Category: Hem/Onc Updates

Universal Genetic Testing Detects More Inherited Mutations Than Guideline Based Approach

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SUMMARY: Hereditary factors play an important role in the risk of developing several cancers. Therefore, identification of a germline predisposition can have important implications for treatment decision making, risk-reducing interventions, cancer screening for early diagnosis, and germline testing of unaffected relatives. Previously published studies have been biased by estimating the prevalence of germline cancer susceptibility in patients with breast, prostate, and colorectal cancer from registry populations, genetic testing companies, and high-risk cancer clinics. Very few studies have compared the prevalence of germline findings in patients with cancer, not selected by practice guidelines, and the impact of universal testing strategy for inherited germline variants in patients with cancer has remained unclear. The purpose of this present study was to determine if universal genetic testing in patients with cancer identifies more inherited cancer predisposition variants than a guideline-based approach, and also find out if there is an association between universal genetic testing and clinical management.

The authors in this prospective, multicenter cohort study, assessed germline genetic alterations among patients with solid tumors, receiving care at Mayo Clinic Cancer Centers and Mayo Clinic Health System community oncology practice in the US, between April 2018, and March 2020, as a part of 2 year Interrogating Cancer Etiology Using Proactive Genetic Testing (INTERCEPT) program. Patients were NOT selected based on cancer type, stage of disease, family history of cancer, race/ethnicity, age at diagnosis, multifocal tumors, or personal history of multiple malignant neoplasms. Clinical, demographic, and family history data and pathologic information were collected on all patients from medical records or self-administered questionnaires.Single-Gene-versus-MultiGene-Testing

Germline sequencing using a Next-Generation Sequencing panel of 84 genes was offered at no cost, utilizing the Invitae Multi-Cancer Panel. Whole Genome Sequencing, deletion and duplication analysis, and variant interpretation were performed and Pathogenic Germline Variants (PGV) were classified as High (relative risk more than 4), Intermediate (relative risk, 2-4), or Low (relative risk less than 2) penetrance, or recessive medically actionable variants. Test results were disclosed to the patient, and those with Pathogenic Germline Variants (PGVs) were invited for genetic counseling.

The authors compared multi-gene panel testing with guideline-based testing, using guidelines from the National Comprehensive Cancer Network (NCCN) and the National Society of Genetic Counselors (NSGC) and the American College of Medical Genetics (ACMG), to determine whether genetic testing was indicated for a particular patient. For patients who met the guidelines, the only genes tested were those recommended by the tumor-specific guideline. This study included patients with a broad mix of cancer types at various stages. The final analytic cohort consisted of 2984 patients, out of the 3095 patients enrolled in the study. The mean patient age was 61 years, 53% were male and 44% of patients had Stage IV disease at the time of genomic analysis. A family history of cancer in a first-degree relative was reported in 34% of the participants. The goals of this study were to examine the proportion of Pathogenic Germline Variants (PGVs) detected with a universal testing strategy compared with a targeted testing strategy based on clinical guidelines, as well as uptake of cascade genetic testing in families, when offered at no cost.

It was noted that Pathogenic Germline Variants (inherited mutation in a gene) associated with the development of their cancer was found in 13.3% of patients, including moderate and high-penetrance cancer susceptibility genes. In this study, 1 in 8 patients had a PGV, half of which would not have been detected using a guideline-based testing approach. Of those with a high-penetrance PGVs, 28.2% had modifications in their treatment, based on the finding. About 6.4% had incremental clinically actionable findings that would not have been detected by phenotype or family history-based testing criteria. However, only 17.6% of participants with PGVs had family members undergoing no-cost cascade genetic testing when offered.

It was concluded that in this large, prospective, multicenter cohort study with a broad mixture of cancer types and stages, universal multigene panel testing was associated with increased detection of clinically actionable heritable variants, compared with a targeted testing strategy based on clinical guidelines. Approximately 30% of patients with high-penetrance variants had modifications in their treatment, suggesting that wider clinical implementation of universal genetic testing and acceptance in oncology practice, may be beneficial.

Comparison of Universal Genetic Testing vs Guideline-Directed Targeted Testing for Patients With Hereditary Cancer Syndrome. Samadder NJ, Riegert-Johnson D, Boardman L, et al. JAMA Oncol. Published online October 30, 2020. doi:10.1001/jamaoncol.2020.6252

LYNPARZA® Superior to Chemotherapy in BRCA Mutated Platinum Sensitive Advanced Ovarian Cancer

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SUMMARY: It is estimated that in the United States, approximately 21,750 women will be diagnosed with ovarian cancer in 2020 and 13,940 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, and accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5 year Overall Survival rate of about 20-30%.

DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The two vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 are tumor suppressor genes and they recognize and repair double strand DNA breaks via Homologous Recombination (HR) pathway. Homologous Recombination is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity.

Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HR repair pathway. At least 15 genes are involved in the Homologous Recombination Repair (HRR) pathway including BRCA1 and BRCA2 genes. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13, and they regulate cell growth and prevent abnormal cell division and development of malignancy. Mutations in BRCA1 and BRCA2 account for about 20-25% of hereditary breast cancers 15% of ovarian cancers, in addition to other cancers such as Colon and Prostate. BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic).MOA-of-LYNPARZA

The PARP (Poly ADP Ribose Polymerase) family of enzymes include PARP1 and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive. LYNPARZA® is a PARP inhibitor that traps PARP onto DNA at sites of single-strand breaks, preventing their repair and generating double-strand breaks that cannot be repaired accurately in tumors harboring defects in Homologous Recombination Repair pathway genes, such as BRCA1 or BRCA2 mutations, leading to cumulative DNA damage and tumor cell death.

Previously published studies demonstrated a durable response to LYNPARZA® administered as treatment (rather than maintenance), in women with heavily pretreated relapsed ovarian cancer and a germline BRCA mutation, with an Objective Response Rate (ORR) of 42% in the subgroup of patients with platinum-sensitive disease, who had received at least 3 prior chemotherapy regimens. Single-agent nonplatinum chemotherapy is often used in heavily pretreated women with relapsed ovarian cancer. The authors conducted this study to evaluate whether LYNPARZA® monotherapy improves outcomes, compared with physician’s choice single-agent nonplatinum chemotherapy, in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA mutation, who have received at least 2 prior lines of platinum-based chemotherapy.

SOLO3 is an International, randomized, controlled, open label Phase III trial, that compared LYNPARZA® with non-platinum chemotherapy, in patients with platinum sensitive, relapsed ovarian cancer, and a germline BRCA1/2 mutation. This study included 266 patients who were randomly assigned 2:1 to LYNPARZA® 300 mg orally given twice a day (N=178) or physician’s choice of single-agent chemotherapy (N=88), which could be either Pegylated Liposomal Doxorubicin (PLD) 50 mg/m2 IV on day 1 every 4 weeks, Paclitaxel 80 mg/m2 IV on days 1, 8, 15, and 22 every 4 weeks, Gemcitabine 1000 mg/m2 IV on days 1, 8, and 15 every 4 weeks or Topotecan 4 mg/m2 IV on days 1, 8, and 15 every 4 weeks. Eligible patients had relapsed high-grade serous or high-grade endometrioid ovarian cancer, primary peritoneal cancer, and/or fallopian tube cancer, with at least 1 measurable and/or nonmeasurable lesion, that could be accurately assessed at baseline, by CT or MRI, and was suitable for repeated evaluation. Patients had received at least 2 prior lines of platinum-based chemotherapy for ovarian cancer and were platinum sensitive (progression more than 6 months after the end of the last platinum-based regimen). Treatment groups were well balanced and the median patient age was 59 years. The Primary end point was Objective Response Rate (ORR) in those with measurable disease, as assessed by Blinded Independent Central Review (BICR). The key Secondary end point was Progression Free Survival (PFS) assessed by BICR in the intent-to-treat population.

It was noted that ORR was significantly higher in the LYNPARZA® group than in the chemotherapy group (72.2% versus 51.4%; Odds Ratio=2.53; P=0.002), suggesting a 2.53 times higher likelihood of responding to LYNPARZA®, than to chemotherapy. In the subgroup who had received 2 prior lines of treatment, the ORR with LYNPARZA® was 84.6% and 61.5% with chemotherapy (Odds Ratio= 3.44), suggesting a 3.44 times higher likelihood of responding to LYNPARZA®, than to chemotherapy. The median time to onset of response was 2 months with LYNPARZA®, versus 3.5 months with chemotherapy, and the median Duration of Response was 9.4 months and 10.2 months respectively. The PFS also significantly favored LYNPARZA® versus chemotherapy (13.4 versus 9.2 months; HR=0.62; P=0.013). Adverse events were consistent with the established safety profiles of LYNPARZA® and chemotherapy. The most common Grade 3 or more adverse events were anemia in the LYNPARZA® group and PPE (Palmar-Plantar Erythrodysesthesia) and neutropenia in the chemotherapy group.

It was concluded that treatment with LYNPARZA® resulted in statistically significant and clinically relevant improvements in Objective Response Rate and Progression Free Survival, compared with nonplatinum chemotherapy, in patients with germline BRCA-mutated, platinum-sensitive, relapsed ovarian cancer, who had received at least 2 prior lines of platinum-based chemotherapy. This chemotherapy-free treatment option will be welcome news for patients with germline BRCA-mutated advanced ovarian cancer.

Olaparib Versus Nonplatinum Chemotherapy in Patients With Platinum-Sensitive Relapsed Ovarian Cancer and a Germline BRCA1/2 Mutation (SOLO3): A Randomized Phase III Trial. Penson RT, Valencia RV, Cibula D, et al. J Clin Oncol. 2020;38:1164-1174.

Single Agent Trilaciclib Prevents Multilineage Myelosuppression during Chemotherapy

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SUMMARY: Chemotherapy remains one of the mainstays of cancer treatment. However, chemotherapy-induced damage of Hematopoietic Stem and Progenitor Cells (HSPC) causes multi-lineage myelosuppression. Currently, available therapies such as Granulocyte-Colony Stimulating Factors (G-CSF) and Erythropoiesis-Stimulating Agents (ESAs) prevent the myelosuppressive effects of chemotherapy in only one lineage. Therapeutic agents that lead to protection of multiple lineages simultaneously would be clinically meaningful.

Trilaciclib is a highly potent, selective, and reversible, intravenous, Cyclin-Dependent Kinase 4 and 6 (CDK 4/6) inhibitor, that transiently maintains G1 cell cycle arrest of Hematopoietic Stem and Progenitor Cells (HSPC), and protects them from damage by cytotoxic chemotherapy. Chemotherapy-induced damage of Hematopoietic Stem and Progenitor Cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib proactively preserves HSPC and immune system function during chemotherapy (myelopreservation). Preclinical studies have demonstrated that Trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery. Additionally, Trilaciclib enhances immune response, and preserves immune system function.

Small Cell Lung Cancer (SCLC) was chosen as the testing platform, to explore the potential myelopreservation benefit of Trilaciclib for the following reasons: 1) Cytotoxic chemotherapy for SCLC is notable for its myelotoxicity. 2) SCLC tumor cells replicate independent of CDK4/6, through the obligate loss of Retinoblastoma (RB1), allowing assessment of Trilaciclib’s effects on the host, without any potential direct effects on the tumor. 3) SCLC is a chemosensitive tumor, and provides an optimal setting to demonstrate that Trilaciclib does not antagonize chemotherapy efficacy.

The authors in this publication, pooled data from three randomized, double-blind, placebo-controlled Phase II trials, in patients with Extensive-Stage Small Cell Lung Cancer (ES-SCLC), to understand the effects of Trilaciclib on specific myelosuppression endpoints, with greater statistical precision. Individual results from these three randomized trials have previously been reported. In this pooled analysis, 123 patients received Trilaciclib along with chemotherapy (N=123), and 119 patients received Placebo along with chemotherapy (N=119). The median age in both treatment groups was 64 years. The objectives of this pooled data analysis was to summarize the utilization of G-CSFs, ESAs and RBC transfusions, and hospitalizations due to Chemotherapy Induced Myelosuppression or sepsis, as well as explore the relationship between supportive care interventions and the myelopreservation benefits of Trilaciclib.

In the first study (NCT02499770), patients with newly diagnosed ES-SCLC received Trilaciclib 240 mg/m2 or Placebo IV, given daily on days 1 to 3, prior to chemotherapy, of each 21-day chemotherapy cycle with Etoposide and Carboplatin. In the second trial (NCT03041311), patients with newly diagnosed ES-SCLC received Trilaciclib 240 mg/m2 or Placebo IV, given daily on days 1 to 3, prior to chemotherapy, of each 21-day chemotherapy cycle with Etoposide, Carboplatin and Atezolizumab (TECENTRIQ®), followed by single-agent Atezolizumab alone, every 21 days. In the third study (NCT02514447), patients with previously treated ES-SCLC in the second or third line setting, received Trilaciclib 240 mg/m2 or Placebo IV daily, prior to Topotecan 1.5 mg/m2 IV given daily on days 1 to 5 of each 21-day cycle. The Primary outcome measures included percentage of patients with Severe (Grade 4) Neutropenia as well as duration of Severe Neutropenia. Supportive intervention endpoints included percentage of patients with RBC transfusions on or after week 5, and number of RBC transfusion events on or after week 5, as well as percentage of patients receiving ESAs. This study also explored the percentage of patients with hospitalizations due to Chemotherapy Induced Myelosuppression (neutropenia, anemia, thrombocytopenia) or sepsis, as well as incidence of hospitalizations due to Chemotherapy Induced Myelosuppression or sepsis, per 100 cycles.

It was noted that fewer patients receiving Trilaciclib had Severe Neutropenia (11.4% versus 52.9%) or Grade 3/4 anemia (20.3% versus 31.9%), compared to Placebo, respectively, and the use of supportive care interventions such as G-CSF and ESAs was significantly reduced. Hospitalizations due to Chemotherapy Induced Myelosuppression or sepsis occurred in significantly fewer patients and significantly less often among patients receiving Trilaciclib prior to chemotherapy, compared to those who received Placebo. Trilaciclib reduced the percentage of patients with Severe Neutropenia and duration of Severe Neutropenia, regardless of G-CSF administration. The proportion of patients receiving RBC transfusions was consistently lower with each cycle, among patients receiving Trilaciclib, whereas RBC transfusions in the Placebo group almost doubled over time.

It was concluded that Trilaciclib prior to chemotherapy significantly and meaningfully reduced Chemotherapy Induced Myelosuppression and the need for supportive care interventions, for the management of Severe Neutropenia and Grade 3/4 anemia, in patients with ES-SCLC. Chemotherapy-induced Severe Neutropenia was reduced with Trilaciclib, irrespective of G-CSF administration.

Trilaciclib Reduces the Need for Growth Factors and Red Blood Cell Transfusions to Manage Chemotherapy-Induced Myelosuppression. Ferrarotto R, Anderson I, Medgyasszay B, et al. Presented at: IASLC 2020 North America Conference on Lung Cancer; October 16-17, 2020.

Adjuvant TAGRISSO® in Resected EGFR-Mutated Non-Small Cell Lung Cancer

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations and 90% of these mutations are either Exon 19 deletions or L858R substitution mutation in Exon 21. Approximately 25% of patients with EGFR mutated NSCLC have brain metastases at diagnosis, increasing to approximately 40% within two years of diagnosis. The presence of brain metastases often reduces median survival to less than eight months. EGFR-Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib), IRESSA® (Gefitinib) and GILOTRIF® (Afatinib), have demonstrated a 60-70% response rate as monotherapy when administered as first line treatment, in patients with metastatic NSCLC, who harbor the sensitizing EGFR mutations. However, majority of these patients experience disease progression within 9-14 months. This resistance to frontline EGFR TKI therapy has been attributed to the most common, acquired T790M “gatekeeper” point mutation in EGFR, identified in 50-60% of patients.

TAGRISSO® (Osimertinib) is a highly selective third-generation Epidermal Growth Factor Receptor (EGFR) TKI presently approved by the FDA, for the first-line treatment of patients with metastatic NSCLC, whose tumors have Exon 19 deletions or Exon 21 L858R mutations, as well as treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, whose disease has progressed on or after EGFR-TKI therapy. Further, TAGRISSO® has higher CNS penetration and is therefore able to induce responses in 70-90% of patients with brain metastases. Among patients with metastatic, EGFR-mutant NSCLC, first-line treatment with TAGRISSO® significantly improved median Overall Survival, compared with TARCEVA® and IRESSA®, and should therefore be considered the preferred regimen.

Surgical resection is the primary treatment for approximately 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. These patients are often treated with platinum-based adjuvant chemotherapy to decrease the risk of recurrence. Nonetheless, 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

ADAURA is a global, double-blind, randomized Phase III study, which assessed the efficacy and safety of TAGRISSO® versus placebo in patients with Stage IB–IIIA EGFR mutated NSCLC, after complete tumor resection and adjuvant chemotherapy, when indicated. In this study, 682 patients with completely resected Stage IB, II, IIIA NSCLC, with or without postoperative adjuvant chemotherapy, were randomly assigned 1:1 to receive either TAGRISSO® 80 mg orally once daily (N=339) or placebo (N=343) once daily, for up to 3 years. Eligible patients had an ECOG Performance Status of 0 or 1, with confirmed EGFR mutations (Exon 19del or L858R). Treatment groups were well balanced and patients were stratified by Stage (IB/II/IIIA), mutation type (Exon 19del/L858R), and race (Asian/non-Asian).
Most patients with Stage II to IIIA disease (76%) and approximately a quarter of the patients with Stage IB disease (26%) received adjuvant platinum-based chemotherapy. The Primary endpoint was Disease Free Survival (DFS) in Stage II–IIIA patients. Secondary endpoints included DFS in the overall population of patients with Stage IB to IIIA disease, Overall Survival (OS) and safety. Following Independent Data Monitoring Committee recommendation, the trial was unblinded early, due to efficacy. The authors reported the results from the unplanned interim analysis.

It was noted that in the patients with Stage II/IIIA disease, the DFS had not been reached with TAGRISSO® versus 19.6 months with placebo (HR=0.17; P<0.001). This was equal to an 83% reduction in the risk of recurrence or death, indicating a significantly longer DFS among patients in the TAGRISSO® group, compared to those in the placebo group. The 2-year DFS rate in this patient group with TAGRISSO® was 90% versus 44% with placebo.

In the overall population, which included Stage IB to IIIA disease, the median DFS was not reached with TAGRISSO® versus 27.5 months with placebo (HR=0.20; P<0.001). This Hazard Ratio equaled an 80% reduction in the risk of disease recurrence or death among patients in the TAGRISSO® group compared to those in the placebo group. The 2-year DFS rate in the overall population was 89% with TAGRISSO® versus 52% with placebo.

The benefit favoring TAGRISSO® with respect to DFS was observed consistently across all predefined subgroups including disease Stages IB, II, and IIIA and use or nonuse of adjuvant chemotherapy. The benefit with TAGRISSO® was greater at more advanced stages of disease (among patients with Stage IIIA disease, the overall HR was 0.12, among those with Stage II disease, the HR was 0.17, and among those with Stage IB disease, the HR was 0.39). At 2 years, 98% of the patients in the TAGRISSO® group and 85% of the patients in the placebo group were alive without CNS-related disease (HR for CNS disease recurrence or death=0.18). This indicated an 82% reduction in the risk of CNS disease recurrence or death with TAGRISSO®. The Overall Survival data were immature at the time of this interim analysis. Adverse Events were consistent with the known safety profile of TAGRISSO®.

The authors concluded that adjuvant TAGRISSO® is the first targeted agent in a global randomized trial, to show a statistically significant and clinically meaningful improvement in Disease Free Survival, among patients with Stage IB/II/IIIA EGFR mutation-positive NSCLC, and provides an effective new treatment strategy for this patient group.

Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer. Wu Y-L, Tsuboi M, He J, et al. for the ADAURA Investigators. N Engl J Med 2020; 383:1711-1723.

ASCO Guideline on Treatment of Metastatic Carcinoma and Myeloma of the Femur

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SUMMARY: The American Society of Clinical Oncology on June 20, 2020, approved the first joint Musculoskeletal Tumor Society (MSTS)/American Society for Radiation Oncology (ASTRO)/ASCO guideline on the care of patients with metastatic carcinoma and myeloma of the femur. The skeleton is a frequent site of metastatic carcinoma and myeloma. Primary malignancies that commonly metastasize to bone include breast, lung, prostate, kidney, and thyroid. The incidence of bone metastases is approximately 70% in patients with breast or prostate cancer and 35% in patients with lung or kidney cancer, based on autopsy studies. The lifetime risk of developing multiple myeloma is 1 in 132, and 70-80% of patients present with osteolytic lesions in the skeleton. Malignant lesions involving the bone can be painful and can result in pathologic fractures, impairing functional capacity, quality of life and Overall Survival (OS). These patients may require radiation therapy, surgery or both. The National Institutes of Health estimated that for the years 2000-2004, the national economic burden of metastatic bone disease was 12.6 billion dollars, representing 17% of the total direct medical cost of oncology care. These costs would be significantly higher in 2020.

The following recommendations were prepared and endorsed by the Musculoskeletal Tumor Society (MSTS), American Society for Radiation Oncology (ASTRO), and American Society of Clinical Oncology (ASCO). The purpose of this Clinical Practice Guideline is to provide medical, radiation, and surgical providers with a practical set of recommendations, regarding the management of patients with metastatic or myelomatous lesions of the femur, based on a systematic review of published information and consensus expert opinion. These guideline recommendations are intended to guide medical oncologists, radiation oncologists, and primary care physicians in making timely referrals, and address three main therapeutic areas-the use of Bone Modifying Agents, radiation therapy, and surgery.

1) Imaging and Clinical Findings: A combination of imaging findings and lesion-related pain is predictive of risk of pathologic femur fracture. There is no reliable evidence to suggest that MRI is a strong predictor of femur fracture.

2) Efficacy of Bone Modifying Agents (BMAs): The use of BMAs may assist in reducing incidence of femur fractures in patients with metastatic carcinoma or multiple myeloma and bone lesions.

3) Dosage Response of BMAs: Clinicians should consider decreasing the frequency of Zoledronic acid dosing to 12 weeks (compared to the standard 4-week interval), as this is associated with non-inferior Skeletal Related Events outcomes and similar adverse event rates, in patients with metastatic carcinoma or multiple myeloma. Clinicians should consider long-term use of BMAs to reduce skeletal related events in patients with multiple myeloma.

4) BMAs for Various Diagnoses: BMAs should be considered in patients with metastatic carcinoma or multiple myeloma with bone lesions at risk for fracture, regardless of tumor histology.

5) Imaging Findings and Atypical Fractures: Imaging findings of lateral cortical thickening may be associated with increased atypical femur fracture risk.

6) Efficacy of Radiation Therapy: Clinicians should consider the use of radiation therapy to decrease the rate of femur fractures in patients with metastatic carcinoma or multiple myeloma lesions, considered at increased risk, based on the combination of imaging findings and lesion-related pain.

7) Radiation Therapy and Prophylactic Femur Stabilization: Clinicians may consider the use of radiation therapy in patients undergoing prophylactic femur stabilization to reduce pain, improve functional status, and reduce the need for further intervention.

8) Radiation Therapy after Resection and Reconstruction: Radiation therapy may be considered after resection and reconstruction to reduce pain, improve functional status, and reduce the need for further intervention in patients with residual tumor, or those at increased risk of tumor recurrence.

9) Multi-Fraction Radiation Treatment: Clinicians should consider the use of multi-fraction in lieu of single fraction radiation treatment to reduce the risk of fracture in patients with metastatic carcinoma in the femur.

10) Estimating Survival and Reconstruction Method: Surgeons should utilize a validated method of estimating survival of the patient in choosing the method of reconstruction. Longer survival estimates may justify more durable reconstruction methods such as arthroplasty, if clinically appropriate.

11) Long Stem Hemiarthroplasty: When treating a femoral neck fracture with hemiarthroplasty, use of a long stem can be associated with increased intra-operative and post-operative complications and should only be used in patients with additional lesions in the femur.

12) Cephalomedullary Nailing: There is no advantage to routine use of cephalomedullary nails for diaphyseal metastatic lesions, as there does not appear to be a high frequency of new femoral neck lesions following intramedullary nailing.

13) Arthroplasty: Clinicians may consider arthroplasty to improve patient function and decrease the need for post-operative radiation therapy in patients with pathologic fractures from metastatic carcinoma in the femur.

http://msts.org/view/download.php/education/mbd-cpg-amended. Accessed October 28, 2020.

GILOTRIF® in EGFR Positive Non Small Cell Lung Cancer Harboring Uncommon Mutations

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Approximately 10-15% of Caucasian patients, and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations. The majority of patients have classical EGFR mutations which are either Exon 19 deletions or L858R substitution mutation in Exon 21, and for those patients with EGFR mutation-positive NSCLC, EGFR-TKIs are the first choice of treatment. However, around 5-20% of tumors harbor Major uncommon mutations, such as G719X, L861Q and S768I, as well as other more rare mutations, and these uncommon EGFR mutations show heterogeneity in their response to EGFR-TKIs. Compared with other EGFR mutations, G719X, L861Q and S768I substitution mutations are associated with a poorer prognosis and have limited treatment options.

GILOTRIF® (Afatinib) is an oral, irreversible blocker of the ErbB family which includes EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4. GILOTRIF® demonstrated clinical activity against Major uncommon EGFR mutations such as G719X, L861Q and S768I which is more often seen in Asian patients, and is FDA approved in this setting. There are however, few clinical data regarding the efficacy of the available EGFR-TKIs against other uncommon EGFR mutations, and there is no knowledge of ethnic differences in prevalence and outcomes.

This study investigated the efficacy of GILOTRIF® in EGFR mutation positive NSCLC among Asian and non-Asian patients with uncommon mutations. Uncommon mutations were classed into five categories– Major uncommon (G719X, L861Q and S768I), Compound, Exon 20 insertions, T790M Mutation, and Other. Patients may have more than uncommon mutation.

The researchers conducted a pooled analysis from randomized clinical trials and Real-World Studies and examined the activity of GILOTRIF® in Asian and non-Asian patients with NSCLC and uncommon EGFR mutations, who had not received prior treatment with EGFR TKIs. All identified patients included in this study had outcome data such as Time to Treatment failure (TTF) or Objective Response Rate (ORR) available. The total number of evaluable patients were 298 (N=298), of whom 60% were Asian (N=178) and 40% were Non-Asian (N=120). The median patient age ranged from 60-66 years across the different mutation groups. Approximately 40% of patients had Major uncommon mutations such as G719X, L861Q and S768I, 24% had Exon 20 insertions, 12% had T790M mutations and 24% had Compound and Other mutations. When broken by ethnicity, among Asian patients, approximately 62% had Major uncommon mutations, 14% had Compound mutations and 16% had Exon 20 insertions. Among non-Asian patients, 35% had Major uncommon mutations, approximately 7% had Compound mutations and 39% had Exon 20 insertions. The Endpoints included Objective Response Rate (ORR), Duration of Response (DoR) and Time to Treatment Failure (TTF), and outcomes were compared in Asian and non-Asian EGFR-TKI-naïve patients.

This analysis showed that the efficacy of GILOTRIF® was unaffected by ethnicity, and the Overall Response Rate (ORR) among tumors with Major uncommon mutations was 66% in Asian patients versus 59% in non-Asian patients, and the median Duration of Response (DoR) was 14.7 months compared with 15.9 months respectively. Among those with Major uncommon mutations, the ORR in tumors harboring G719X mutation was 62% in Asian patients and 65% in non-Asian patients. Among those tumors with a L861Q mutation, the ORRs were 60% versus 50%, respectively and among those with a S768I mutation, the ORRs were 80% versus 25%, respectively. The Overall Response Rate (ORR) among tumors with Compound mutations was 81% in Asian patients versus 100% in non-Asian patients and the median Duration of Response (DoR) was 11.5 months compared with 18.6 months respectively. Among patients who harbored Exon 20 insertions, the ORR with GILOTRIF® in Asian patients was 21% versus 23% in non-Asian patients, with a Duration of Response of 11 months and 10.7 months, respectively.

It was concluded that GILOTRIF® shows clinical activity against uncommon EGFR mutations in both Asian and non-Asian patients, with durable clinical responses, and should be considered as a first-line treatment option in Asian and non-Asian patients with Major uncommon (G719X, L861Q and S768I) and Compound EGFR mutations.

Afatinib in Asian and non-Asian patients (pts) with EGFR mutation-positive (EGFRm+) NSCLC harboring major uncommon mutations. Yang JC-H, Schuler M, Popat S, et al. Presented at: 2020 IASLC North America Conference on Lung Cancer; October 16-17, 2020; Virtual. Abstract MO01.36.

American Society of Clinical Oncology Policy Statement on Skin Cancer Prevention

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SUMMARY: Skin Cancer is the most common cancer diagnosed in the US and around the world. Basal Cell Carcinoma (BCC) and Squamous Cell Carcinoma (SCC) are the two most common types of skin cancers. It is estimated that 5.4 million cases of BCC and SCC are diagnosed each year in the US (occurring in about 3.3 million Americans, as some individuals have more than one type of skin cancer), and 8 of 10 are BCCs, whereas SCCs occur less often. Although the overall mortality rate from these cancers are low, SCCs are almost exclusively responsible for approximately 3,000 deaths per year in the US, with the greatest mortality risk among transplant recipients, who are immunocompromised. Malignant Melanoma of the skin occurs less frequently than BCC and SCC, and the American Cancer Society estimates that in the US for 2020, about 100,350 new melanomas will be diagnosed and about 6,850 people are expected to die of the disease. The rates of skin cancer have been rising rapidly over the past several years, with the economic cost estimates of $8.1 billion annually in the US.

Exposure to UltraViolet (UV) rays is a major risk factor for most skin cancers. Sunlight is the main source of UV rays. UV rays-emitting indoor tanning devices such as tanning beds, sunlamps, and UV lamps, are another source of UV rays. The risk of UV rays associated skin cancers, particularly for SCC, is dose dependent, and increases with greater duration and intensity of exposure. This risk is increased with cumulative solar UV rays exposure over an individual’s lifetime. For a given level of UV rays exposure, skin cancer risk is highest among UV ray sensitive phenotypes who typically are fair skinned, and have a propensity to sunburn, blister and/or freckle, upon exposure to UV rays. National surveys on sun exposure in the US illustrate the high rates of sunburn among adults (35%) and high school students (57%), emphasizing the importance of primary and secondary prevention strategies in the younger population. The ASCO’s 2019 National Cancer Opinion Survey found that only 49% of respondents reported using sunscreen to prevent skin cancer. Skin cancer is less common in individuals with darker skin colors (Black and Latino individuals), due to greater levels of melanin in the skin, which inherently has photoprotective ability. Nonetheless, when skin cancers do occur in individuals with darker skin tones, they tend to be more aggressive, possibly due to delayed diagnosis, as these individuals may be less aware of their skin cancer risks.

Given that skin cancer has such a major impact on society, the American Society of Clinical Oncology (ASCO) earlier this year published a policy statement aimed at lessening the burden of skin cancer through reducing exposure to UV radiation for youth and adults. This policy statement included a review of the risk factors for skin cancer, disparities in incidence, diagnosis and survival among different populations, and public health strategies for Primary and Secondary skin cancer prevention.

ASCO presented recommendations across the following four themes:

Reduce Exposure to Indoor Tanning
1) A major opportunity to prevent skin cancer is by reducing UV ray exposure through avoidance of indoor tanning.
2) Avoidance of indoor tanning holds particular promise in influencing adolescents and sexual minority men because of their higher rate of exposure to tanning.
3) The International Agency for Research on Cancer concluded that UV ray-emitting indoor tanning devices were carcinogens and there is now high-quality scientific evidence documenting strong and consistent associations between indoor tanning devices and skin cancer risk.
4) Indoor tanning is higher among non-Hispanic white females compared with all other population subgroups, and its direct association with melanoma risk likely explains the higher melanoma incidence in this group compared with male adolescents and young adults.
5) There is evidence suggesting the presence of “tanning dependence”, similar to substance use dependence, among individuals who engage in indoor tanning.
6) Recognizing that indoor tanning devices are a threat to public health, several cancer care and public health organizations support strong restrictions designed to prevent the use of UV ray-emitting tanning devices. ASCO supports strengthened laws and regulations restricting such products

Increase Public Efforts to Promote Sun Protection
1) Local, state, and federal laws should support policies that allow students to carry and use sunscreen products without physician authorization.
2) Enhance the protection of young people by encouraging the increased use of broad-spectrum sunscreen and protective clothing, through educational programs.
3) Improvement in sunscreen products and public education to prevent intentional sun exposure, for promoting Vitamin D synthesis.
4) Private and public institutions should be encouraged in their efforts to create more shaded areas in places used for outdoor recreation.
5) Development of new educational efforts, to change the social perceptions of tanned skin.

Community Education and Outreach
1) Investing in prevention research, and continued support for the National Cancer Institute’s Division of Cancer Prevention and the Centers for Disease Control and Prevention’s National Skin Cancer Prevention Education Program, to address the burden of this disease among persons of color, lower socioeconomic status populations, and sexual minorities.
2) ASCO and the cancer care community should work together to develop effective methods for outreach and health communication, to the diverse segments of the population at risk of skin cancer.

Role of Oncology Providers
1) Research has shown that cancer survivors do not adhere to skin-protective behaviors, anymore than the lay public who have not been diagnosed with cancer.
2) Oncologists should discuss with their patients the regular use of properly applied broad-spectrum sunscreen and the use of sun-protective clothing such as hats, long sleeves, and long pants when outdoors, as well as avoidance of UV rays either from sunlight, or from UV ray-emitting indoor tanning devices.
3) Oncology providers should be vocal supporters of skin cancer prevention policies and should educate patients of color, so that they understand that they are also at risk of skin cancer.

American Society of Clinical Oncology Policy Statement on Skin Cancer Prevention. Alberg AJ, LoConte NK, Foxhall L, et al. JCO Oncology Practice. 2020;16:490-499.

FDA Approves OPDIVO® plus YERVOY® for Malignant Pleural Mesothelioma

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SUMMARY: The FDA on October 2, 2020, approved the combination of OPDIVO® (Nivolumab) plus YERVOY® (Ipilimumab), as first-line treatment for adult patients with unresectable Malignant Pleural Mesothelioma. It is estimated that about 3,000 new Malignant Mesothelioma cases are diagnosed each year. Mesothelioma is more common in Whites and Hispanics/Latinos than in African Americans or Asian Americans, and is also much more common in older people. Mesothelioma is more common in men than in women and the average age at the time of diagnosis for pleural mesothelioma is 72 years. The main risk factor for pleural mesothelioma is exposure to high levels of asbestos, usually in the workplace. Malignant Pleural Mesothelioma is relatively rare and has limited treatment options. The five-year survival rate for patients diagnosed with advanced disease is approximately 10 percent. There is currently only one FDA-approved first-line treatment, and there remains an unmet need for this patient group.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the immune system T cells. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response.OPDIVO® is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4.Unleashing-T-Cell-Function-with-Combination-Immunotherapy

The present FDA approval was based on a prespecified interim analysis of CheckMate 743 trial. This study is an open label, multi-center, randomized Phase III trial, evaluating OPDIVO® plus YERVOY® compared to chemotherapy (Pemetrexed and Cisplatin or Carboplatin), in patients with previously untreated Malignant Pleural Mesothelioma. This study enrolled 605 patients with unresectable pleural mesothelioma and patients were randomized 1:1 to receive either OPDIVO® 3 mg/kg IV once every 2 weeks, in combination with YERVOY® 1 mg/kg IV once every 6 weeks, for up to 2 years (N=303), or six cycles of combination chemotherapy with Cisplatin or Carboplatin plus Pemetrexed every 3 weeks (N=302). The Primary endpoint of the trial was Overall Survival (OS). Secondary endpoints included Objective Response Rate (ORR), Disease Control Rate (DCR), Progression Free Survival (PFS) and efficacy measures according to PD-L1 expression level.

Based on a pre-specified interim analysis conducted by the Independent Data Monitoring Committee (IDMC), at 22.1 months of follow up, the median OS was 18.1 months with the combination immunotherapy versus 14.1 months with combination chemotherapy (HR=0.74; P=0.002), suggesting a 26% reduction in the risk of death when treated with OPDIVO® plus YERVOY®. The 12- month OS rates were 68% and 58%, and 2-year OS rates were 41% and 27%, respectively. This OS benefit with combination immunotherapy was observed in both non-epithelioid and epithelioid Malignant Pleural Mesothelioma, regardless of PD-L1 expression.

The median PFS per Blinded Independent Central Review (BICR) was 6.8 months in the combination immunotherapy group, and 7.2 months in the combination chemotherapy group. However, combination immunotherapy resulted in a higher PFS rate at both 12 months and 24 months compared to the combination chemotherapy arm, at 30% versus 16%, and 24% versus 7%, respectively. The confirmed Objective Response Rate was 40% and 43% in the OPDIVO® plus YERVOY® and combination chemotherapy groups, respectively. The median Duration of Response was 11.0 months in the OPDIVO® plus YERVOY® group and 6.7 months in the combination chemotherapy group, with notable differences in response at 12 months (47% versus 26%) and 24 months (32% versus 8%) respectively. The most common adverse reactions in patients receiving the combination of OPDIVO® plus YERVOY® were fatigue, musculoskeletal pain, rash, pruritus, nausea, decreased appetite, diarrhea, cough and dyspnea.

The authors concluded that this is the first positive randomized trial of dual immunotherapy, in the first line treatment of patients with Malignant Pleural Mesothelioma, and the combination of OPDIVO® plus YERVOY® should be considered as the new standard of care.

First-line nivolumab + ipilimumab vs chemotherapy in unresectable malignant pleural mesothelioma: CheckMate 743. Baas P, Scherpereel A, Nowak A, et al. Presented at the International Association for the Study of Lung Cancer 2020 Presidential Symposium; August 8, 2020; Virtual. Abstract 3.

Immune Checkpoint Inhibitors Associated with High Activity in MSI-H Cancers

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SUMMARY: The DNA MisMatchRepair (MMR) system plays a crucial role in repairing DNA replication errors in normal and cancer cells. It is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and accumulation of mutations (hypermutation) and the generation of neoantigens, triggering an enhanced antitumor immune response.

MSI is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system. Defective MMR can be a sporadic or heritable event. Defective MMR can manifest as a germline mutation occurring in MMR genes including MLH1, MSH2, MSH6 and PMS2. This produces Lynch Syndrome often called Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC, an Autosomal Dominant disorder that is often associated with a high risk for Colorectal and Endometrial carcinoma, as well as several other malignancies including Ovary, Stomach, Small bowel, Hepatobiliary tract, Brain and Skin. MSI is a hallmark of Lynch Syndrome-associated cancers. MSI tumors tend to have better outcomes and this has been attributed to the abundance of Tumor Infiltrating Lymphocytes in these tumors from increase immunogenicity. These tumors therefore are susceptible to blockade with Immune Checkpoint Iinhibitors (ICIs). The positive outcomes following ICI treatment in MSI-H tumors may be related to the possible association with Programmed Death-Ligand 1 (PD-L1) expression and the high Tumor Mutational Burden (TMB) of these diseases.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options, by improving Overall Response Rate and prolongation of survival, across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response.Testing-for-Micro-Satellite-Instability-and-MisMatch-Repair-Deficiency

MSI testing is performed using a PCR based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors. Tumors considered MSI-H have deficiency of one or more of the DNA MMR genes. MMR gene deficiency can be detected by ImmunoHistoChemistry (IHC).

The authors in this publication conducted a systematic review and meta-analysis which included a total of 14 published articles that evaluated ICIs in the treatment of advanced MSI-H tumors from inception to December 2019. These articles were identified by searching the PubMed, EMBASE, and Cochrane Library databases. Overall, 939 patients in the 14 studies were analyzed, and the purpose of this study was to determine the outcomes in patients with advanced, MSI-H cancers, following treatment with ICIs. The selected studies for analysis had prospectively accrued patients with advanced or metastatic MSI-H/dMMR cancers, regardless of line of therapy, and data was available for Overall Response Rate (ORR) and/or survival analysis (Overall Survival and/or Progression Free Survival).

The studies included use of either, Avelumab (BAVENCIO®), Pembrolizumab (KEYTRUDA®), Ipilimumab (YERVOY®), Nivolumab (OPDIVO®), Atezolizumab (TECENTRIQ®) or Durvalumab (IMFINZI®). This analysis included a range of tumor types, and the Primary outcome of interest was Overall Response Rate (ORR). Secondary end points were median Progression Free Survival (PFS), median Overall Survival (OS), pooled rate of patients alive at 1, 2 and 3 years, and pooled rate of patients that attained Disease Control Rate (DCR), which is the sum of Stable Disease rate and ORR.

The pooled ORR was 41.5%, the pooled DCR was 62.8%, the pooled median PFS was 4.3 months and the pooled median OS was 24 months. The pooled 1 and 2-year OS were 75.6% and 56.5% respectively. Since only one study provided 3-year OS data, a formal pooled analysis for 3 years was not possible. The ORR was similar according to histologic analysis with the higher values for Gastric cancer (61.2%) and the lowest ORR associated with Colorectal cancer (47.1%), Endometrial (36.1%), and other tumors (35.5%).

It was concluded from this meta-analysis that Immune Checkpoint Inhibitors were associated with high activity, independent of tumor type and drug used, and molecular biomarkers such as MisMatch Repair proteins may have a predictive value for the activity of immunotherapy.

Outcomes Following Immune Checkpoint Inhibitor Treatment of Patients With Microsatellite Instability-High Cancers. A Systematic Review and Meta-analysis. Petrelli F, Ghidini M, Ghidini A, et al. JAMA Oncol. 2020;6:1068-1071.

Risk of Prostate Cancer Associated With Familial and Hereditary Cancer Syndromes

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SUMMARY: Prostate Cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate Cancer during their lifetime. It is estimated that in the United States, about 191,930 new cases of Prostate Cancer will be diagnosed in 2020 and 33,330 men will die of the disease. The five year survival among patients first diagnosed with metastatic disease is approximately 30%. Early detection and treatment may improve outcomes. Risk factors for Prostate Cancer include age, ethnicity, and family history of Prostate Cancer. In individuals with a family history of Prostate Cancer in one or more first-degree relatives, the Relative Risk of Prostate Cancer increases approximately 2-3 fold, and the risk increases with an increasing number of affected relatives, and is inversely related to the age at time of diagnosis among those relatives.

It is estimated that approximately 40% of all diagnosed Prostate Cancers are inherited and Prostate Cancer risk also has been implicated in other familial cancer syndromes such as Hereditary Breast and Ovarian Cancer (HBOC) syndrome and Lynch Syndrome (LS). HBOC syndrome typically is found in families with early onset cancer and multiple cancer diagnoses such as, breast, ovarian and pancreatic cancer. Tumor suppressor DNA repair genes BRCA1 and BRCA2, has been implicated in Prostate Cancer, particularly in HBOC families. Patients with a BRCA1 mutation have a nearly 2-fold Relative Risk of Prostate Cancer among men less than 65 years, whereas those with BRCA2 mutations have a more than 7 fold Relative Risk. Further, patients with BRCA2 mutations are also associated with clinically aggressive disease, progression, and higher rates of cancer-specific mortality. It is estimated that the frequency of BRCA2 mutations ranges from 1-3%. The National Comprehensive Cancer Network (NCCN) recommends that BRCA2 mutation carriers begin Prostate Cancer screening with PSA testing and a digital rectal exam by age 40, and that BRCA1 mutation carriers consider testing at age 40, as well.

Lynch Syndrome, or Hereditary Non-Polyposis Colorectal Cancer, is associated with germline DNA mismatch repair defects, and individuals with Lynch Syndrome are 2-5 times more likely to develop Prostate Cancer during their lifetimes.

The purpose of this population-based study was to quantify the Relative Risk of Prostate Cancer associated with different family cancer histories such as Hereditary Prostate Cancer, Hereditary Breast and Ovarian Cancer syndrome and Lynch Syndrome. The Utah Population Database was chosen as it is very large and linked to the Utah Cancer Registry. The Relative Risk for Prostate Cancer in general, as well as the risks for three Prostate Cancer subgroups- early onset, lethal, and clinically significant Prostate Cancers, was evaluated.

The authors using the Utah Population Database identified 619,630 men, 40 years or older, who were members of a pedigree that included at least 3 consecutive generations. Each individual was then assessed for family history of Hereditary Prostate Cancer, Hereditary Breast and Ovarian Cancer (HBOC) or Lynch syndrome, as well as his own Prostate Cancer status. The participant’s own cancer disease status was not used in any of the family history definitions. Family history of Hereditary Prostate Cancer was defined as 3 or more first-degree relatives with Prostate Cancer, or Prostate Cancer in 3 or more affected relatives diagnosed in 3 successive generations of the same lineage (paternal or maternal), or 2 or more first-degree relatives both diagnosed with early-onset disease (55 years or less). The NCCN Guidelines for BRCA-related Breast and/or Ovarian Cancer Syndrome were adapted for a family history of HBOC and revised Bethesda Guidelines were adapted for Lynch Syndrome, to determine if an individual had a positive family history of Lynch Syndrome. All Prostate Cancer occurences were classified into one or more subtypes: Early-onset Prostate Cancer defined as Prostate Cancer diagnosed at age 55 years or less, Lethal Prostate Cancer was identified if Prostate Cancer was listed as the primary cause of death on a death certificate, and Clinically significant Prostate Cancer if the Gleason score was 7 or more, direct extension, regional lymph node involvement or presence of distant metastases.

The overall prevalence of Prostate Cancer for the cohort was 5.9% (N=36,360), of whom 7% had Early onset disease, 11.1% had Lethal disease and 41.8% had Clinically significant disease. The median age at time of diagnosis was 69 years, approximately 70% of men were diagnosed with organ-confined disease, and approximately 6% were first diagnosed with metastatic disease.

Family history of Hereditary Prostate Cancer was associated with the highest risk for all Prostate Cancer subtypes combined, with a 2.3-fold increase in risk for Prostate Cancer overall (Relative Risk 2.30). This was followed by Hereditary Breast and Ovarian Cancer, with a Relative Risk of 1.47, and Lynch syndrome with a Relative Risk of 1.16.

Hereditary Prostate Cancer was associated with a near 4-fold increase in risk for early onset Prostate Cancer (RR=3.93). Hereditary Prostate Cancer also was associated with higher risks for both Lethal Prostate Cancer (RR=2.21) and Clinically significant disease (RR=2.32). Overall, modest elevations in risk were associated with Lynch Syndrome, with a 34% increase in risk for early onset disease (RR=1.34) and a small increase in the risk for Clinically significant disease (RR=1.15).

It was concluded from this investigation of a large, population-based family database that, targeting high-risk populations such as those with Hereditary Prostate Cancer early, with genetic screening and cancer surveillance, is indicated. This study also demonstrated the importance of well-ascertained family history information, for determining Prostate Cancer risk, as well as determining important Prostate Cancer subsets such as Early onset and Lethal disease. The authors added that this is the first study that compared the risk of Prostate Cancer in men with Hereditary Prostate Cancer, with families having HBOC or Lynch syndrome in the same population.

Risk of Prostate Cancer Associated With Familial and Hereditary Cancer Syndromes. Beebe-Dimmer JL, Kapron AL, Fraser AM, et al. J Clin Oncol. 2020;38:1807-1813