Laronga, Christine

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate are intended to serve as a resource for health care providers to identify individuals who may benefit from cancer risk assessment and genetic counseling and testing; help guide decisions related to genetic testing; and facilitate a multidisciplinary approach in the comprehensive care of individuals at increased risk for hereditary breast, ovarian, pancreatic, and prostate cancer. The current guidelines focus primarily on assessment of pathogenic and likely pathogenic (P/LP) variants associated with increased risk of breast, ovarian, pancreatic, and prostate cancer and recommended approaches to genetic counseling/testing and care strategies in individuals with these P/LP variants associated with increased risk of these cancers. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding screening for prostate cancer and pancreas cancer, as well as testing criteria for nonepithelial ovarian cancer.

PURPOSE To develop recommendations for germline mutation testing for patients with breast cancer. METHODS An ASCO–Society of Surgical Oncology (SSO) panel convened to develop recommendations based on a systematic review and formal consensus process. RESULTS Forty-seven articles met eligibility criteria for the germline mutation testing recommendations; 18 for the genetic counseling recommendations. RECOMMENDATIONS BRCA1/ 2 mutation testing should be offered to all newly diagnosed patients with breast cancer ≤65 years and select patients >65 years based on personal history, family history, ancestry, or eligibility for poly(ADP-ribose) polymerase (PARP) inhibitor therapy. All patients with recurrent breast cancer who are candidates for PARP inhibitor therapy should be offered BRCA1/ 2 testing, regardless of family history. BRCA1/ 2 testing should be offered to women who develop a second primary cancer in the ipsilateral or contralateral breast. For patients with prior history of breast cancer and without active disease, testing should be offered to patients diagnosed ≤65 years and selectively in patients diagnosed after 65 years, if it will inform personal and family risk. Testing for high-penetrance cancer susceptibility genes beyond BRCA1/ 2 should be offered to those with supportive family histories; testing for moderate-penetrance genes may be offered if necessary to inform personal and family cancer risk. Patients should be provided enough pretest information for informed consent; those with pathogenic variants should receive individualized post-test counseling. Variants of uncertain significance should not impact management, and patients with such variants should be followed for reclassification. Referral to providers experienced in clinical cancer genetics may help facilitate patient selection and interpretation of expanded testing, and provide counseling of individuals without pathogenic germline variants but with significant family history. Additional information is available at www.asco.org/breast-cancer-guidelines .

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic/likely pathogenic (P/LP) variants associated with increased risk of breast, ovarian, pancreatic, and prostate cancer, including BRCA1 , BRCA2 , CDH1 , PALB2 , PTEN , and TP53 , and recommended approaches to genetic counseling/testing and care strategies in individuals with these P/LP variants. These NCCN Guidelines Insights summarize important updates regarding: (1) a new section for transgender, nonbinary and gender diverse people who have a hereditary predisposition to cancer focused on risk reduction strategies for ovarian cancer, uterine cancer, prostate cancer, and breast cancer; and (2) testing criteria and management associated with TP53 P/LP variants and Li-Fraumeni syndrome.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic provide recommendations for genetic testing and counseling for hereditary cancer syndromes, and risk management recommendations for patients who are diagnosed with syndromes associated with an increased risk of these cancers. The NCCN panel meets at least annually to review comments, examine relevant new data, and reevaluate and update recommendations. These NCCN Guidelines Insights summarize the panel’s discussion and most recent recommendations regarding criteria for high-penetrance genes associated with breast and ovarian cancer beyond BRCA1/2 , pancreas screening and genes associated with pancreatic cancer, genetic testing for the purpose of systemic therapy decision-making, and testing for people with Ashkenazi Jewish ancestry.

Findings suggest that more intensive efforts than audit and feedback will be required to improve the quality of psychosocial care, and that greater recognition of problems with emotional well-being may tax the ability of practices to link patients with appropriate services.

Abstract Purpose. The Oncotype DX assay predicts likelihood of distant recurrence and improves patient selection for adjuvant chemotherapy in estrogen receptor–positive (ER-positive) early stage breast cancer. This study has two primary endpoints: to evaluate the impact of Oncotype DX recurrence scores (RS) on chemotherapy recommendations and to compare the estimated recurrence risk predicted by breast oncology specialists to RS. Methods. One hundred fifty-four patients with ER-positive early stage breast cancer and available RS results were selected. Clinicopathologic data were provided to four surgeons, four medical oncologists, and four pathologists. Participants were asked to estimate recurrence risk category and offer their chemotherapy recommendations initially without and later with knowledge of RS results. The three most important clinicopathologic features guiding their recommendations were requested. Results. Ninety-five (61.7%), 45 (29.2%), and 14 (9.1%) tumors were low, intermediate, and high risk by RS, respectively. RS significantly correlated with tumor grade, mitotic activity, lymphovascular invasion, hormone receptor, and HER2/neu status. Estimated recurrence risk by participants agreed with RS in 54.2% ± 2.3% of cases. Without and with knowledge of RS, 82.3% ± 1.3% and 69.0% ± 6.9% of patients may be overtreated, respectively (p = 0.0322). Inclusion of RS data resulted in a 24.9% change in treatment recommendations. There was no significant difference in recommendations between groups of participants. Conclusions. Breast oncology specialists tended to overestimate the risk of tumor recurrence compared with RS. RS provides useful information that improves patient selection for chemotherapy and changes treatment recommendations in approximately 25% of cases.

The Florida Initiative for Quality Cancer Care has identified how multiple aspects of breast cancer care can be improved.

Abstract Background: The decision to use adjuvant chemotherapy in patients with early stage breast cancer is based in part on the estimation of risk of tumor recurrence by physicians, which traditionally relies heavily on tumor size, nodal status and a set of biologic tumor characteristics such as hormone receptor and HER2 expression. The Oncotype DX® assay is a 21-gene expression profile aiming to improve risk stratification, recurrence prediction and optimize selection of patients for adjuvant chemotherapy.Methods: We selected 154 consecutive patients with early stage estrogen receptor (ER) positive breast cancer and available Oncotype Dx® recurrence score (RS) for the study. Clinicopathologic data, including patient age, menopausal status, tumor size, histologic type, grade, mitotic activity, presence of lymphatic invasion (LVI), nodal status, hormone receptor and HER2 status on all patients were provided to four surgical oncologists, four medical oncologists and three pathologists, specializing in breast cancer diagnosis and management. Participants were asked to estimate the risk of recurrence of tumors based on available clinicopathologic data and to provide the three most important tumor features their risk estimates were based on. Risk estimates of participants were compared with RS results.Results: Based on the Oncotype Dx® results, 95 (61.7%), 45 (29.2%) and 14 (9.1%) tumors were of low (RS <18), intermediate (RS 18-30) and high (RS ≥31) risk, respectively. RS values showed a highly significant correlation with tumor grade, mitotic activity, LVI, hormone receptor and HER2 status, while no correlation with patient age, menopausal status, tumor size and histologic type was found. Participants' risk estimates agreed with those of the Oncotype Dx® assay in 54.2 ± 2.3 % (mean ± SEM, range 41.6 - 63.0%) of cases, while the risk of recurrence was over- and underestimated compared to RS results in 31.8 ± 3.1% (16.2 - 43.5%) and 14.1 ± 1.4% (7.1 - 22.7%), respectively. The rates of overestimation were significantly higher than those of underestimation (p = 0.0003). Although medical oncologists tended to overestimate the risk more frequently (38.1 ± 2.0%) compared to surgeons (28.7 ± 5.9%) and pathologists (27.5 ± 7.8%), the difference did not reach statistical significance. Estimation of the agreement of participants' risk assessment with RS results showed a mean kappa value of 0.2955 (range 0.1506 - 0.4123). No statistically significant difference in overall concurrence with RS results was found between surgeons, medical oncologists and pathologists. Participants ranked tumor stage/nodal status, hormone receptor status and tumor size to be the most important features when estimating recurrence risk.Conclusions: Based on traditional clinicopathologic features alone, surgeons, medical oncologists and pathologists tend to overestimate the risk of tumor recurrence as compared to Oncotype Dx® assay results. The RS may provide additional information regarding the intrinsic biological features of ER positive breast cancers and help tailoring treatment recommendations. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4061.

Abstract Background: Current guidelines recommend administration of chemotherapy for patients with breast carcinomas >1 cm in size, with consideration for patient age, comorbidities and tumor grade. However, it is unknown which patients actually benefit from therapy and overtreatment of a significant proportion of patients is a major concern. We investigated the impact of the Oncotype Dx® Recurrence Score (RS) on chemotherapy recommendations in early stage estrogen receptor (ER) positive breast cancer patients.Methods: We selected 154 patients with early stage ER positive breast cancer and available RS for the study. Clinicopathologic data, including age, menopausal status, tumor size, type, grade, mitotic activity, presence of lymphatic invasion, nodal status, hormone receptor and HER2 status on all patients were provided to four surgical oncologists, four medical oncologists and three pathologists, specializing in breast cancer diagnosis and management. Assuming that all patients were in good general health and would receive endocrine therapy, participants were asked whether they would also advovate adjuvant chemotherapy based on clinicopathologic data with and without knowledge of the RS, and to provide the three salient clinicopathologic features on which their recommendations were based. Changes in recommendations of participants following inclusion of RS data were compared.Results: Based on RS results, 95 (61.7%), 45 (29.2%) and 14 (9.1%) tumors were of low (RS <18), intermediate (RS 18-30) and high (RS ≥31) risk, respectively. The results are summarized in Table 1. Assuming that the hypothesis previously put forward that patients with low to intermediate risk RS are not likely to benefit from chemotherapy, 82.3 ± 1.3% (75.5 - 89.0%) and 69.0 ± 6.9% (5.9 - 85.7%) of patients for whom chemotherapy was recommended by the participants would be "overtreated" without and with the use of RS results (p = 0.0322). No statistically significant difference was found among surgeons, medical oncologists and pathologists. Participants ranked patient age/menopausal status, hormone receptor status and tumor stage/nodal status to be the most important features when recommending chemotherapy.Conclusions: Although current recommendations for adjuvant chemotherapy for early stage ER positive breast cancer patients are largely in line with published guidelines, inclusion of RS alters recommendations in about 25% of cases. While medical oncologists recommended chemotherapy more frequently compared to surgeons and pathologists, they were more likely to change recommendations in light of RS results.Table 1. Summary of results SurgeonsMedical oncologistsPathologistsp* Mean ± SEMRangeMean ± SEMRangeMean ± SEMRange Chemo without RS (%)29.2 ± 1.824.0 - 31.859.0 ± 5.046.8 - 70.846.8 ± 3.741.6 - 53.90.0156Chemo with RS (%)27.0 ± 5.611.0 - 36.438.6 ± 9.517.5 - 63.644.4 ± 5.833.8 - 53.90.1794No change (%)75.3 ± 7.054.5 - 85.766.7 ± 6.851.3 - 83.885.9 ± 6.478.6 - 98.70.3682Add chemo (%)11.2 ± 4.13.2 - 22.76.5 ± 1.93.2 - 11.75.8 ± 3.20.6 - 11.70.6882Avoid chemo (%)13.5 ± 3.94.5 - 22.726.8 ± 7.94.5 - 41.68.2 ± 4.50.6 - 16.20.2186*Kruskal-Wallis test Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4058.