Liu B, Pant V, Celii F, Chau G, Elizondo-Fraire AC, Yang P, You MJ, El-Naggar AK, Navin NE, Lozano G. Somatic Trp53 mutations differentially drive breast cancer and evolution of metastases. 

. 2018 Sep27;9(1):3953. doi: 10.1038/s41467-018-06146-9. PubMed PMID: 30262850; PubMed Central PMCID: PMC6160420.

https://www2.tri-kobe.org/nccn/guideline/gynecological/english/genetic_familial.pdf

4. Committee on Practice Bulletins—Gynecology, Committee on Genetics, Society of Gynecologic Oncology. Practice Bulletin No 182: Hereditary Breast and Ovarian Cancer Syndrome. Obstet Gynecol. 2017 Sep;130(3):e110-e126. doi:10.1097/AOG.0000000000002296. PubMed PMID: 28832484.

5. Berliner, J.L., Fay, A.M., Cummings, S.A. 

 NSGC Practice Guideline: Risk Assessment and Genetic Counseling for Hereditary Breast and Ovarian Cancer. J Genet Counsel 22

155—163 (2013). https://doi.org/10.1007/s10897-012-9547-1

6. Lancaster JM, Powell CB, Chen LM, Richardson DL; SGO Clinical Practice Committee. Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol. 2015 Jan;136(1):3-7. doi: 10.1016/j.ygyno.2014.09.009. Epub 2014 Sep 17. Erratum in: Gynecol Oncol.2015 Sep;138(3):765. PubMed PMID: 25238946.

7. ASCO Guidelines on Assessing and Managing your Patient’s Hereditary Cancer Risks. 

https://www.asco.org/practice-policy/cancer-care-initiatives/genetics-toolkit/assessing-managing-your-patients-hereditary

8. Beitsch PD, Whitworth PW, Hughes K, Patel R, Rosen B, Compagnoni G, Baron P, Simmons R, Smith LA, Grady I, Kinney M, Coomer C, Barbosa K, Holmes DR, Brown E, Gold L, Clark P, Riley L, Lyons S, Ruiz A, Kahn S, MacDonald H, Curcio L, Hardwick MK, Yang S, Esplin ED, Nussbaum RL. Underdiagnosis of Hereditary Breast Cancer: Are Genetic Testing Guidelines a Tool or an Obstacle? J Clin Oncol. 2019 Feb 20;37(6):453-460. doi: 10.1200/JCO.18.01631. Epub 2018 Dec 7. PubMed PMID:30526229; PubMed Central PMCID: PMC6380523.

9. Yang, S., Axilbund, J.E., O’Leary, E. 

 Underdiagnosis of Hereditary Breast and Ovarian Cancer in Medicare Patients: Genetic Testing Criteria Miss the Mark. Ann Surg Oncol 

2925—2931 (2018). https://doi.org/10.1245/s10434-018-6621-4

10. Manahan, E.R., Kuerer, H.M., Sebastian, M. 

 Consensus Guidelines on Genetic` Testing for Hereditary Breast Cancer from the American Society of Breast Surgeons. Ann Surg Oncol 

https://doi.org/10.1245/s10434-019-07549-8

11. U.S. Preventive Services Task Force. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer in Women: Recommendation Statement. Am Fam Physician. 2015 Jan 15;91(2): Online. PubMed PMID: 25591222.

12. Yadav S, Hu C, Hart SN, Boddicker N, Polley EC, Na J, Gnanaolivu R, Lee KY, Lindstrom T, Armasu S, Fitz-Gibbon P, Ghosh K, Stan DL, Pruthi S, Neal L, Sandhu N, Rhodes DJ, Klassen C, Peethambaram PP, Haddad TC, Olson JE, Hoskin TL, Goetz MP, Domchek SM, Boughey JC, Ruddy KJ, Couch FJ. Evaluation of Germline Genetic Testing Criteria in a Hospital-Based Series of Women With Breast Cancer. J Clin Oncol. 2020 Mar 3: JCO1902190. doi:10.1200/JCO.19.02190. [Epub ahead of print] PubMed PMID: 32125938.

13. American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol.2003 Jun 15;21(12):2397-406. Epub 2003 Apr 11. PubMed PMID: 12692171.

14. Amendola LM, Hart MR, Bennett RL, Horike-Pyne M, Dorschner M, Shirts B, Jarvik GP. Insurance coverage does not predict outcomes of genetic testing: The search for meaning in payer decisions for germline cancer tests. J Genet Couns. 2019 Dec;28(6):1208-1213. doi: 10.1002/jgc4.1155. Epub 2019 Jul 17. PubMed PMID: 31317629; PubMed Central PMCID: PMC6901727.

Genetic Risk, Assessment, Application, and Recommendations in Breast Cancer

Some patients with breast cancer might be apprehensive to undergo genetic testing, but it is crucial both for them and their family members. Lauren Carcas, MD, medical oncologist at the Miami Cancer Institute, discusses some main points nurses can make to these patients to encourage them to get tested.

I always argue that knowing family history is arguably one of the most important things to know about what your risk is for breast cancer. And just like I said, I think that genetic testing is a situation where knowledge is power. If you know your risk, you can potentially take action to reduce that risk, and potentially nearly eliminate that risk. But if you already have a diagnosis of breast cancer, it's really important because that might impact your treatment decision.

Really you have to be your own advocate, and part of advocating for yourself is knowing the total history and knowing the total diagnosis. Knowing that you have a gene mutation that is the underlying cause of your diagnosis is really important.

Videos

Genetic Testing: Knowledge Is Power

For this month’s episode, we spoke with Katherine Crew, MD, an associate professor of medicine and epidemiology at the Columbia University Herbert Irving Comprehensive Cancer Center. Crew discusses her recent research on genetic testing in young women with breast cancer. While she was happy to see that the testing rates were not much different between ethnic groups, there were some differences when it came to the results.

Crew also offers advice for nurses in discussing genetics with their patients, as well as easing the worry of not knowing what some genetic testing results may mean.

Genetics: Discovering the Unknown in Breast Cancer

Genetic alterations could mean different (and more effective) treatment choices for patients with gastrointestinal (GI) cancers, according to Tanios S. Bekaii-Saab, MD.

Bekaii-Saab, medical oncologist, and medical director of the Cancer Clinical Research Office, vice chair and section chief of Medical Oncology in the Department of Internal Medicine, at Mayo Clinic, said that all patients with GI cancers should undergo next-generation sequencing (NGS), at the very least.

The filed of cancer overall is moving toward more universal next-generation sequencing, and even in some instances, in our institution for example, we try to get even beyond NGS to more whole-genome [sequencing].

Every colon cancer patient, every biliary cancer patient, every gastric patient, and I would argue every [pancreatic] cancer patient, and every GI cancer patient should be screened for alterations through, at least, next-generation sequencing. Why is this important? Well, it's important because of a lot of reasons. One, what's approved, and two, what's being studied.

The results of genetic testing could change a patient's treatment regimen.

All Patients With GI Cancers Should Undergo NGS

The presence of the proteins p16 and p21 has shown to be predictive of treatment response in patients with osteosarcoma, a disease that previously had no identified biomarkers to indicate whether or not patients would benefit from therapy, explained C. Parker Gibbs, MD.

“We may finally have a way to predict how well a patient is going to do with osteosarcoma prior to initiating any therapy,” said Gibbs.

In a study, 104 patients with osteosarcoma were evaluated to determine if p16 and p21 expression are able to serve as predictive biomarkers for this patient population. All patients received standard neoadjuvant chemotherapy after initial diagnosis followed by surgical resection. Immunohistochemistry (IHC) for the cell cycle checkpoint regulator proteins p16 and p21 was performed on paraffin-embedded chemotherapy-naïve biopsy specimens.

The study showed that >90% expression of p16 in the initial biopsy is strongly related with good histologic response to neoadjuvant chemotherapy (P <.0001), a lower rate of metastasis (P = .0118), and a higher rate of survival (P = .0294).

Meanwhile, tumors that had p21 expression at <1% or >50% were related to poor chemotherapy—induced tumor necrosis (P = .025), a higher rate of metastatic disease (P = .002), and overall poor survival (P = .0305). Higher expression of both markers showed a stronger relationship to predicting necrotic response to chemotherapy, metastasis, and survival versus each biomarker alone.

Overall, the findings showed that p16 alone as well as p16 plus p21 combined are independent predictors of response to chemotherapy, overall survival (OS), and metastatic disease in patients with osteosarcoma.

, Gibbs, a Eugene L. Jewett Professor of Orthopaedic Surgery, Division Chief of Orthopaedic Oncology and Chief Medical Officer of University of Florida Health Department of Orthopaedics and Rehabilitation College of Medicine, discussed the research behind p16 and p21 as predictive biomarkers for treatment response in patients with osteosarcoma.

: What are the current unmet needs of osteosarcoma?

: Osteosarcoma is a highly malignant disease in both children and adolescents. Currently, there are very few prognostic markers to tell us how a child or an adolescent is going to do long-term after chemotherapy and surgery. The gold standard for predicting how well a patient will do with this disease is looking at the tumor after chemotherapy and after surgical resection to determine how necrotic the tumor is. We don't have a way to predict response to chemotherapy or risk of metastatic disease or death prior to the initiation of chemotherapy or surgery.

What are the findings of the study looking at p16 and p21 as predictive biomarkers?

Our study looked at 2 cell cycle checkpoint regulators—p21 and p16&mdash;that had previously shown promise for indicating biologic aggressiveness in our cell culture studies. When we looked at these 2 biologic markers in over 100 osteosarcoma cases, we found a strong correlation between their expression, metastatic disease, and OS in children and young adults with osteosarcoma. We believe this is a major advance because it gives us the opportunity to stratify patients going forward prior to therapy, as opposed to submitting them to terribly toxic chemotherapy upfront with no real indication of whether or not it will help them.

How does the testing of p16 and p21 occur?

The testing for p16 and p21 is done on the biopsy tissue. When a patient presents with osteosarcoma, we always do a surgical or a needle biopsy to obtain tissue to learn the diagnosis and how to treat it. Right now, we take a piece of that tissue and we stain it via IHC for p21 or p16, which are cell cycle checkpoint regulator proteins. We are able to determine what the relative risk of metastatic disease or death is in these patients by how much [these proteins] are expressed.

How can physicians implement this information into their practice?

The potential for including this information in individual surgeon or pediatric oncologist practice is that we may be able to change what chemotherapy drugs we offer upfront. Instead, we may offer surgery upfront rather than after chemotherapy, as well as counsel patients regarding how well they may or may not do, depending on the results of this test that we perform on the biopsy tissue. This is an early study and needs to move on to a much larger prospective analysis before I would incorporate it in daily practice.

The next steps of the study are to incorporate other institutions to validate the statistical significance of our results across other groups of patients and the hands of other surgeons and oncologists.

Nasri E, Vasilopoulos T, Knapik J, et al. Cell cycle checkpoints p16 and p21 — strong predictors of clinicopathologic outcome in high-grade osteosarcoma. Presented at: 2019 Musculoskeletal Tumor Society Annual Meeting; October 2-4, 2019; Portland, OR. Abstract 37.

This article originally appeared on OncLive as, "

P16, P21 Biomarkers Linked to Treatment Response in Osteosarcoma

The presence of the proteins p16 and p21 has shown to be predictive of treatment response in patients with osteosarcoma, a disease that previously had no identified biomarkers to indicate whether or not patients would benefit from therapy, explained C. Parker Gibbs, MD.
 

Biomarkers Predict Osteosarcoma Treatment Response

Not all patients with advanced non—small cell lung cancer (NSCLC) are recommended for genomic testing when treated in a community setting, and are therefore not being appropriately tested for potential molecular drivers of their disease, explained Nathan Pennell, MD, PhD.

In a retrospective study of 1203 patients with stage IIIb or IV NSCLC treated since January 1, 2017, records were manually reviewed to find evidence of molecular testing and targeted treatment. Between 11% and 54% of the identified patients had any evidence of testing for at least 1 of 7 genes recommended for testing by the National Comprehensive Cancer Network at the time: EGFR, ALK, ROS1, BRAF, RET, MET, and ERBB2 (HER2). The genes EGFR, ALK, ROS1, and BRAF can be targeted with FDA-approved treatment options while the rest have investigational agents being tested in ongoing studies.

Overall, 54% of patients received testing for EGFR mutations and the rates decreased for the rest of the genes.

 Testing for all 4 genes with FDA-approved treatment options were given to 22% of patients. Furthermore, 48% of patients received testing for PD-L1 expression.

However, liquid biopsies have the potential to increase the number of patients who receive molecular testing with a quicker turnaround time and less-invasive approach than standard tissue biopsies, according to Pennell.

“The benefit is you can test a larger number of people, you can get all the testing that's necessary, and it can be done fast,” said Pennell. “You also don't need to do repeat tissue biopsies, making it very low risk.”

Additionally, results of the Noninvasive versus Invasive Lung Evaluation (NILE) study showed that a liquid biopsy test detected all of the guideline-recommended biomarkers in newly diagnosed patients with metastatic NSCLC at a similar rate but faster turnaround time compared with tissue genotyping. The 73-gene next-generation sequencing panel Guardant360 increased biomarker detection rate by 48%, from 60 patients identified with ≥1 guideline-recommended biomarker using tissue-based tests alone to 77 patients with liquid biopsy (21.3% vs 27.3%; P <.0001). Moreover, the time it took to receive results after ordering was 9 days for liquid biopsy versus 15 days for tissue biopsy.

In an interview with OncLive®, a sister publication of 

Oncology Nursing News®, Pennell, director of the Lung Cancer Medical Oncology Program at the Cleveland Clinic Taussig Cancer Institute, discussed the emerging widespread role of liquid biopsies in lung cancer and how to best utilize the approach in clinical practice.

: Why is molecular testing underutilized in practice?

 It's a number of things. There is certainly an aspect of education and need for people to understand that testing is necessary, but most biomarker testing for cancer is not done at the oncologist level; rather, it's done at the pathologist level. For example, if someone does a biopsy and is diagnosed with breast adenocarcinoma, then the pathologists automatically order a panel of important biomarker tests, such as estrogen receptor, progesterone receptor, and HER2 expression. With lung cancer and a lot of cancers, on the other hand, [biomarker testing] is only done when requested by an oncologist. However, even when oncologist makes a request, the kind of testing done is determined by the hospital's pathology department, whether they do their own internal testing or whether they have contracted an outside vendor to get it done.

There is a wide variety of how [biomarker testing] is done. There are some places, such as Cleveland Clinic, where it's done reflexively at the time of diagnosis. However, for most places, there has to be a request and then it will be sent out and done from a commercial company that does broad testing or a series of hotspot tests—where they do single gene tests in a combination. That same process could also be done internally, either with a broader, next-generation sequencing test that covers all targets of interest, or a series of single-gene tests. It's a big mess of how testing is done, which is not a good way to systematically design something that's important.

If you look at the most common genetic tests for EGFR mutations, we do a respectable job at testing for that. Probably between 80% and 90% of eligible patients get tested for EGFR mutations in the United States, depending on what study you look at. It's been a decade since that has been recommended, making it in everyone's mind. Additionally, for more than 8 years, we have had treatments for ALK-positive lung cancer, making its prevalence close behind at 70% to 80% of patients getting tested for ALK.

Beyond those 2 biomarker tests, there is PD-L1 testing. Other genetic markers, such as ROS1, BRAF, MET, RET, KRAS, HER2, and NTRK, are done at a much lower rate, either because they're not ordered or because the [tissue] is used up. After the first 2 single-gene tests, there is a major drop off in the ability to do any further testing because the [there is no more available tissue]. For patients with metastatic lung cancer, many weeks, or a month, have gone by when they get the results of this test and a lot of them may have proceeded to other treatments, such as immunotherapy, because they may not feel they can wait for the results.

Additionally, they may not have tissue available, and they may not be able to be biopsied in an area that's easily accessible. Even if they have [tissue], there may not be enough to do all the testing and the patient might require another biopsy. The patient may not want to go through that or the doctor may not feel it's safe or there is enough time. There are lots of different process-related reasons for why testing is inadequate.

How can liquid biopsies improve these testing rates?

The major advantage of plasma testing or liquid biopsy, which is a blood test, is that you can get blood from every single patient. You don't have to worry about where the biopsy was done, if there's enough material from the biopsy, or if it was done properly. The major commercial vendors for plasma testing do a comprehensive multiplexed test that covers all of the targets of interest. You can get testing on every patient and when you order the testing, you can get all of the targets of interest upfront. That immediately takes away a lot of the issues with it. That's something that you can automate: to make it standard to test everyone [upon diagnosis].

The other big advantage with liquid biopsy is the timing because, with preparation of material in order to perform the test, [results take a lot] longer [to come back] with tissue. First, you have to locate the tissue and cut sections. Then, you either have to process them to extract the DNA and RNA or send it to another company. If you send it to another company, you have to consider shipping and logistical processing times before they can extract the material and you can get those results.

With something like plasma testing, the median time for testing results in the NILE trial was 9 days, which was significantly faster than the turnaround time for tissue. Those are the big advantages and has the potential to dramatically increase the number of people who get tested for the appropriate genetic markers for lung cancer.

How else do liquid biopsies compare with standard tissue biopsies?

People have spent a lot of focus on the disadvantages of the liquid biopsy, including the sensitivity. If you're extracting DNA from an actual tumor and you have a piece of the tumor, you're getting DNA that's coming from that cancer. If you test it, you have a high likelihood that you'll accurately be able to assess if there's a mutation or a gene fusion in that cancer because you're testing the cancer itself.

If you're looking at circulating-free DNA in the blood, then you're relying on some of the DNA from the cancer cells, which is not in the blood and is usually in the lung, bone, or wherever the tumor is, to leak into the bloodstream and become detectable amid a huge amount of DNA that is not tumor DNA; it's normal DNA from the person. The technology has gotten phenomenally better at being able to detect extremely low amounts of circulating tumor DNA and being able to filter it out to detect the difference between the tumor and normal DNA from a person.

However, not every cancer is going to be detectable in that way. Some cancers don't shed DNA as much as others. Some patients who have a relatively low amount of cancer and a low tumor burden may not have as much detectable DNA. The sensitivity is always going to be a relative disadvantage of doing liquid biopsies compared with an actual tumor biopsy. If you look at comparisons between tumor biopsies and plasma biopsies, for example, in the NILE study, you probably get somewhere in the range of about 80% sensitivity of mutations and other genetic alterations that are known to be in the tumor from a tumor biopsy that are detectable in the blood, meaning you may miss 20% of actual findings that are there by solely doing a blood test.

What targets can be identified via liquid biopsy?

In 2019, there are 4 must-have biomarker tests for genetic testing in lung cancer. You have to test for EGFR, ALK, ROS1, and BRAF V600E in every patient with lung adenocarcinoma and nonsquamous non—small cell lung cancer. Then, there are a number of tests that should be done on everyone but we don’t yet have FDA-approved treatments for—including RET and MET exon 14 skipping mutations. Therefore, you could argue that they are not necessary, but getting very close [to being necessary].

Similarly, the FDA is reviewing data from drugs for approval in this space. HER2 activating mutations are still investigational, but there are promising drugs and trials. KRAS mutations, historically, have not been targetable, but that's changing with multiple drugs now in early-phase trials. KRAS is also very valuable because it’s very common, and these drivers are mutually exclusive. If you find it, there likely are not any other targetable oncogenes present.

There are also NTRK fusions, which are extremely rare but have extremely effective treatments if you identify them. When you're doing a broad multiplex test, you can test for all of these at around the same cost as testing for any of them [individually].

The NILE trial looked into the impact of liquid biopsies in lung cancer. Could you highlight the findings from this study?

This is a very simple test. They took 282 patients with lung cancer who were going to undergo standard tissue testing. All of them had their blood drawn and sent for plasma testing at the same time. In the end, they described the success rate for identifying guideline-recommended biomarkers with the plasma testing compared with the tissue testing. This was a nice, real-world study because they were using a commercially available, FDA-approved plasma test and whatever was done by local testing centers for tissue testing, which is a very realistic real-world way of doing it.

In one aspect, this is a glaring way of illustrating that with many biomarkers to test, using a combination of single-gene tests is completely ineffective. There's no practical way to test for 8 different biomarkers using single-gene tests. If you just looked at EGFR and ALK, for example, more than 80% of patients were tested, which is pretty close to what literature has described regarding patients who were tested for EGFR and ALK nationwide. However, even 80% for ALK 83% for EGFR, compared with 95% of patients getting tested with plasma testing, shows that liquid biopsy captures a much larger group of eligible patients and ensures they have at least some testing done.

The disadvantage [of liquid biopsy] is the sensitivity. Although a relatively small number of patients had all of the tissue testing done, the plasma testing results in patients who had tissue testing showed they had about an 80% sensitivity. In other words, 80% of the genetic alterations that were found in tissue were also found in the plasma. The flipside is if you had done plasma and not tissue testing, you probably would have missed about 20% of those.

However, since only 18% of people got all the tissue testing done, you probably picked up a lot more actionable alterations by doing the plasma testing than you would have if you had solely done tissue testing. In a way, they are complementary. The perfect solution would be to do tissue testing and get it done correctly on 100% of patients. However, since that's impractical currently, plasma testing has a huge role to play in improving the number of people getting testing.

Is there any pushback regarding the payment aspect liquid biopsies?

A major outstanding question when it comes to plasma testing is reimbursement for paying for these tests. There are FDA-approved plasma tests. Hopefully, payers understand the importance of the role of testing and are covering this. We as a field have to be careful about routinely recommending double testing using plasma and tissue for every patient. We have to set up an algorithm that optimally try to identify [optimal testing] for patients without doing wasteful testing. I'm encouraged by what I've seen, at least in the last couple of years, with payer coverage for plasma testing when it's appropriate.

What steps can we take as a community to make liquid biopsies more widespread?

[We must work on] education and letting people know about plasma testing, including the advantages and disadvantages. I do not want to put out the message that, “Plasma testing should replace tissue testing universally, that it's every bit as good, and that the result of plasma testing is adequate if it shows you don't have an actionable result.” If you have good tissue testing and you're going to get the [results from plasma too], then that's adequate. If you have any questions about your tissue testing, then doing plasma testing upfront makes perfect sense. However, if you get a negative result and there are no actionable results from your plasma test, you have to follow up with tissue testing because you may have missed some [alterations].

1. Gierman HJ, Goldfarb S, Labrador M, et al. Genomic testing and treatment landscape in patients with advanced non-small cell lung cancer (aNSCLC) using real-world data from community oncology practices. J Clin Oncol. 2019;37(suppl; abstr 1585). doi: 10.1200/JCO.2019.37.15_suppl.1585.

2. Leighl N, Page RD, Raymond VM, et al. Clinical utility of comprehensive cell-free DNA (cfDNA) analysis to identify genomic biomarkers in newly diagnosed metastatic non-small cell lung cancer (mNSCLC) [published online ahead of print, April 15, 2019]. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-19-0624.

Liquid Biopsies Are Link to Increasing Molecular Testing in Lung Cancer.

Not all patients with advanced non–small cell lung cancer (NSCLC) are recommended for genomic testing when treated in a community setting, and are therefore not being appropriately tested for potential molecular drivers of their disease, explained Nathan Pennell, MD, PhD.

Expert Talks Liquid Biopsies, Molecular Testing in Lung Cancer

The American Cancer Society estimates that 5%-10% of cancers are connected with mutations in the DNA that are inherited through generations.

 For millions of patients in the United States, genetic testing allows for a deeper understanding of one’s risks, prompting more comprehensive screening and services in an effort to prevent the onset of a disease or detect cancer at an earlier stage. Despite heightened awareness of the BRCA gene, breast cancer is far from the only cancer associated with inherited risks. Melanoma, pancreatic, prostate, colon, ovarian, stomach, and brain cancers may be associated with family cancer syndromes caused by inherited genetic mutations.

Most insurance companies that pay for genetic testing do so at the request of a primary care physician or genetic counselor who has agreed that there are enough immediate family relatives with cancer diagnoses to warrant a genetic test on the patient. Patients often have to recite a painful list of family members who have had cancer diagnoses, and this in itself is unsettling, given that they may have lost family members from the disease and may still be grieving. The emotional context of a family medical history is compounded by the implication that patients themselves may be diagnosed with cancer in the future.

For people with genetic mutations that lead to an increased risk of cancer, occupying the same clinical spaces designed for people with cancer diagnoses may be challenging. The protocol for many genetic mutations involves annual or biannual scans or follow up on concerns.

 As a result, patients can form lasting relationships with oncology nurses without ever having a diagnosis of cancer. The discovery of a genetic mutation allows people to take power over an uncertain future, but places them in the same medical setting they are hoping to avoid. For those living in more rural areas, access to genetic counseling may be limited. Patients will look to oncology nurses for assurance that their screenings or preventive measures will be effective, and may feel discomfort at being treated as though they are already a person with cancer.

Because most patients with genetic mutations will have family members who have been diagnosed with cancer, it can be a fine line between patient and caregiver. When working with clients who compare their diagnoses and experience with cancer to those of similarly diagnosed family members, it is important to remember the individuality of patient experience. Working with caregivers can present unique topics, as their concerns are both for the patient and for their own futures. It is important as oncology nurses to remember that patients identified with family cancer syndromes usually have a lengthy personal narrative that includes multiple losses of family members. This creates the need for a delicate balance in which oncology nurses have to be aware of their patients’ need for support while not assuming that the patient will become ill themselves. 

People with genetic mutations are often confronted with an abundance of screening protocols that can be overwhelming. Oncology nurses have the rare chance to form long-term relationships with patients and help contextualize the data behind what “increased risk” means. Various cancer syndromes can have different timelines; one may involve an  increase in cancer diagnoses for those under the age of 30 while another might involve a lifetime of gradually increasing risk. Oncology nurses can help put these things into context. For example, oncology nurses can help patients understand that a high risk of cancer by the age of 70 only remains true if nothing is done to lessen risks associated with cancer

 and that increased screening, changes in diet, reduction in alcohol and avoidance of tobacco can prevent or reduce chances of cancer.

Oncology nurses are at the front lines of meeting a patient where they are emotionally. If a patient comes to an oncology center for screenings, oncology nurses can treat them with care and empathy while being mindful that the patient might not need the same degree of support as someone with a cancer diagnosis. In the same vein, a patient with a family cancer syndrome may experience increased anxiety due to previous scans and tests and require more information and reassurance.

It is essential to remember that people with family cancer syndromes may never receive a cancer diagnosis. This may be due to preventive surgeries to remove organs and body tissue or prophylactic medication.

 For those patients who are unable to take preventive surgeries and rely on increased screening measures, there may eventually be a cancer diagnosis. The emotional comparison to other family members challenges the notion that everyone’s experience with cancer is unique, and oncology nurses can help contextualize and support a patient who transitions from screenings to cancer care. Oncology nurses are often in a prime position to validate the patient experience and provide essential support in long-term relationships with patients and caregivers.

The American Cancer Society. Family Cancer Syndromes. 

https://amp.cancer.org/cancer/cancer-causes/genetics/family-cancer-syndromes.html

 January 4, 2018. Accessed December 10, 2019

Schmeler KN, Lynch HT, Chen L, et. al. Prophylactic Surgery to Reduce the Risk of Gynecologic Cancers in the Lynch Syndrome. 

. Jan. 9, 2006. DOI: 10.1056/NEJMoa052627

 Garber JE, Offit K. Hereditary Cancer Predisposition Syndromes. 

People with genetic mutations are often confronted with an abundance of screening protocols that can be overwhelming.

Genetic Testing and Inherited Increased Risk of Cancer

Single-agent vorasidenib or ivosidenib (Tibsovo) led to brain penetrance and 2-hydroxyglutarate (2-HG) suppression in patients with low-grade glioma who harbor 

 mutations, according to updated data from an ongoing, 2-cohort, perioperative study (NCT03343197) that were presented at the 2019 Society for Neuro-Oncology Annual Meeting.

Findings were available from 42 efficacy-evaluable patients on vorasidenib (n = 21) or ivosidenib (n = 21). Among those who received postoperative vorasidenib at 50 mg, 4 (31%) patients achieved objective tumor responses, which comprised 2 partial responses (PRs) and 2 minor responses, according to the investigator by Response Assessment in Neuro-Oncology for low-grade glioma (RANO-LGG).

The objective response rate was also 31% for patients who received 500 mg of ivosidenib in the postoperative setting, also according to investigator by RANO-LGG. This included 2 PRs and 2 minor responses. Moreover, stable disease was achieved in 15 and 16 patients on vorasidenib and ivosidenib, respectively, which led to respective disease control rates of 90% and 95%.

Vorasidenib is an investigational, oral, selective IDH1/IDH2 inhibitor that is designed to enhance brain penetrance and has been in clinical development in 

Ivosidenib is currently approved by the FDA for the treatment of adult patients with relapsed/refractory 

-mutant acute myeloid leukemia (AML), and for the first-line treatment of adult patients with 

Two new single agents led to brain penetrance and 2-hydroxyglutarate (2-HG) suppression in patients with low-grade glioma who harbor IDH1 mutations, according to updated findings.

Genetics