Average Recurrence Risk Research Articles

ENDOCRINE TUMOURS: Our experience with the management of patients with non-metastatic adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) accounts for a minority of all malignant tumors in adults. Surgery remains the most important therapeutic option for non-metastatic ACC. Whether a subset of patients with small ACC may benefit from minimally invasive surgery remains a debated issue, but we believe that surgeon's expertise is more important than surgical technique to determine outcome. However, even a state-of-the-art surgery cannot prevent disease recurrence that is determined mainly by specific tumor characteristics. We consider that the concomitant presence of the following features characterizes a cohort of patients at low risk of recurrence, (i) R0 resection (microscopically free margin), (ii) localized disease (stage I-II ACC), and (iii) low-grade tumor (ki-67 <10%). After the ADIUVO study, we do not recommend adjuvant mitotane as a routine measure for such patients, who can be managed with active surveillance thus sparing a toxic treatment. Patients at average risk of recurrence should be treated with adjuvant mitotane. For patients at very high risk of recurrence, defined as the presence of at least one of the following: Ki67 >30%, large venous tumor thrombus, R1 resection or stage IV ACC, we increasingly recommend to combine mitotane with four cycles of platinum-based chemotherapy. However, patients at moderate-to-high risk of recurrence should be ideally enrolled in the ongoing ADIUVO2 trial. We do not use adjuvant radiotherapy of the tumor bed frequently at our institutions, and we select patients with incomplete resection, either microscopically or macroscopically, for this treatment. In the long-term, prospective multicenter trials are required to improve patient care.

Selection bias induced by reproductive stoppage in estimates of recurrence risk for autism spectrum disorders

BackgroundIn observational studies it is implicitly assumed that the data are representative of the general population. Self-selection by individuals may undermine this assumption, inducing sample selection bias. In studies of recurrence risk of autism spectrum disorder (ASD) it is implicitly assumed that parents who had no further children face the same recurrence risk as parents who had further children. If this assumption is false, estimates of recurrence risk may be too high or too low. MethodTwo canonical statistical methods for detecting and correcting for sample selection bias, including incidental truncation and inverse probability weighting, are applied to population cohort data for Israel. The data comprise 8205 younger siblings of 9117 children diagnosed with ASD, among which there were 371 recurrences. Reproductive stoppage occurred in 4216 out of 9117 families. Participants are distinguished by demographics (gender, age), ethnicity (Jews and Arabs), religiosity, birth cohort and socioeconomic status. ResultsCorrecting for selection bias using the incidental truncation method, the average risk of recurrence is 3.83 (95 %CI: 3.41 %–4.24 %) instead of 4.53 % (95 %CI: 4.08 %–4.98 %). The bias has p-value 0.082. Since the incidental truncation method may be sensitive to parametric assumptions regarding the joint distribution of unobserved heterogeneity in stoppage and recurrence risk, robustness tests are carried out using alternative parametric assumptions, including copulas. Results using the method of inverse probability weighting were unsatisfactory because they were sensitive to hidden confounders. ConclusionsStudies of recurrent risk of ASD should take account of potential selection bias induced by reproductive stoppage.

Abstract P5-18-12: Effectiveness of Oncotype DX DCIS scoring in a community setting

Abstract The Oncotype DX DCIS Score was developed to assist in determining a low risk for recurrence subgroup of patients who can avoid radiation therapy following breast conserving surgery. We sought to evaluate our experience using the Oncotype DX DCIS Score and to see if a greater number of patients who did not receive radiation therapy were experiencing a local recurrence than the score predicted. Between February 23, 2011 and November 29, 2017, 145 women were diagnosed with ductal carcinoma in situ (DCIS) without an invasive component. 126 (87%) underwent breast conserving surgery. Thirty-five underwent Oncotype DX DCIS Score, of whom 26 (74%) were low risk, four were intermediate risk (11%), and five were high risk (14%). The scores ranged from 0 (7 patients) to 100 (1 patient). Of the 26 patients with low risk scores, one chose to undergo mastectomy, three received radiation therapy, 20 chose observation without radiation therapy, and two patients were unknown because they had no further treatment or follow-up at our facility. Two of the four intermediate risk patients underwent radiation therapy and two did not. Four of the five high risk patients underwent radiation therapy, but one did not. Twenty-two of the 35 patients who underwent Oncotype DX Score met the criteria for size (based on grade) and margins (at least 3 mm). Ten patients had margins that were less than 3 mm but met the size criteria. Two patients did not meet the size criteria but had at least 3 mm margins. One patient did not meet either the size or margin criteria. None of our 20 patients with low risk Oncotype DX DCIS Score and who met both the size and margin criteria recurred. With the median follow-up of approximately 2-1/2 years, three of the 21 patients (14%) with low or intermediate risk scores who underwent Oncotype DX DCIS Score and did not receive radiation therapy suffered a local recurrence. The predicted average recurrence risk for these patients based on their Oncotype DX DCIS Score was 12%. Two of these patients who recurred had margins less than 3 mm, and one patient met the size and margin criteria, but had an intermediate risk score. By comparison, five of 61 (8%) of patients who underwent breast conserving surgery and adjuvant radiation therapy had a local recurrence. Twenty of the 23 (87%) low risk Oncotype DX DCIS Score patients did not receive radiation therapy and overall 20/35 (57%) of the patients undergoing Oncotype DX DCIS Score did not receive radiation therapy. Although the follow-up is still relatively short, Oncotype DX DCIS Score allows a considerable number of women to avoid adjuvant radiation therapy. Citation Format: Wheeler JA, Vaghefi H, Liu F, Owens V, Morris L, Denham F, Coody L. Effectiveness of Oncotype DX DCIS scoring in a community setting [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-18-12.

Development and pilot testing of a Decision Aid (DA) for women with early-stage breast cancer considering contralateral prophylactic mastectomy

ObjectiveDescribe the development, acceptability and feasibility of a Decision Aid (DA) for women with early-stage breast cancer (BC) at average contralateral breast cancer (CBC) risk considering contralateral prophylactic mastectomy (CPM). MethodsThe DA was developed using the International Patient Decision Aid Standards (IPDAS) and the Ottawa Decision Support Framework. It provides evidence-based information about CPM in a booklet format combining text, graphs and images of surgical options. Twenty-three women with a history of early-stage breast cancer were interviewed in person or over the phone using a ‘think aloud approach’. Framework analysis was used to code and analyse data. ResultsTwenty-three women participated in the study. Mean age of participants was 58.6 years and time since diagnosis ranged from 14 months to 21 years. Five women had CPM and eighteen had not. Women strongly endorsed the DA. Many felt validated by a section on appearance and found information on average risk of recurrence and metastases helpful, however, noted the importance of discussing personal risk with their surgeon. Many requested more information on surgery details (time taken, recovery) and costs of the different options. ConclusionThe DA was acceptable to women, including the format, content and proposed implementation strategies. Practical and financial issues are important to women in considering treatment options. Practice implicationsWomen appreciate information about CPM at diagnosis and emphasised the importance of discussing potential downsides of the procedure in addition to benefits. The DA was considered acceptable to facilitate such discussions.

Abstract P6-01-06: Feasibility of the PROSIGNA® multigene test in core biopsies and comparison to corresponding surgical breast cancer sections

Abstract Background: The PROSIGNA® (PAM50) gene assay has been validated on formalin-fixed paraffin embedded (FFPE) surgical resection specimens (SRS) to identify the intrinsic subtypes of breast cancer and to estimate the 10-year risk of recurrence (ROR) in post-menopausal patients treated with adjuvant endocrine therapy. However, demonstration of the ability to perform PAM50 assay in diagnostic core biopsy specimens (CBS) before primary surgery and/or systemic therapy could be clinically useful. The objectives of this study were to 1) evaluate the feasibility of performing the PAM50 assay in CBS and 2) compare the PAM50 results from paired CBS and SRS. Methods and materials: Baseline tissue surface area, cellularity and RNA yield (obtained after ∼10 FFPE 10μm sections) were determined in CBS from 30 newly diagnosed breast cancer patients. The tissue volume requirements determined from these samples reflected the lower 95% confidence limits of a minimum RNA concentration of &amp;gt;20ng/µL. The RNA yield and assay pass rate of the established tissue volume requirements were then tested in 30 independent CBSs. Intrinsic subtype concordance, and ROR score variability, were determined from 1) multiple extractions of the same CBS (10 independent cases for a total of 84 extractions) and 2) multiple CBS of the same tumor (30 independent cases for a total of 79 CBS). To test the PAM50 assay concordance between paired CBS and SRS, the following PAM50 data were evaluated in an independent and retrospective set of 33 paired samples: 4-class subtype classification (Luminal A, Luminal B, HER2-enriched and Basal-like), 3-class subtype classification (Luminal A/B, HER2-enriched and Basal-like), ROR score (0-100), proliferation score and the correlation to each subtype centroid. Correlation and concordance between CBS and SRS were estimated using Pearson coefficients and multi-rater kappa values, respectively. Results: Baseline median surface area, cellularity and RNA yield concentration were 10.2 mm2, 45% and 155.3 ng/µl, respectively. Correlation of surface area and cellularity with RNA yield concentration was low (Person coefficient &amp;lt;0.25). Minimum tissue requirements were determined based on surface area: &amp;gt;12 mm2 = 2 10-micron slides, 6-12 mm2 = 4 slides; &amp;lt;6 mm2 = 8 slides. Subtype calls on multiple extractions from the same CBS were 98% concordant (82/84) and the average ROR score standard deviation (SD) was 2.2 units. Subtype calls on different CBS of the same tumor were 94% concordant (74/79) and the average ROR score SD was 6.8 units. All 7 discordant cases were between Luminal A and B calls. Comparison between paired CBS and SRS revealed correlations of ≥0.90 (range 0.90-0.98) for ROR scores, proliferation scores and subtype centroid correlations. Intrinsic subtype concordance between paired CBS and SRS was 87% (kappa=0.81) and 97% (kappa= 0.91) for the 4-subtype and 3-subtype classifications, respectively. Finally, the overall PAM50 assay pass rate in CBS was &amp;gt;95%. Conclusions: The PAM50 assay in CBS is feasible and measurements are comparable with surgical resections, which suggest that PAM50 can be performed on diagnostic core biopsy tissues. Citation Format: Aleix Prat, Patricia Galván, Wesley Buckingham, Maria Vidal, Sherley Díaz, Paolo Nuciforo, Sean Ferree, Barbara Adamo, Santiago Ramon y Cajal, Vicente Peg. Feasibility of the PROSIGNA® multigene test in core biopsies and comparison to corresponding surgical breast cancer sections [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-01-06.

Abstract P3-13-07: Clinicopathologic and Biologic Recurrence Risk in African-American Versus Caucasian Women with Early-Stage Hormone Receptor Positive Breast Cancer, a Single Institution Experience

Abstract Background: African-American women with hormone receptor positive breast cancer have an inferior survival compared to Caucasians (Sparano, et al (SABCS, 2009, Abstract #37) and Albain, et al (ASCO, 2010, Abstract #511)). It is not clear whether this difference is a result of disparities in access to care and stage at presentation or biological factors. We sought to examine whether African-American women with early-stage hormonereceptor positive breast cancer had a higher risk of recurrence than similarly staged Caucasians using a standard clinicopathologic risk prediction algorithm (AdjuvantOnline!) and a biologic risk prediction algorithm (Oncotype DX). Materials and Methods: Women with early stage, hormone receptor positive, Her2 normal, lymph node negative breast cancer seen at the University of Tennessee Cancer Institute between 2007-2009 were retrospectively reviewed. All patients had an AdjuvantOnline! recurrence risk calculated. For patients in whom an Oncotype DX was available, differences in risk of recurrence between clinicopathologic and biologic algorithms were evaluated with respect to race (African-American versus Caucasian). Results: 96 women were identified, 38 of whom were African-American and 58 of whom were Caucasian. 50 women had an Oncotype DX available. Clinicopathologic factors were well-balanced between the groups (see Table 1). Using AdjuvantOnline!, there was no significant difference between African-American and Caucasian patients in their average risk of recurrence (25% versus 23%, P=0.15). Using Oncotype DX, there was similarly no significant difference in the average risk of recurrence by race (18.6% for African-American versus 18.9% for Caucasian, P=0.55). Patient Characteristics Grade was not available for 1 Caucasian patient. Discussion: When matched for stage and general clinicopathologic factors (hormone receptor positivity, Her2 normal, lymph node negative), African-American and Caucasian patients have similar risk of recurrence using AdjuvantOnline! and Oncotype DX, though the expected risk was somewhat lower with Oncotype DX in both groups. This would suggest that there may be little biologic difference between African-American and Caucasian women with early stage hormone receptor positive breast cancer and that any difference in survival is likely related to non-biological factors. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-13-07.

Impact of OncoType DXTM Recurrence Score and Tumor Size on Making Chemotherapy Decisions in Breast Cancer Patients.

Abstract Background: Oncotype DXTM is a 21 gene assay that calculates recurrence score(RS) and recurrence risk(RR) over 10 years. Despite the contention that this genomic assay is more accurate than tumor size(TS) and age in predicting outcome, these factors continue to have major impact in decision-making regarding chemotherapy(CT). We analyzed the impact of TS, RS, and age on the decision to give CT.Methods: An IRB-approved chart review of 105 lymph node(LN) negative patients with ER+ T1 and T2 tumors was performed, reviewing age, RS, TS, CT history, Her-2 status, and pathology. RS was low(0-17), intermediate(18-30), or high(&amp;gt;30). TS was divided into T1a(0.1-0.5 cm), T1b(0.51–1.0 cm), T1c(1.1–2.0 cm), and T2(2.1-5.0 cm).Results: Mean patient age was 60.9 years(range 35-82 years). Average(AVG) RS was 20.9; AVG RR at 10 years, 13.6%. Mean TS was 1.5 cm(median 1.3 cm). Overall, 29 patients(27.6%) received CT; 76(72.4%) did not. AVG TS for CT patients was 1.8cm, AVG RS was 29.5, and AVG age was 56.4(range 35-75). Non-CT patients' AVG TS was 1.4cm; AVG RS, 17.7; AVG age, 62.6(range 44-86). 9 patients(8.5%) had T1a tumors with an AVG RS of 19.1, and no patient received CT. 25(23.8%) had T1b tumors with an AVG RS of 21.0, and 5(20.0%) received CT. 51(48.6%) had T1c tumors with an AVG RS of 20.4, and 15(29.4%) received CT. 20(19.0%) had T2 tumors with an AVG RS of 23.1; 9(45.0%) received CT. 41 patients(39.0%) had low RS: 4(9.8%) received CT; 37(90.2%) did not. AVG TS and RS were 1.6cm and 15.0 respectively for CT patients, and 1.5cm and 11.6 for no CT patients. 49 patients(46.7%) had intermediate RS: 13(26.5%) received CT; 36(73.5%) did not. AVG TS and RS were 1.9cm and 22.7 for CT patients; 1.3cm and 22.2 for no CT patients. 15 patients(14.3%) had high RS: 12(80.0%) received CT; 3(20.0%) did not. AVG TS and RS were 1.7cm and 44.7 for CT patients; 1.3cm and 39.3 for no CT patients. 10 patients were Her-2+, 5 with high, 4 with intermediate, and 1 with low RS. 7 had CT. 5 of the 15(33.3%) high RS patients were Her-2+. AVG RS for the Her-2+ patients was 36.2, and AVG TS was 1.9cm. AVG RS was 19.3 for the non-Her-2+ patients. 16 patients were &amp;lt;50 years old. AVG TS was 1.5cm and AVG RS was 24.2. 8 received CT and 8 did not. 89 patients were ≥50. AVG TS was 1.5cm and AVG RS was 20.3. 21(23.6%) received CT and 68 did not. Discussion: AVG RS was 20.9 for all T stages. Overall, 27.6% of patients received CT. Of the 64 with RS&amp;gt;18, only 25(39.1%) received CT; 4(9.8%) of low RS patients still received CT. Patients with larger tumors and younger age were more likely to receive CT. Neither RS, TS, nor age alone seemed to influence the final decision. Multiple factors are still considered by oncologists when making CT decisions, and conversely, patients may not accept CT despite high RS. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6039.

Nerve growth factor receptor (p75NTR) and pattern of invasion predict poor prognosis in oral squamous cell carcinoma

To evaluate the expression of p75 neurotrophin receptor (p75(NTR)) in oral squamous cell carcinoma (OSCC). The results were related to tumour node metastasis (TNM) stage, World Health Organization (WHO) grade, invasive front grading (IFG) and prognosis. Immunohistochemically, the expression of p75(NTR) was assessed in 53 T1-T2 OSCCs. Clinical data were recorded prospectively. The end-point was disease-free survival. All tumours expressed p75(NTR), and this expression, both in central/superficial tumour areas and at the invasive front, was associated with poor prognosis (P = 0.03 and P = 0.02) (log rank test). Tumours with marked cellular dissociation (IFG parameter) had more recurrences than tumours with collective tumour cell invasion (P = 0.03). In tumours showing both p75(NTR) at the invasive front and marked tumour cell dissociation, the average risk of recurrence was increased about 17 times (Cox regression analysis) compared with tumours with low p75(NTR) expression and collective invasion. Traditional prognostic systems were of no prognostic significance. p75(NTR) was expressed in all OSCCs. p75(NTR) expression and the pattern of invasion were significantly associated with a poor prognosis in OSCCs, and both were better prognostic factors than traditional prognostic parameters. The combination of p75(NTR) expression and the pattern of invasion strongly increased precision in the identification of tumours with poor disease-free survival.

Modeling for cost-effective-adjuvant aromatase inhibitor strategies for postmenopausal women with breast cancer

To determine cost-effective (CE) strategies comparing adjuvant upfront aromatase inhibitor (AI) with sequential tamoxifen (TAM) AI in postmenopausal (PM) women with breast cancer (BC). A Markov model was constructed to calculate cumulative costs and quality-adjusted life year (QALY) gains for upfront AI and TAM-AI in a hypothetical cohort of 60-year-old PM women with BC. Costs, utilities and probabilities were derived from the literature. The hazard ratios (HRs) of AI strategies were applied to a baseline cancer recurrence risk (RR) to determine CE strategies at the $50,000/QALY gain threshold. A direct payer perspective is utilized, and costs and benefits were discounted at 3%. Two-way sensitivity analyses are presented to determine CE strategies across a wide range of HRs and in different clinical scenarios including varying RRs (low, average, high and very high). TAM-AI is the preferred CE strategy at low and average RR, while upfront AI is CE at very high RR. The CE strategy in patients with high RR was dependent on the scenario examined. This model may help health care providers select CE-adjuvant AI strategies in PM women with BC, until further direct evidence is available from randomized clinical trials.

Withdrawal of antiepileptic drugs.

Recent literature on withdrawing antiepileptic drug therapy in patients who are seizure free on antiepileptic drugs is reviewed. The average recurrence risk across studies is 29% at 2 years. Factors such as age of onset, etiology of seizures, the electroencephalogram and the epileptic syndrome influence outcome. Factors that need to be considered by the clinician include not just the statistical risk of recurrence but also the consequences of a recurrence, which will be a function of age and sex.

The risk of seizure recurrence following a first unprovoked seizure

Knowledge of the recurrence risk following a first unprovoked seizure and the predictors of that risk are necessary for rational treatment decisions. Published estimates of recurrence risk range from 23% to 71%. In a meta-analysis of 16 reports, three methodologic factors explained much of the reported variation: (1) study inclusion criteria, ie, whether patients were enrolled at the time of their first seizure or if patients with prior seizures were included; (2) retrospective versus prospective ascertainment of patients; (3) the interval between the first seizure and the time at which risk was assessed. The average recurrence risk across the 16 studies was 51%. The risk was 40% and 52% in prospective and retrospective studies that employed first-seizure methods and 67% in non-first seizure studies. At or near 2 years following the first seizure, the recurrence risk was 36% and 47% in prospective and retrospective first-seizure studies. The distribution of prognostic factors was also important. Seizure etiology and the EEG were the strongest predictors of recurrence distinguishing between patient subgroups, with recurrence risks as low as 24% and as high as 65%. Partial seizures were associated with an increased recurrence risk, but not consistently. There is considerable agreement among studies concerning the recurrence risk following a first seizure, and much of the discrepancies among studies can be explained by differences in study methods and distributions of important prognostic factors.