As targeted therapies continue to evolve in the cancer space, it is essential for clinicians to understand the basics of genomics, especially when it comes to hematologic malignancies.

“There are many different lymphoma subtypes, and they’re distinguished by their histology, their immune phenotyping, and their underlying genetic abnormalities,” said Eric Hsi, section head of hemapathology and medical director of the automated hematology, flow cytometry, and immunohistochemistry laboratories in the Institute of Pathology and Laboratory Medicine at the Cleveland Clinic.

Hsi recently discussed the basics of blood cancer pathology at the 2020 NCCN Virtual Congress on Hematologic Malignancies.

There are 3 types of abnormalities that can occur in a patient’s DNA, Hsi explained. They are:

Gene copy number abnormalities: In this situation, clinicians would be looking for gains and losses. These can be detected by routine karyotyping, flourescense in situ hybridization (FISH), DNA microarrays, and next-generation sequencing (NGS).

Structural variants: This is known as translocations and rearrangements, and occurs when genes or chromosomes move. This can also show up on routine karyotyping, and FISH tests, as well as PCR-based assays and NGS-based methods.

Mutations: When a DNA sequence changes, it can alter the function of that protein. To see if a patient has a genetic mutation, clinicians will conduct Sanger sequencing, allele-specific PCR, or NGS-based methods.

Undergoing molecular testing is crucial for patients with blood cancers, because not only will it give better insight to the type of cancer the patient has, but also what the best treatment regimens may be.

Anaplastic large cell lymphoma (ALCL) is characterized by expression of CD30. However, it is also crucial to know patients’ ALK status, which can be determined by an immunohistochemical test.

“We distinguish positive and negative anaplastic large lymphomas because of the favorable prognosis of positive cases,” Hsi said. “So it’s important to know whether ALK is translocated and overexpressed in these lymphomas.”

ALK-positive ALCL tends to have a much better prognosis than ALK-negative disease, because there are treatments that target ALK, a tyrosine kinase.

Patients with follicular lymphoma should also undergo genetic testing. In June, the 

 for relapsed/refractory follicular lymphoma that harbors an EZH2 mutation.

The drug was approved alongside a companion diagnostic test that would determine if a patient has the mutation.

“This is another example of where detecting a molecular abnormality would help us select a therapy,” Hsi said.

Oncology nurses can be advocates in ensuring that their patients undergo the genetic testing that is needed for their disease type and treatment options.

“Molecular testing is routinely used by pathologists for diagnosis, prognosis, and also guiding therapy selection either for targeted or non-targeted therapies,” Hsi said.

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It is imperative that patients diagnosed with blood cancer undergo the proper molecular testing, one expert says.
 

Molecular Testing Guides Diagnosis, Treatment in Blood Cancers

With the emergence of several targeted treatments that have shown efficacy in individuals with germline pathogenic variants, specifically in DNA mismatch repair, the need for germline genetic testing has become even more pronounced, according to Elena M. Stoffel, MD, MPH. Results could lead to the identification of Lynch syndrome and other hereditary cancer syndromes associated with the risk of developing colorectal cancer (CRC) and other diseases.

“We [have] information on the importance of assessing for Lynch syndrome: How to test people for Lynch syndrome, how to treat Lynch-associated cancers, and how to prevent cancers in Lynch syndrome,” said Stoffel. “However, really being able to translate [what we learn] from the studies into clinical [practice] and the care for patients is really where we are now. Building the awareness, developing the systems, and providing the education to both providers and patients is [what is needed].

One study led by investigators at Memorial Sloan Kettering Cancer Center enrolled 15,405 patients with Lynch syndrome pan-cancer with microsatellite instability—high (MSI-H) and MSI-indeterminant tumors.

The MSK-IMPACT next-generation sequencing platform was used to identify Lynch syndrome in 16.3%, 1.9%, and 0.3% of patients with MSI-H, MSI-indeterminate, and microsatellite-stable tumors, respectively (P < .001). The study also indicated that Lynch syndrome extends beyond CRC and endometrial cancers and affects numerous other tumor types, including urothelial cancers, ovarian cancers, specific sarcomas, and several other hypermutated tumors, Stoffel added.

“What we were diagnosing as Lynch syndrome, historically, was probably just the tip of the iceberg. Many more patients are out there with Lynch syndrome who remain undiagnosed,” explained Stoffel. “The potential of making that diagnosis, not only for the treatment of patients with cancer, but also for the cancer prevention in their family members is really important.”

, during the 2020 Institutional Perspectives in Cancer webinar on Precision Medicine, Stoffel, an associate professor at Michigan Medicine, University of Michigan, further discussed the importance of genetic testing in detecting Lynch syndrome and other hereditary syndromes associated with risk of CRC and other cancers.

What has been learned in recent years with regard to germline testing for Lynch syndrome cancers?

[Results from] many of the published studies have told us that the number of patients who carry germline alterations associated with genetic predisposition is actually much higher than we previously thought. The clinical presentations of some of these patients can be very different from what has been described in the original papers. Now, we know that Lynch syndrome, which is one of the most common hereditary cancer syndromes, has a population prevalence of about 1 in 300. Many patients who develop Lynch syndrome cancers could be identified if we broaden our search for these germline mutations. Given recent advances in therapy for hypermutated tumors, this is especially relevant in both cancer treatment and also prevention in these affected families.

Do any barriers to genetic counseling or germline testing exist for Lynch syndrome?

Barriers exist on multiple levels. First, the patient's physician or clinician needs to consider the possibility of Lynch syndrome, because if they don't think about that, they’re going to miss the diagnosis.

Secondly, although there are recommendations for universal tumor testing for colon and endometrial cancers, many clinical sites don't have access to testing tumors for dMMR. That universal screening only gets applied at centers where they have the pathology resources available. Thirdly, even when the providers have identified the need for genetic testing, being able to convey the importance of that to patients and make it easier for them to seek genetic evaluation remains a barrier.

Fortunately, over the past few years, many more insurances are covering genetic testing; the cost of testing has [also] decreased. Additionally, new models for accessing genetic services exist so patients no longer have to travel to a genetic specialty clinic. In many cases, providers can order the testing themselves if they're comfortable with that. They can also refer [their patients] to telehealth services, which are trying to improve access to genetic testing. [However], a patient has to be motivated to seek out that extra testing. Our ability to explain to patients why this information is important is really the key to improve access to genetic testing.

How should genetic testing be approached in a clinical practice? When should this testing take place in the treatment journey?

We can think about this in different ways. In an oncology practice, ASCO has recommended that, at the basic intake appointment, the clinician obtain a family history from patients that includes cancer diagnoses, as well as dates and ages of diagnoses for all first- and second-degree relatives. The goal of that should be to prompt the question: How likely is it that this patient's tumor developed in the context of a genetic predisposition syndrome?

If the answer to that is possibly or likely, then a discussion should take place in terms of further evaluation. For many tumor types now, testing tumors has become a part of the treatment pathway. Certainly, being able to identify whether tumors are hypermutated and whether tumors have dMMR should also be [done] early on in the treatment algorithm, as well as the diagnostic evaluation for hereditary cancer syndromes.

Now that many targeted treatments have emerged as being particularly effective in individuals who have germline pathogenic variants, specifically in DNA mismatch repair or in double-stranded DNA repair, germline genetic testing should be part of the discussion at the first intake when patients are discussing what possible treatments are in store for them.

Could you discuss the importance of testing MSI-H patients for Lynch syndrome?

Approximately 15% to 30% of all colon cancers are MSI-H. Of all colon cancers, about 3% correspond to Lynch syndrome. For several years now, universal tumor screening for dMMR has been recommended as a best practice. Doing universal tumor testing is 1 thing; following up on all those results is another. When a patient has colon cancer, what’s the mismatch repair status of the cancer? If it's dMMR, has this patient been evaluated for the possibility of Lynch syndrome? Making this part of our systematic checklist is an important way to proceed.

What studies are particularly important in this field?

First of all, Matthew Yurgelun, MD, of Dana-Farber Cancer Institute, [has a] study that was published in the Journal of Clinical Oncology and demonstrated that of all unselected CRCs, approximately 10% carry germline pathogenic variants. Of those, Lynch syndrome is the most important group of genes involving the DNA mismatch repair genes. However, other genes are there as well, including genes associated with hereditary breast and ovarian cancer, or BRCA genes. BRCA1/2 and PALB2 emerge in some individuals with CRC. It just goes to show that there is overlap among the different hereditary predisposition syndromes with regard to cancer development and risk.

Another important study was [conducted at the University of Michigan] and the Ohio State University Comprehensive Cancer Center—James. Results showed that among unselected individuals with colon cancer diagnosed at an age under 50 years, the prevalence of germline mutations is about 20%; this translates to about 1 in 5 [patients]. As such, it’s particularly important to offer germline genetic testing to that group.

Finally, the group from Memorial Sloan Kettering Cancer Center looked at the prevalence of Lynch syndrome among hypermutated tumors, which basically shows us that the spectrum of cancers associated with Lynch syndrome goes beyond CRC and endometrial cancers, which are the 2 hallmark cancers. It also extends to urothelial cancers, ovarian cancers, certain sarcomas, and several other tumors for which the diagnosis of Lynch syndrome would not have necessarily been considered, except for the fact that these tumors are hypermutated and look very different from other tumors in their group.

As with most [findings] in oncology, once there is a therapeutic implication, that tends to gain traction; even though we've known that diagnosing Lynch syndrome makes a big difference for the care of [patients with] cancer and family members, the fact that it can actually influence our treatment algorithms now makes it really important to address up front.

What significant clinical challenges remain in implementing genetic testing?

From the provider end of things, many are uncomfortable with genetic testing to the point where they're uneasy discussing it with patients because they don't have the familiarity with the process for diagnostic testing or for the interpretation of genetic test results. The more we can educate our clinical providers in what genetic testing is and why it's important, the easier it's going to be to talk to patients about it, and the more patients are going to recognize the importance of getting tested.

What is your take-home message regarding genetic testing?

For every patient we see, we should consider the likelihood that the cancer was the result of a hereditary cancer syndrome and what can be done to figure that out. Now that tumor testing has become a part of many of our treatment algorithms, that provides us with a great opportunity to be able to look for the tumor phenotypes. We can also do a better job of taking family histories from patients and think about the pattern of cancer in the family, and [whether it points to the] possibility of an underlying genetic predisposition. If we think about it, then we're less likely to miss it.

Latham A, Srinivasan P, Kemel Y, et al. Microsatellite instability is associated with the presence of lynch syndrome pan-cancer. J Clin Oncol. 2018;37(4):286-295. doi:10.1200/JCO.18.00283

This article was originally published on OncLive as, "

Stoffel Underscores Importance of Germline Testing for Lynch Syndrome

With the emergence of several targeted treatments that have shown efficacy in individuals with germline pathogenic variants, specifically in DNA mismatch repair, the need for germline genetic testing has become even more pronounced. 

Germline Testing for Lynch Syndrome: More Important Than Ever

As genetics continue to play a major role in gynecologic cancer treatment, it is imperative that patients understand its implications. Nurses can be key in educating patients and dispelling any myths and misconceptions that they may have.

A recent study presented at the 2020 ONS Bridge virtual conference analyzed patients’ understanding of cancer in the world of oncology. Study author Rachel Pozzar, PhD, RN, of the Dana-Farber Cancer Institute, recently discussed her team’s findings with 

: Can you explain your study and its significance? 

This was a secondary analysis of data collected as part of a larger study, led by Meghan Underhill-Blazey, PhD, APRN, AOCNS, that assessed the experiences of breast and gynecologic cancer survivors who underwent genetic counseling and multigene panel testing. The purpose of this study was to better understand knowledge of cancer genetics among participants with a primary diagnosis of ovarian cancer.

Knowledge of cancer genetics in this population is an important topic because more than 20% of ovarian cancer cases are associated with an inherited pathogenic variant. From prior research, we know that individuals who are confident in their knowledge of cancer genetics are more likely to share their genetic test results with relatives. In turn, these relatives may benefit from genetic testing and certain risk-reducing interventions. 

One of our main findings was that participants who scored below the sample average on our measure of cancer genetics knowledge expressed interest in face-to-face results disclosure, visual learning aids, and simplified language in written and verbal communication. We also found that older age was significantly associated with lower cancer genetics knowledge, which is important because older adults may serve as a resource for family members who seek information about their family's health history. 

Are there misconceptions or gaps in knowledge for patients with ovarian cancer when it comes to genetics? Why?

One important gap in knowledge we observed was that only about half of participants were aware that female-specific cancer risk, such as for ovarian cancer, can be inherited from either the father or the mother. Similarly, fewer than half of participants were aware that people with an inherited risk for cancer may get cancer at a younger age, or that they may be at risk for more than one type of cancer. These misconceptions are likely common because the principles of cancer genetics are complex, and the field is rapidly evolving. 

What role does the oncology nurse play in educating patients and their families? 

The findings of this study highlight the need for nurses and other clinicians to ensure that the language and materials they use to educate patients is clear, free of jargon, and perhaps supported by a visual aid. Although genetic counselors provide much of the initial education that takes place prior to genetic testing, nurses can reinforce this teaching, identify unmet learning needs, and help the patient identify reliable sources of cancer genetics information.

What are the next steps in this line of research? Are there any unanswered questions? 

The results of this study highlight the role of patient-provider communication in cancer genetics education. My broader program of research is focused on promoting patient-provider communication that meets patients’ unique needs and preferences—what is often called “patient-centered communication.” Research suggests patient-centered communication has the potential to promote knowledge retention and to prompt family conversations about hereditary cancer risk.

One priority for nurse scientists is to develop and test strategies that promote patient-centered communication in the ovarian cancer care setting. As nurses, it’s crucial for us to ensure that all patients, regardless of age or diagnosis, understand what their genetic test results mean for themselves and their families.

Nurses play a key role in ensuring that patients with gynecologic cancer understand the results and implications of genetic testing.
 

Gynecologic Cancer Genetics: Patient-Provider Communication Is Critical

The FDA has approved Guardant360® CDx for comprehensive genomic profiling in patients with any solid malignant cancer, according to an announcement from Guardant Health, Inc.

 The assay is also approved as a companion diagnostic to detect EGFR mutations in patients with non&shy;—small cell lung cancer (NSCLC) who could potentially benefit from osimertinib (Tagrisso).

The regulatory decision was based on both clinical and analytical data from over 5,000 samples, which provided validation for the test.

“The FDA approval of Guardant CDx is a landmark decision, demonstrating the value liquid biopsy delivers to oncologists and more importantly, the patients they treat. Traditional tissue biopsy-based tumor profiling, which is often invasive and has longer turnaround times, can contribute to delays in starting treatment and possibly suboptimal therapy,” Helmy Eltoukhy, CEO of Guardant Health, stated in a press release.

“We applaud the FDA for their collaborative review process and for approving the first comprehensive genomic profiling liquid biopsy test,” added Eltouky. “We are confident that our FDA approval will help accelerate wider adoption of guideline-recommended genomic profiling, increase the number of advanced cancer patients who receive potentially life-changing treatments, and pave the way for new companion diagnostic developments for the Guardant360 CDx.”

Results from a retrospective analysis of findings from the phase 3 FLAURA and AURA3 trials showed that patients who had been identified for osimertinib treatment by the Guardant360 CDx test experienced progression-free survival (PFS) rates that proved to be consistent with those identified through the use of traditional biomarker testing, according to Guardant Health.

Data from the phase 3 FLAURA trial indicated that treatment with osimertinib led to a significant overall survival compared with erlotinib (Tarceva) or gefitinib (Iressa) in patients with EGFR-mutated locally advanced or metastatic NSCLC.2 Previously reported PFS data from the trial led to the April 2018 FDA Approval of the agent for use in this setting.

Data from the trial demonstrated that osimertinib led to a 54% reduction in the risk of progression or death compared with erlotinib or gefitinib. The median PFS with osimertinib was 18.9 months with osimertinib versus 10.2 months with standard treatment (HR, 0.46; 95% CI, 0.37-0.57; P <.0001).

A total of 556 patients with treatment-naïve EGFR-mutated locally advanced or metastatic NSCLC were enrolled on the trial. These participants were randomized to receive either osimertinib (n = 279) or erlotinib or gefitinib (n = 277). Notably, participants with central nervous system (CNS) metastases were permitted to participate. All included had exon 19 deletions or L858R mutations. Patients received oral osimertinib at 80 mg daily, or 250 mg of gefitinib or 150 mg of erlotinib daily.

Notably, the PFS benefit was found to be upheld across all of the patient subgroups analyzed. In the 116 patients with CNS metastases, the median PFS with osimertinib versus a standard TKI was 15.2 months and 9.6 months, respectively (HR, 0.47; 95% CI, 0.30-0.74; P = .0009). In the 440 participants who did not have CNS involvement, the median PFS was 19.1 months in the osimertinib arm compared with 10.9 months in the standard arm (HR, 0.46; 95% CI, 0.36-0.59; P <.0001).

Moreover, the objective response rates (ORRs) were 77% versus 69% with osimertinib and standard treatment, respectively, and the median duration of response was 17.6 months and 9.6 months, respectively.

With regard to safety, the most commonly reported toxicities with osimertinib included diarrhea (58%) and dry skin (32%); in the control group, the most common all-grade adverse effects (AEs) were diarrhea (57%) and dermatitis acneiform (48%). Grade 3 or higher effects were reported in 33.7% of patients in the investigational arm versus 44.8% of those in the control arm. Notably, those who received treatment with osimertinib were less likely to discontinue treatment because of toxicities compared with those who receive standard TKI treatment, at 13.3% versus 18.1%, respectively.

In March 2017, the FDA has granted a regular approval to osimertinib for use in patients with EGFR T790M mutation—positive NSCLC post treatment with an EGFR TKI, based on PFS data from the pivotal phase 3 AURA3 trial.

In this trial, treatment with osimertinib resulted in a median PFS of 10.1 months versus just 4.4 months with platinum-based chemotherapy (HR, 0.30; 95% CI, 0.23-0.41; P <.001). In those with CNS metastases, the median PFS with osimertinib was 8.5 months versus 4.2 months with chemotherapy (HR, 0.32; 95% CI, 0.21-0.49).

In the open-label trial, a total of 419 patients were randomly assigned 2:1 to receive either osimertinib (n = 279) versus a platinum-based chemotherapy regimen (n = 140). Oral osimertinib was given at 80 mg once daily in a 21-day treatment cycle. Those in the chemotherapy arm received either pemetrexed/carboplatin or pemetrexed/cisplatin. Pemetrexed was given at 500 mg/m2, carboplatin at a dose of 5 AU, and cisplatin at 75 mg/m

Results showed that osimertinib led to a 71% ORR compared with 31% in those who received chemotherapy (odds ratio, 5.39; 95% CI, 3.47-8.48; P <.001). Moreover, osimertinib showed a 6-month PFS rate of 69% versus 37% with chemotherapy. The 12-month PFS rates were 44% and 10% in the osimertinib and chemotherapy arms, respectively.

Regarding safety, the most common toxicities reported with osimertinib were diarrhea (41%), rash (34%), dry skin (23%), and paronychia (22%). In patients who received the chemotherapy, the most common all-grade AEs included nausea (49%), decreased appetite (36%), constipation (35), and fatigue (28%).

Grade 3 or higher toxicities occurred in 23% and 47% of those on the osimertinib and chemotherapy arms, respectively. Neutropenia (12%), anemia (12%), and thrombocytopenia (7%), were among the most commonly reported grade 3 or higher AEs experienced in the chemotherapy arm.

“Personalized medicines such as [osimertinib] have been truly life-changing for many [patients with] who have certain EGFR mutations and are most likely to benefit from this medicine,” Jhanelle Gray, MD, senior member and chair in the Department of Thoracic Oncology and co-leader of Chemical Biology & Molecular Medicine Program at Moffitt Cancer Center, added in the release. “It is crucial that all patients are comprehensively tested before starting treatment to ensure they receive the most appropriate personalized treatment option available.”

1. Guardant Health Guardant360® CDx first FDA-approved liquid biopsy for comprehensive tumor mutation profiling across all solid cancers. News release. Guardant Health, Inc. August 7, 2020. Accessed August 7, 2020. https://bit.ly/2C6asTE.

2. Tagrisso significantly improves overall survival in the Phase III FLAURA trial for 1st-line EGFR-mutated non-small cell lung cancer. AstraZeneca. Posted August 9, 2019. Accessed August 9, 2019. https://bit.ly/2ZGF7gZ.

3. Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. Ann Oncol. 2017;28(suppl 5):v635. doi:10.1093/annonc/mdx440.050

4. Mok TS, Wu YL, Ahn MJ, et al. AURA3 Investigators. Osimertinib or platinum—pemetrexed in EGFR T790M—positive lung cancer. N Engl J Med. 2017;376(7):629-640. doi:10.1056/NEJMoa1612674

FDA Approves Guardant360 CDx Liquid Biopsy for Comprehensive Genomic Profiling Across All Solid Cancers

The FDA has approved Guardant360® CDx for comprehensive genomic profiling in patients with any solid malignant cancer.

FDA Approves Guardant360 CDx Liquid Biopsy for Genomic Profiling for Solid Cancers

Genetic testing is more important now than ever before, as biomarker-driven cancer treatments continue to receive approval across many tumor types. While these personalized treatments are improving outcomes, navigating the landscape of genetic testing can leave patients with questions for their providers.

In a presentation during the 4th Annual School of Nursing Oncology virtual meeting hosted by Physicians’ Education Resource®, LLC (PER®), Emily Mazzei, MS, MPH, CGC, a licensed, certified genetic counselor, provided an overview of current recommendations for genetic counseling in oncology and discussed some of the questions commonly asked.

Mazzei reviewed the difference between somatic testing, also known as germline or tumor testing, and germline testing. Somatic changes are not hereditary, as they occur in the cancer cells themselves, according to Mazzei; germline mutations are present in a patient since birth, since they are passed down from parents to children.

“Depending on what your patient population looks like, you may be seeing that your patients have 1 of these types of genetic tests or both,” Mazzei said. “Somatic testing is becoming a little more commonplace, or [even as] routine as genetic testing. Generally speaking, panel testing is now standard of care.”

In a panel test, patients will be tested for genes associated with their cancer, as well as those that typically fall outside of their cancer type. However, patient choice also plays a role in what kind of testing they will receive, noted Mazzei.

“It also depends on the patient’s preferences. Some want to just focus on the specific cancer type that they have,” Mazzei said. “It also depends on the institution and what the genetic counselors and ordering physicians prefer.”

Genetic Findings Affect Treatment and Family Members

Genetic testing results have become crucial in determining the type of treatment a patient receives. For example, the FDA most recently approved the combination of atezolizumab (Tecentriq) plus cobimetinib (Cotellic) and vemurafenib (Zelboraf) for patients with BRAF V600 mutation—positive melanoma. Only when a mutation or alteration has been detected can a patient be considered for a potential targeted treatment.

Additionally, if a germline mutation is detected in a patient, their immediate family may also be at higher risk for cancer, according to Mazzei. Family members are then faced with the decision of whether they want to undergo testing—that is not an easy choice for many people, Mazzei explained.

“A large part of our role is providing psychosocial support to these patients,” she said. “Essentially, we give them the information they need to help them make the decisions on whether they want to pursue genetic testing when it’s medically indicated.”

The cost of genetic testing is another concern that patients and their family members often have, particularly with regard to whether it will be covered by insurance, Mazzei noted.

“Most insurance companies will cover their genetic counseling, a face-to-face appointment with a genetic counselor,” Mazzei said. “Most insurance companies will cover all, or some, of the genetic or germline testing, if ordered appropriately and clinically indicated.”

As such, Mazzei recommended that prescribing clinicians work closely with genetic counselors to ensure that testing is correctly ordered, thus increasing the chance that it will be covered by their patients’ insurance.

While the majority of patients who undergo genetic testing for cancer are adults, there are some instances when children under the age of 18 should be tested, according to Mazzei.

Children who should be tested include those with a family history of a pathogenic gene mutation, such as polyposis syndromes, multiple endocrine neoplasia type 2, and Li Fraumeni syndrome (LFS). Those with a personal history or current diagnosis of cancer may also be tested. LFS can lead to potential increased risk of sarcoma, leukemia, and brain tumors, and PTEN Hamartoma Tumor Syndrome can lead to increased risk of macrocephaly, developmental delay, or thyroid cancer.

“The reason for [this testing in this population] is for medical intervention for these specific conditions,” Mazzei said.

However, not everyone under the age of 18 should be tested, despite their relatives’ genetic testing results or cancer history. For example, there is no medical intervention for children with BRCA mutations or Lynch syndrome.

“We also want the patient or the person pursuing genetic testing to be autonomous when making this decision, so that’s why we only recommend testing these childhood conditions and not adult-onset conditions, even though the parents may be wondering whether their child does have that,” Mazzei concluded.

Mazzei E. Cancer genetic counseling. Presented at: 4th Annual School of Nursing Oncology. July 31-August 1, 2020.

Cancer and Genetic Testing: Expert Answers Common Questions

Hematologic malignancies are widely known to be among the top 10 cancer-related diagnoses and causes of mortality annually.

 However, genetic diagnostic data have been limited in the field of hematology due to the low rate of proliferation of myeloid and lymphoid malignancies. Providers have made wide use of morphological testing and immunophenotyping to guide clinical decisions when treating these disorders. Diagnostic tests currently being used include cytogenetic karyotype, fluorescent in-situ hybridization (FISH), polymerase chain reaction (PCR), gene expression profiling, and next-generation sequencing (NGS).

Cytogenetic karyotyping, used since 1882 to evaluate chromosomes, analyzes chromosome balance in hematologic malignancies as well as reciprocal translocation. Karyotyping is the most common test for diagnosing chronic myelogenous leukemia and other disorders with large structure abnormalities.

The FISH test identifies abnormalities by hybridizing a patient’s tissue sample under a fluorescent microscope. The test provides a rapid analysis when karyotyping is highly variable, which limits the ability to diagnose a hematologic malignancy. The clinical utility of FISH is used by medical providers to determine prognostic outcomes in acute and chronic illnesses.

PCR is a molecular assay for detecting genes that are fused, mutated, or cloned in hematologic malignancies. It can also provide an evaluation of chimerism between the donor and recipient of an allogeneic transplant. Gene expression profiling is a diagnostic technique that evaluates numerous genes expressed in tumors for their classification.

Although currently limited to research centers, the technique has demonstrated significant utility in the stratification of plasma cell disorders, lymphoma, and lymphoproliferative disorders.

Finally, NGS provides sequencing for millions of DNA fragments at a time. The presence of mutations such as TP53, ATM, RAS, IDH1, IDH2, DNMT3A, and SF3B1 can be discovered through this diagnostic test. Future advancements will use these abnormalities as prognostic indicators and for guidance on personalized treatment for patients.

Given the recent use of genes to determine prognosis and treatment decisions in the field of hematology, it is important for providers to collaborate with geneticists.

 Their expertise is needed to ensure a comprehensive diagnostic workup is performed and the appropriate genetic analysis exams included. It is also important to implement the following interventions to optimize patient care:

• Perform baseline complete blood count with differential

• Perform bone marrow aspiration and biopsy (cytogenetic karyotyping and molecular testing)

• Consult with experts to reduce the likelihood of delayed diagnosis

• Refer patients to a genetic counselor

• Provide targeted and systemic therapy based on national recommendations

• Discuss potential need for hematopoietic stem cell transplantation for curative intent

• Carry out clinical follow-up and surveillance based on the hematologic malignancies

As the world of genetics continues to change, it is crucial that nurses stay up to date on best practices and the newest advances.

Prakash, G., Kaur, A., Malhotra, P., Khadwal, A., Sharma, P., Suri, V., Varma, N., & Varma, S. (2016). Current role of genetics in hematologic malignancies. 

Indian Journal of Hematology and Blood Transfusions, 

32 (1), 18-31. Doi:10.1007/s12288-015-0584-4.

Fonseca, R. (2020). Clinical utility of genetic marks in the management of hematologic malignancies. 

Retrieved on May 4, 2020 from https://www.medscape.org/viewarticle/457536. 

Godley, L. & Shimamura, A. (2017). Genetic predisposition to hematologic malignancies: management and surveillance. 

130 (4), 424-432. DOI: 10.1182/blood/-2017-02-735290.

The Evolution of Genetics Among Hematologic Malignancies

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.”

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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2. The Genetics of Cancer. National Cancer Institute. Updated October 12, 2017. Accessed May 4, 2020. 

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

3. Genetic Testing, Screening, and Prevention for People with a Strong Family History of Colorectal Cancer. American Cancer Society. Updated February 21, 2018. Accessed May 4, 2020. 

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

4. NCCN. Clinical Practice Guidelines in Oncology. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, version 1.2020. Accessed May 4, 2020. 

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

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 2013;18(10):1093-1100. doi:10.1634/theoncologist.2013-0053

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:

Genetics