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Clinical Insights: August 2020

Wednesday, September 02, 2020

Release Date: August 22, 2020
Expiration Date: August 22, 2021


This activity is provided free of charge.

STATEMENT OF NEED

This CE article is designed to serve as an update on cancer detection and prevention and to facilitate clinical awareness of current and new research regarding state-of-the-art care for those with or at risk for cancer.

TARGET AUDIENCE

Advanced practice nurses, registered nurses, and other healthcare professionals who care for cancer patients may participate in this CE activity.
 
EDUCATIONAL OBJECTIVES

Upon completion, participants should be able to:
  • Describe new preventive options and treatments for patients with cancer
  • Identify options for individualizing the treatment for patients with cancer
  • Assess new evidence to facilitate survivorship and supportive care for patients with cancer
ACCREDITATION/CREDIT DESIGNATION STATEMENT

Physicians’ Education Resource®, LLC is approved by the California Board of Registered Nursing, Provider #16669 for 1 Contact Hour.
 
DISCLOSURES/RESOLUTION OF COI

It is the policy of Physicians’ Education Resource®, LLC (PER®) to ensure the fair balance, independence, objectivity, and scientific objectivity in all of our CE activities. Everyone who is in a position to control the content of an educational activity is required to disclose all relevant financial relationships with any commercial interest as part of the activity planning process. PER® has implemented mechanisms to identify and resolve all conflicts of interest prior to release of this activity.The planners and authors of this CE activity have disclosed no relevant financial relationships with any commercial interests pertaining to this activity.

METHOD OF PARTICIPATION
  1. Read the articles in this section in its entirety.
  2. Go to  www.gotoper.com/go/ONN20August
  3. Complete and submit the CE posttest and activity evaluation.
  4. Print your CE Certificate.
OFF-LABEL DISCLOSURE/DISCLAIMER

This CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CE activity is for continuing medical nursing purposes only and is not meant to substitute for the independent medical judgment of a nurse or other healthcare provider relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual authors and do not reflect those of PER®.

Myeloma

Carfilzomib Triplet Regimen Is Not Superior To Standard of Care in Myeloma

By Jessica Skarzynski

The combination of next-generation proteasome inhibitor carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (Decadron) (KRd) did not demonstrate superior progression-free survival (PFS) in newly diagnosed multiple myeloma (NDMM) compared with the current standard-of-care triplet of bortezomib (Velcade), lenalidomide, and dexamethasone (VRd), according to results of the ENDURANCE (E1A11) trial (NCT01863550) presented in a presscast ahead of the 2020 American Society of Clinical Oncology Virtual Scientific Program.1

In the VRd cohort, median PFS was 34.4 months compared with 34.6 months in the KRd arm. Moreover, there were no PFS differences based on age, t(4;14) status, or disease stage.

The randomized phase 3 trial also assessed whether indefinite maintenance with lenalidomide improved overall survival (OS) compared with 2-year maintenance. Data are not yet mature for this end point.For the maintenance phase, patients received lenalidomide at 15 mg on days 1 to 21 every 4 weeks.

Given previous phase 3 trial results showing superior efficacy of carfilzomib compared with bortezomib in the relapsed setting, investigators sought to determine whether carfilzomib could replace bortezomib in the current standard-of-care triplet induction regimen for patients with standard- and intermediate-risk NDMM.

Patients who were enrolled in the trial lacked high-risk features such as chromosome 17p deletion, translocation t(14;16) or t(14;20), plasma cell leukemia, a high-risk profile based on the GEP70 test of 70 genes associated with multiple myeloma aggressiveness. The median age of all patients was 65 years.

The 542 patients in the VRd arm received 12 cycles (3 weeks each) of bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11 (days 1 and 8 for cycles 9-12); lenalidomide at 25 mg on days 1 to 14; and dexamethasone at 40 mg on days 1, 2, 4, 5, 8, 9, 11, and 12.

The 545 patients in the KRd arm received 9 cycles (4 weeks each) of carfilzomib at 36 mg/m2 on days 1, 2, 8, 9, 15, and 16; lenalidomide at 25 mg daily on days 1 to 21; and dexamethasone at 40 mg weekly.

The second of 3 planned interim analyses revealed that substituting carfilzomib for bortezomib did not affect PFS (HR, 1.04; 95% CI, 0.83-1.31; P = .74). Three-year OS rates were also similar in both arms, at 84% in the VRd arm (95% CI, 80%-88%) and 86% in the KRd arm (95% CI, 82%-89%).

In the VRd cohort, 57% of patients did not complete the induction treatment. The most common reasons for leaving the trial were pursuit of an alternative therapy (18%), adverse events (AEs; 17%), patient choice (7%), and disease progression (6%).

In the KRd arm, 39% of patients withdrew from treatment early due to pursuit of an alternative therapy (14%), AEs (10%), patient choice (4%), and disease progression (4%).

Overall, treatment-related AEs (TRAEs) of grade 3 or higher occurred in 59% of VRd and 66% of KRd patients. Nonhematologic TRAEs accounted for the majority, with rates of 41% and 48%, respectively. Although peripheral neuropathy was more common with VRd (53% compared with 24% in KRd; P < .001), the KRd arm experienced a significantly higher rate of cardiopulmonary and renal TRAEs (16% compared with 5% in the VRd arm; P < .001).

Based on these study results, investigators determined that VRd remains the superior triplet induction regimen in this patient population, making it a suitable backbone for 4-drug combinations as well.

Reference

Kumar S, Jacobus SJ, Cohen AD, et al. Carfilzomib, lenalidomide, and dexamethasone (KRd) versus bortezomib, lenalidomide, and dexamethasone (VRd) for initial therapy of newly diagnosed multiple myeloma (NDMM): results of ENDURANCE (E1A11) phase III trial. J Clin Oncol. 2020;38(suppl 18): LBA3. doi:10.1200/JCO.2020.38.18_suppl.LBA3
 

Prostate Cancer

Diagnostic Performance of PSMA-Targeted PET Tracer Excels in the Treatment of Recurrent Prostate Cancer

By Lisa Astor

Imaging with 18F-DCF pyrrolysine (PyL) positron emission tomography (PET)/CT outperformed standard imaging modalities—such as bone scan, CT, MRI, and fluorodeoxyglucose PET—in patients with biochemically recurrent prostate cancer in the phase 3 CONDOR trial (NCT03739684).

“The CONDOR study met its primary end point. Indeed, it well exceeded it. And it demonstrated excellent diagnostic performance of PyL PET in men with biochemically relapsed prostate cancer, even at very low PSA [prostate-specific antigen] values,” said Michael J. Morris, MD, when presenting findings during the 2020 American Society of Clinical Oncology Virtual Scientific Program. “It clearly showed superiority to the standard imaging these men received as part of their local work-ups.”

Prostate-specific membrane antigen (PSMA)–targeting PET has been suggested to be a superior method for imaging in prostate cancer compared with standard imaging modalities, although it is not yet approved for use in the United States. DCFPyL labeled with fluorine 18 (18F-DCFPyL) is an investigational PSMA-targeted PET tracer. PyL is a lysine-linked, urea-based small molecule that targets the extracellular domain of PSMA. For imaging, 9 (±20%) mCi of tracer is administered intravenously as a bolus injection, and then PET imaging is completed 1 to 2 hours later.

CONDOR explored the use of 18F-DCFPyL in patients with rising PSA concentrations. Eligible patients had biochemical recurrence, defined as a PSA of at least 0.2 ng/mL following radical prostatectomy or at least 2 ng/mL above the nadir following radiation therapy or cryotherapy. Eligibility also required negative or equivocal findings on standard-of-care imaging. Patients who were undergoing systemic therapy or who had received androgen deprivation therapy within 3 months were excluded from participating in the trial.1

The primary end point was the correct localization rate (CLR), which is equivalent to positive predictive value with an added requirement of anatomical lesion location matching. The latter was accomplished with an anatomic atlas created before the study. CLR was defined as the percentage of patients with a 1:1 correspondence between 18F-DCFPyL PET/CT and the composite truth standard.

A secondary end point, the percentage of patients who had a change in their treatment plan as a result of the 18F-DCFPyL PET scan, was assessed with pre- and postimaging questionnaires completed by the clinician. Disease detection rate was an exploratory end point.

“Because this patient population has neither available tissue nor informative standard imaging, the end points of this study warrant special scrutiny,” said Morris, clinical director of the Genitourinary Medical Oncology Service and Prostate Cancer Section Head in the Division of Solid Tumor Oncology at Memorial Sloan Kettering Cancer Center in New York, New York. A composite truth standard was used to distinguish true-positive from false-positive test results. For the sake of the trial, the composite truth standard was defined as either evaluable local histopathology findings from surgery or biopsy, informative conventional imaging, or a confirmed PSA response (≥50% decline from baseline) in patients treated with radiotherapy only following 18F-DCFPyL PET/CT imaging. These options, listed in order of importance, were based on feasibility.

For a positive test result, the study assumed that the lower bound of the 95% confidence interval of the CLR would exceed 20% for at least 2 of 3 blinded, independent central readers. This rather modest goal was chosen based on previous studies of patient populations with low PSA values. Additionally, 60% of patients were expected to have positive 18F-DCFPyL PET/CT findings, and 30% of positive PSMA PET scan results were expected to be confirmed per the composite truth standard.

All patients who had a positive result on standard imaging were required to undergo a confirmatory study to define the composite truth standard. To further minimize the risk of bias, 2 adjudicators examined the composite truth standard and a statistician compared the outcomes to arrive at a final true-/false-positive verdict.

A total of 208 men were dosed with 18F-DCFPyL in the study. These patients had a median age of 68 years (range, 43-91) and had been diagnosed a median of 71 months (range, 3-356) prior. Nearly half (49.5%) of all patients had undergone radical prostatectomy only, 35.6% had undergone radical prostatectomy and radiation therapy, 14.9% had received only radiotherapy, and 27.9% had received at least 1 systemic therapy for their prostate cancer. Almost three-fourths of the men (73.6%) had a total Gleason score below 8.

The median PSA was 0.8 ng/mL (range, 0.17-98.45), and 31.2% of patients had a PSA of at least 2.0 ng/mL.

“The PSA values were representative of this group of men. As expected, the median PSA of this population was quite low at 0.8,” Morris commented. “And generally, these are the values at which most decisions regarding salvage therapy and therapeutic plans are made.”

Across the 3 readers, the rate of positive 18F-DCFPyL scans ranged from 59.1% to 65.9%; in 11.5% to 15.9% of cases, the detection rate was unevaluable due to the composite truth standard not being submitted or suggesting a false-negative finding.

The CLR, or the rate of true positives divided by the sum of true and false positives, was 84.8% (95% CI, 77.8%-91.9%), 85.6% (95% CI, 78.8%-92.3%), and 87.0% (95% CI, 80.4%-93.6%) for the 3 readers.

“For every reader, the CLR was excellent. The lower bound of the 95% confidence interval was well in excess of the 20% benchmark,” Morris said. High CLRs were found across all PSA levels, with median values of 73.3% (95% CI, 51.0%-95.7%) for patients with a PSA below 0.5 ng/mL and 96.4% (95% CI, 89.6%-100%) for those with a PSA of at least 5 ng/mL.

Even at the lowest PSA levels (<0.5 ng/mL), 18F-DCFPyL had a median disease detection rate of 36.2% (95% CI, 24.9%-47.6%). In patients with a PSA of at least 5 ng/mL, the detection rate was 96.7% (95% CI, 90.2%-100%).

The 18F-DCFPyL PET/CT scan led to a change in the management plan of 63.9% of evaluable patients, with 78.6% of changes due to positive scans and 21.4% due to negative scans. The goal of disease management changed from a noncurative approach to salvage local therapy for 21.0% of the men, from salvage local therapy to systemic therapy in 28.3%, from observation alone to initiation of therapy in 23.9%, and from planned treatment to observation alone in 4.4%.

“The results demonstrated that actionable information was furnished to clinicians in order to make clinically significant decisions,” Morris said, although optimized treatment patterns still need to be further defined.

No significant safety issues were associated with 18F-DCFPyL. Only 3 patients had treatment-related adverse events, with 1 case each of fatigue, hypersensitivity, and headache. Hypersensitivity, the only grade 3 event reported, was observed in a patient with a significant history of allergy. This safety profile was considered similar to that seen in the OSPREY trial.

Reference

1. Progenics reports results of phase 2/3 trial of PSMA PET imaging agent PyL for the detection of prostate cancer. News release. Progenics Pharmaceuticals Inc; October 5, 2018. Accessed May 30, 2020. https://bit.ly/2BgbeNg
 
Kidney Cancer

Efficacy of Cabozantinib in Previously Treated RCC Is Consistent Regardless of Prior Therapy


By Audrey Sternberg

A pooled analysis of clinical trial data revealed that systemic therapy with cabozantinib (Cabometyx) in advanced renal cell carcinoma (RCC) induced reliable responses for patients regardless of whether or not they had received prior immunotherapy. Patients from both the phase 3 METEOR (NCT01865747) and the phase 2 Japanese C2001 (NCT03339219) trials comprised the efficacy population whose results were presented as part of the 2020 American Society of Clinical Oncology Virtual Scientific Program.

Both groups had similar rates of progression-free survival at 6 months, with 65.5% of patients in the immune-oncology (IO )group and 58.3% of those in the non-IO group remaining free of disease progression or death. The median progression-free survival in months for both groups were not reached versus 7.4, respectively.

More than 90% of patients were alive at 6 months in both the IO (90.8%) and the non-IO (90.6%) groups. Median overall survival was 19.5 months (95% CI, 12.4-not reached) in patients with prior IO and 21.9 months (95% CI, 18.7-23.7) in those without IO.

Tumor response by independent review committee was similar between patients who were treated with prior immunotherapy and those without. In the prior IO group (n = 33), the objective response rate was 21.2% (95% CI, 9.0%-38.9%). Similar rates were observed in patients who had never received IO (n = 332), at 17.2% (95% CI, 13.3%-21.7%). In both groups, the objective response rate was made up exclusively of partial responses.

Rates of stable disease were similar in the 2 groups, at 54.5% of patients in the prior IO group and 66.6% in the non-IO group. Corresponding clinical benefit rates, or the rate of responses plus stable disease, were 75.8% (95% CI, 57.7%-88.9%) and 83.7% (95% CI, 79.3%-87.5%).

“Results of this pooled analysis suggest that cabozantinib is effective regardless of previous treatments in patients with [advanced] RCC,” the study authors, who were led by Mototsugu Oya, MD, PhD, of the Department of Urology of Keio University School of Medicine in Tokyo, Japan, wrote in their poster.

All patients experienced treatment-emergent adverse effects (TEAEs) and the rate of grade 3 or greater events was comparable between the 2 groups. Treatment discontinuation due to TEAEs occurred in 12.1% who had prior IO and 14.4% of those who never received IO. Corresponding rates of serious TEAEs were 51.5% and 46.2%. The investigators reported that most TEAEs were manageable with dose modifications.

A greater proportion of those treated in the non-IO group experienced diarrhea (75.7% vs 54.5% with prior IO) and nausea (36.4% vs 50.8%). Patients in the IO group experienced a greater proportion of palmar-plantar erythrodysesthesia syndrome (57.6% vs 44.4% with no prior IO) and proteinuria (30.3% vs 16.5%). Notably, there were no differences in TEAEs typically associated with IO treatment, such as pneumonitis, endocrinopathy, or infusion-related reactions.

Baseline patient characteristics were well balanced between the 2 arms, with a slightly higher proportion of patients considered to have poor-risk disease (by International Metastatic Renal Cell Carcinoma Database Criteria) being in the prior IO group (24.2% vs 16.0% with no prior IO). The median patient age in both groups was 62 years and most patients were men. Karnofsky performance status was 80% to 100% in 93.9% and 91.6% of patients in the IO and non-IO groups, respectively. At least half of the patients in each group had 3 or more involved organs per independent review committee.

The median number of prior systemic therapy regimens was higher in the IO group at 3 versus 1 in the non-IO group. Patients in the IO group were more likely to have received greater than 1 prior vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor. Patients receiving 2 prior VEGFR inhibitors accounted for 51.5% of those in the IO group and 22.6% of those in the non-IO group; 9.1% and 3.3% of patients, respectively, had 3 or more prior VEGFR inhibitors. The most common prior VEGFR inhibitors received were sunitinib (Sutent), pazopanib (Votrient), and axitinib (Inlyta). In the IO group, the most common prior IO therapy received was nivolumab (Opdivo) in 84.8% of patients.

The pooled analysis included patients from both clinical trials who received oral cabozantinib 60 mg daily. Inclusion criteria for both studies included advanced or metastatic clear-cell RCC, the receipt of prior VEGFR inhibitor therapy with disease progression within 6 months, and a Karnofsky performance status of 70% or greater. There were no limits on the number of prior therapies received, and patients with a history of exposure to PD-1/L1/L2 inhibitors were eligible.

Out of 331 patients treated with cabozantinib in the METEOR trial, 18 were included in the prior IO group and 313 were in the non-IO cohort. Out of 35 patients treated in the C2001 study, prior IO was used in 15 versus 20 who never received IO. This resulted in an efficacy analysis population of 365 patients.

Reference

Oya M, Tamada S, Tatsugami K, et al. A pooled analysis of the efficacy and safety of cabozantinib post immunotherapy in patients with advanced renal cell carcinoma. J Clin Oncol. 2020;38(suppl):5089. doi:10.1200/JCO.2020.38.15_suppl.5089

 
Hodgkin Lymphoma

Pembrolizumab Shows Superior PFS in Relapsed/Refractory Classic Hodgkin Lymphoma


By Kevin Wright

Treatment with pembrolizumab (Keytruda) induced a 4.9-month progression-free survival (PFS) benefit over brentuximab vedotin (BV; Adcetris) in patients with relapsed/refractory classic Hodgkin lymphoma, according to findings presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program.1

“Pembrolizumab should be considered the preferred treatment option and the new standard of care in relapsed/refractory classical Hodgkin’s lymphoma in patients [who] have relapsed post autologous stem cell transplant or are ineligible for autologous stem cell transplant,” said lead author John Kuruvilla, MD, of the Princess Margaret Cancer Centre in Toronto, Canada.

Treatment with pembrolizumab showed an increase in PFS of 4.9 months (13.2 months vs 8.3 months; HR, 0.65; 95% CI, 0.48-0.88; P = .00271), and the benefit extended to several key subgroups, including patients ineligible for autologous stem cell transplant (auto-SCT; HR, 0.61; 95% CI, 0.42-0.89), those with primary refractory disease (HR, 0.52; 95% CI, 0.33-0.83), and those who were BV naïve (HR, 0.67; 95% CI, 0.49-0.92).

A total of 304 patients were enrolled in the randomized, open-label, phase 3 KEYNOTE-204 study (NCT02684292), with 151 patients assigned to the pembrolizumab arm and 153 assigned to receive BV. All patients were aged at least 18 years and had either relapsed after auto-SCT or were ineligible for auto-SCT. Both BV-naïve and BV-exposed patients were eligible for the trial.

The primary end points of the study were PFS per blinded independent central review according to the 2007 International Working Group response criteria, including clinical and imaging data after auto-SCT or allogeneic SCT, along with overall survival.

The objective response rate was higher for pembrolizumab (65.6%; 95% CI, 57.4-73.1) compared with the BV arm (54.2%; 95% CI, 46.0-62.3; P = .0225), with 24.5% of patients in the pembrolizumab arm achieving a complete response and 41.1% seeing a partial response. Duration of response also favored the pembrolizumab arm, with an increase of 6.9 months compared with BV (20.7 months vs 13.8 months). The data cutoff was January 16, 2020.

Safety was consistent with the known profile of each agent. Serious treatment-related adverse events (TRAEs) were slightly more common among patients receiving pembrolizumab (16.2%; n = 24) compared with the BV group (10.5%; n = 16).

The most commonly reported TRAEs in the pembrolizumab arm were hypothyroidism (15.5%), pyrexia (12.8%), pruritis (10.8%), and fatigue (8.8%). Nineteen patients (12.8%) receiving pembrolizumab discontinued treatment due to TRAEs compared with 25 (16.4%) in the BV arm. There was 1 death due to a TRAE; the patient, who was receiving pembrolizumab, died from grade 5 pneumonia.

The rate of immune-mediated adverse events was higher in the pembrolizumab arm, with the most common being hypothyroidism (18.9%) and pneumonitis (10.8%, half of which were grade 3/4). Of the 16 patients in this arm who reported pneumonitis, 15 required treatment with corticosteroids, which led to resolution in 12 patients.

Reference

1. Kuruvilla J, Ramchandren R, Santoro A, et al. KEYNOTE-204: randomized, open-label, phase III study of pembrolizumab (pembro) versus brentuximab vedotin (BV) in relapsed or refractory classic Hodgkin lymphoma (R/R cHL). J Clin Oncol. 2020;38(suppl 15): 8005. doi:10.1200/JCO.2020.38.15_suppl.8005

Nurse Perspective

Mariam Odisho, RN
UCLA Bowyer Oncology Center Los Angeles, California


DURING INFUSION [WITH PEMBROLIZUMAB(KEYTRUDA)], nurses should look out for any allergic reaction or anaphylaxis, which [is something] you should do whenever any new drug is introduced into the body. Then there are common late effects that can happen 6 to 12 weeks into treatment. We use the LEGS acronym [and look for toxicity] in the liver, endocrine system, gastrointestinal system, and skin.

It is important to tell patients that they are on an immunotherapy agent, not chemotherapy— a common misconception. I give patients highlighted handouts and explain what the drug is doing in their body. So for example, chemotherapy completely wipes you out. It gets rid of the good cells and the bad cells. Monoclonal antibodies, like pembrolizumab, are activating the immune response and ramping up [immune] cells, activating an immune response. I tell patients that they’re not going to have the adverse events of chemotherapy— they’re not going to lose their hair. I’ll go over that with patients and the [adverse] effects to look for, such as rash, diarrhea, or difficulty breathing.


 
Lynch Syndrome

Microsatellite Instability Status Linked to Lynch Syndrome Found in Broad Array of Cancers


By Kristie L. Kahl

The finding of microsatellite instability (MSI) in a tumor indicates increased likelihood of Lynch syndrome, a hereditary cancer predisposition condition. Because colorectal and endometrial tumors are most frequently associated with Lynch syndrome, testing has typically not been emphasized for patients with other types of cancer.

However, according to results of a large genomic study,1 45% of patients with Lynch syndrome with MSI-high (MSI-H) or MSI-indeterminate (MSI-I) non-colorectal/endometrial tumors would not qualify for germline genetic testing under traditional criteria. These findings reveal that Lynch syndrome is associated with a wider range of cancer types than previously assumed and support germline genetic testing in all patients with MSI-H tumors.

MSI, a genomic marker that indicates a defect in a cell’s ability to repair damaged DNA, results in the accumulation of mutations and is a hallmark of Lynch syndrome–associated cancers. Lynch syndrome, which accounts for approximately 3% of all colorectal and endometrial cancers, is an autosomal dominant inherited cancer predisposition syndrome caused by germline mutations in the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, PMS2, and EPCAM.2

MSI testing is recommended for patients with colorectal and endometrial cancers as an initial screen for Lynch syndrome; however, the prevalence of Lynch syndrome across heterogeneous MSI-H and MMR-deficient tumors was unknown.

Therefore, investigators analyzed 15,045 tumor samples collected from patients with more than 50 different types of advanced cancer using a comprehensive next-generation sequencing–based test called MSK-IMPACT. MSI status was then determined with a computational algorithm called MSIsensor, with scores less than 3, from 3 to less than 10, and 10 or greater designating microsatellite-stable (MSS), MSI-I, and MSI-H status, respectively.

Overall, most tumors were found to be MSS (93.2%; n = 14,020), whereas 4.6% (n = 699) were MSI-I, and 2.2% (n = 326) were MSI-H. Analyses of germline mutations identified Lynch syndrome in 0.3%, 1.9%, and 16.3% of cases in the MSS, MSI-I, and MSI-H groups, respectively (P < .001).

MSI-H status was identified in 25% of small bowel, 16% of endometrial, 14% of colorectal, and 6% of gastric cancers. However, of the 66 patients with MSI-H/MSI-I tumors who were found to have germline MMR mutations diagnostic of Lynch syndrome, half (n = 33) had cancer types not previously, or rarely, linked to the syndrome, including urothelial cancer (n = 12); pancreatic cancer (n = 5); prostate cancer (n = 3); sarcoma and small bowel, gastric, and adrenocortical cancers (n = 2 each); and mesothelioma, melanoma, ovarian germ cell cancer, CNS tumors, and other (n = 1 each).

“Our study supports that MSI-high is predictive of Lynch syndrome across tumor types,” said senior study author Zsofia Kinga Stadler, MD, clinic director of the Clinical Genetics Service and medical oncologist at Memorial Sloan Kettering Cancer Center, New York, New York. “Our study also supports that the spectrum of cancers associated with Lynch syndrome seems to be much broader than previously thought.”

Among the 33 patients with cancers not typically linked to Lynch syndrome, 45% did not meet germline genetic testing criteria based on family or personal cancer history. In addition, these patients had lower MSIsensor scores, and their tumors were more likely to be MSI-I (30.3% of non-colorectal/endometrial cancers vs. 9.1% of colorectal/endometrial cancers; P = .03).

As expected, most patients with Lynch syndrome had MSI-H/MSI-I tumors; however, a substantial minority (36%; 37 of 103) were MSS. Germline testing revealed that 78% of the MSS cases were accompanied by mutations in the MSH6 and PMS2 genes, which are known to have lower penetrance; meanwhile, 71% of the MSI-H/MSI-I cases were associated with higher-penetrance MLH1, MSH2, or EPCAM mutations (P < .001).

Similar findings were generated from an analysis of genomic mutational signatures, characteristic combinations of mutation types known to be associated with specific carcinogenesis-related molecular events, such as MMR deficiency. Among patients with Lynch syndrome, 88% of MSI-H/MSI-I tumors had MMR deficiency signatures, whereas 89% of MSS tumors did not (P < .001). The combination of the above single-gene and signature results led investigators to speculate that the observed germline MMR gene mutations may have been an incidental finding, rather than the cause of cancer, in MSS tumors.

Lastly, immunohistochemistry was performed in 86.4% (57 of 66) of MSI-I/MSI-H tumor samples from patients with Lynch syndrome, and the results confirmed deficient expression of MMR proteins in nearly all (98.2%) of those tumors.

“Our study suggests that an MSI-high signature, regardless of tumor type and irrespective of the family history, should prompt germline genetic assessment for the evaluation of Lynch syndrome,” Stadler said. “This will result in an increased ability to recognize Lynch syndrome, not only in our patients [with cancer] but also in at-risk family members who may benefit from genetic testing for Lynch and subsequent enhanced surveillance and risk reduction measures.”

References

1. Latham A, Srinivasan P, Kemel Y, et al. Microsatellite instability is associated with the presence of Lynch syndrome pan-cancer. J Clin Oncol. 2019;37(4):286-295. Published correction appears in J Clin Oncol. 2019;37(11):942. doi:10.1200/JCO.18.00283
2. Strafford JC. Genetic testing for Lynch syndrome, an inherited cancer of the bowel, endometrium, and ovary. Rev Obstet Gynecol. 2012;5(1):42-49. doi:10.3909/riog0187

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