Baseline Risk Of Recurrence Research Articles

Development and validation of the Baseline Recurrence Risk in Cellulitis (BRRISC) score

Cellulitis is often treated with antibiotics for longer than recommended by guidelines. Prolonged therapy may reduce recurrence in certain patients, but it is not known which patients are at greatest risk. Our objective was to develop and temporally validate a risk prediction score to identify patients attending hospital with cellulitis at highest risk of recurrence. We included UK adult patients with cellulitis attending hospital in an electronic health records (EHR) study to identify demographic, comorbid, physiological, and laboratory factors predicting recurrence (before death) within 90 days, using multivariable logistic regression with backwards elimination in complete cases. A points-based risk score integerised model coefficients for selected predictors. Performance was assessed using the C-index in development and temporal validation samples. The final model included 4938 patients treated for median 8 days (IQR 6-11); 8.8% (n=436) experienced hospitalisation-associated recurrence. A risk score using eight variables (age, heart rate, urea, platelets, albumin, previous cellulitis, venous insufficiency, and liver disease) ranged from 0-15, with C-index=0.65 (95%CI:0.63-0.68). Categorising as low (score 0-1), medium (2-5) and high (6-15) risk, recurrence increased fourfold; 3.2% (95%CI: 2.3-4.4%), 9.7% (8.7-10.8%), and 16.6% (13.3-20.4%). Performance was maintained in the validation sample (C-index=0.63 (95%CI:0.58-0.67)). Among patients at high risk, four distinct clinical phenotypes were identified using hierarchical clustering 1) young, acutely unwell with liver disease; 2) comorbid with previous cellulitis and venous insufficiency; 3) chronic renal disease with severe renal impairment; and 4) acute severe illness, with substantial inflammatory responses. Risk of cellulitis recurrence varies markedly according to individual patient factors captured in the Baseline Recurrence Risk in Cellulitis (BRRISC) score. Further work is needed to optimise the score, considering baseline and treatment response variables not captured in EHR data, and establish the utility of risk-based approaches to guide optimal antibiotic duration.

Evolution of suppressing TSH therapy at diagnosis and in the long-term follow-up in a cohort of differentiated thyroid cancer

IntroductionTo evaluate the adequacy of TSH suppression therapy (TSHst) at the first disease assessment and the last follow-up visit. MethodsRetrospective observational study of those patients under follow-up of DTC in a reference hospital. Results216 patients (79.2% women) were evaluated, with a mean age 59.0 ± 13.1 years-old and a mean follow-up of 6.9 ± 4.3 years. 88.4% were papillary carcinomas.At diagnosis, 69.2% had a low risk of recurrence (RR) compared to 13.6% with a high RR. Dynamic risk stratification (DRS) classified patients at first disease assessment and the last visit as excellent response (ER) in 60.0% and 70.7%, respectively.Those patients with ER in the first and last follow-up control maintained TSHst in 30.7% and 16.3% of the cases, respectively (p < 0.001).The factors associated with maintaining TSHst at the last control were younger age, higher RR at diagnosis, DRE at follow-up, presence of multifocality and histological vascular invasion (p < 0.05).In a logistic regression analysis adopting tsTSH at follow-up as the dependent variable, exclusively age (β = −0.062; p < 0.001), RR at diagnosis (β = 1.074; p < 0.05) and EDR during follow-up (β = 1.237; p < 0.05) maintained statistical significance. ConclusionsDespite the current recommendations, 30.7% of patients with low RR and initial ER are under TSHst. This percentage reduced to 16.3% in those patients with ER after a mean follow-up of 6.9 years. Age, baseline RR, and DRE during follow-up were associated to maintaining tsTSH.

Evolución del tratamiento supresor de la TSH al diagnóstico y en el seguimiento en una cohorte de carcinoma diferenciado de tiroides

IntroductionTo evaluate the adequacy of TSH suppression therapy (TSHst) at the first disease assessment and the last follow-up visit. MethodsRetrospective observational study of those patients under follow-up of DTC in a reference hospital. Results216 patients (79.2% women) were evaluated, with a mean age 59.0±13.1 years-old and a mean follow-up of 6.9±4.3 years. 88.4% were papillary carcinomas.At diagnosis, 69.2% had a low risk of recurrence (RR) compared to 13.6% with a high RR. Dynamic risk stratification (DRS) classified patients at first disease assessment and the last visit as excellent response (ER) in 60.0% and 70.7%, respectively.Those patients with ER in the first and last follow-up control maintained TSHst in 30.7% and 16.3% of the cases, respectively (p < 0.001).The factors associated with maintaining TSHst at the last control were younger age, higher RR at diagnosis, DRE at follow-up, presence of multifocality and histological vascular invasion (p < 0.05).In a logistic regression analysis adopting tsTSH at follow-up as the dependent variable, exclusively age (β = -0.062; p < 0.001), RR at diagnosis (β = 1 074; p < 0.05) and EDR during follow-up (β =1 237; p < 0.05) maintained statistical significance. ConclusionsDespite the current recommendations, 30.7% of patients with low RR and initial ER are under TSHst. This percentage reduced to 16.3% in those patients with ER after a mean follow-up of 6.9 years. Age, baseline RR, and DRE during follow-up were associated to maintaining tsTSH.

Adjuvant nivolumab in high-risk stage IIb/IIc melanoma patients: Results from investigator initiated clinical trial.

9583 Background: Recent studies have shown 5-yr recurrence rates for Stage IIB and IIC melanoma of up to 46%. These high-risk patients currently have few options for adjuvant therapy to prevent this inevitable recurrence, with the only FDA approved therapy being high-dose interferon-alfa, which is quite toxic. However, there are now immunotherapies (anti-PD1) and targeted therapies (anti-BRAF and anti-MEK combinations) which are approved as adjuvants for Stage III patients, some of whom will have a lower baseline recurrence risk than those with Stage IIB/IIC melanoma. We sought to determine if adjuvant PD1 inhibition with nivolumab (N) would improve the recurrence free survival (RFS) compared to historical RFS rates. Methods: Our study (NCT03405155) is a single-arm, open label, multi-center, phase 2 clinical trial evaluating RFS at 24 months in patients with Stage IIB/IIC melanoma on treatment with N at 480 mg IV every 4 weeks for 12 cycles. Overall survival is a secondary endpoint. Associated translational research includes circulating tumor cell DNA and immune correlates. Results: Twenty three patients with Stage IIB and three patients with Stage IIC melanoma were enrolled onto the study and received at least one dose of N. At data cutoff, 22 patients remain in follow up, as four patients withdrew consent at different time points in the study – one patient after one dose who wished to discontinue, one due to concern for COVID and need for repeat visits, one due to insurance issues, and one due to recurrence and wish to discontinue (which was captured in study data and RFS calculations). Seventeen patients have been on the clinical trial for at least two years with nine patients having finished treatment but with less than two years follow-up; the median follow-up is currently 21.9 months. Two patients demonstrated melanoma recurrence, one after receiving cycle six of N and another one year after completing treatment, resulting in a 87.8% RFS (90% CI (64.2%-96.3%) at 2 years, compared to the historical RFS at 2 years of 70%. No N related serious adverse events (SAEs) were observed, with only 2% Grade 3 AEs observed (varied and unrelated to treatment) and all others were Grade 1-2, including 21% GI, 18% cutaneous, and 10% musculoskeletal, respiratory, and fatigue, each; overall, 2% of these Grade 1-2 AEs were treatment related. Conclusions: Our preliminary results show a trend towards improved RFS in patients with Stage IIB/IIC melanoma treated with nivolumab. The cohort has not reached a minimum follow up of at least 2 years for RFS; patients are continuing to be monitored. On study, we observed the expected adverse events, without evidence of new toxicities. Data maturation will reveal the full effect of adjuvant N on disease relapse and overall survival and distant metastasis-free survival in stage IIB/IIC melanoma patients. Clinical trial information: NCT03405155.

Unique prognostic features of grade 3 endometrioid endometrial carcinoma: Findings from 101 consecutive cases at a Japanese tertiary cancer center

ObjectiveThe prognosis of and optimal treatment for grade 3 endometrioid endometrial carcinoma (G3EEC) currently remain unclear. This study aimed to clarify the baseline recurrence risk in patients with early-stage (stage I–II) G3EEC without adjuvant therapy and the prognosis of patients with advanced-stage (stage III–IV) G3EEC. Materials and methodsA total of 101 patients with pathologically confirmed G3EEC from 1997 to 2018 were identified. Their clinicopathological characteristics and survival outcomes were reviewed retrospectively. Disease-free survival and overall survival values were estimated according to the Kaplan–Meier method and compared using a log-rank test. ResultsRecurrence was observed in eight (13%) of 63 patients with early-stage G3EEC, none of whom had received adjuvant therapy. The 5-year disease-free survival and 5-year overall survival rates for these patients were 86.7% and 96.4%, respectively. Recurrence was also observed in 12 (41%) of 29 patients with stage III G3EEC. The 5-year overall survival rates for stage III patients who underwent adjuvant chemotherapy and adjuvant radiotherapy were 85.6% and 42.9%, respectively. The 3-year overall survival rate among stage IVB patients was only 12.7% despite multidisciplinary treatment provision. ConclusionOur study newly demonstrates that patients with early-stage G3EEC have a favorable prognosis and a low recurrence rate in the absence of adjuvant therapy. In patients with stage III G3EEC, adjuvant chemotherapy was more beneficial than adjuvant radiotherapy. The poor prognosis of patients with stage IV G3EEC indicates the need for more effective treatments. Unique therapeutic approaches based on staging are recommended for treatment of G3EEC.

The baseline recurrence risk of patients with intermediate-risk cervical cancer.

ObjectiveThis study aimed to investigate the prognosis of patients with intermediate-risk cervical cancer and to evaluate the necessity of adjuvant therapy.MethodsWe conducted a retrospective chart review of patients with stage IB–II cervical cancer who underwent type III radical hysterectomy with pelvic lymphadenectomy between 2008 and 2017. In our institution, radical hysterectomy is performed as an open surgery and not as a minimally invasive surgery, and adjuvant therapy is not administered to patients with intermediate-risk cervical cancer. The intermediate-risk group included patients with 2 or more of the following factors: tumor size >4 cm, stromal invasion >1/2, and lymphovascular stromal invasion. Intermediate-risk patients with squamous cell carcinoma were included in the I-SCC group, whereas those with endocervical adenocarcinoma, usual type, or adenosquamous carcinoma were included in the I-Adeno group.ResultsThere were 34 and 18 patients in the I-SCC and I-Adeno groups, respectively. The 5-year recurrence-free survival (RFS) and overall survival rates in the I-SCC group were 90.5% (95% confidence interval [CI], 85.3–95.7%) and 100% (95% CI, 100%), respectively, whereas those in the I-Adeno group were 54.9% (95% CI, 42.0–67.9%) and 76.1% (95% CI, 63.7–88.4%), respectively. Multivariate analysis revealed that endocervical adenocarcinoma, usual type, or adenosquamous carcinoma, and tumor size >4 cm had worse RFS.ConclusionThe I-SCC group had good prognosis without adjuvant therapy; therefore, adjuvant therapy may be omitted in these patients. In contrast, the I-Adeno group had poor prognosis without adjuvant therapy; therefore, adjuvant therapy should be considered in their treatment.

Paratubal Cyst Recurrence in Children and Adolescents.

To examine the association between patient characteristics and risk for recurrence risk of paratubal cysts (PTC) in children and adolescents. Retrospective chart review at a single institution. Single academic children's hospital. Pediatric patients presenting to Texas Children's Hospital between July 2007 and March 2019. Patients were identified for the study by reviewing pathology reports and were included if they met inclusion criteria of a pathologic diagnosis of a paratubal or paraovarian cyst removed during any surgical procedure between July 2007 and March2019. Subjects with pathologic diagnoses of a paratubal cyst during the study period underwent chart review for the following data points: age at presentation, ethnicity, pathologic recurrence of paratubal cysts, pubertal status, body mass index (BMI), diagnosis of polycystic ovary syndrome (PCOS), size of cyst, laterality of cysts, and number of cysts. Recurrence, Pathology types. Of the 627 patients that met inclusion criteria, the incidence of recurrence was 11.3%. Group 1 included those with recurrence of PTC (N=70). Group 2 was identified as those without recurrence of PTC (N=557). There were no differences related to age, BMI, ethnicity, history of PCOS, cyst size, laterality or number of cysts present. PTC NOS and serous PTC occurred most frequently. Of the unique cases involving recurrence, 70.1% recurred on the ipsilateral side. There were no cases of paratubal cyst malignancies in this cohort. The range of pathology diagnoses included pathologies that may occur in ovarian cysts. This is particularly interesting, given the known origins of ovarian cancer from fallopian tube transformations. Rare pathology diagnoses likely did not occur with frequency to determine definitive risks of recurrence in these cases. There appears to be a baseline recurrence risk for PTC, for which patients can be counseled. Recurrence does not appear to be associated with any particular pathology type, cyst size, number of cysts, BMI, PCOS, or puberty stage. Recurrence, should it occur, appears to occur more commonly on the ipsilateral side.

Combination of FDG-PET and FMISO-PET as a treatment strategy for patients undergoing early-stage NSCLC stereotactic radiotherapy

BackgroundWe investigated the prognostic predictive value of the combination of fluorodeoxyglucose (FDG)- and fluoromisonidazole (FMISO)-PET in patients with non-small cell lung carcinoma (NSCLC) treated with stereotactic body radiation therapy (SBRT).Patients and methodsWe prospectively examined patients with pathologically proven NSCLC; all underwent FDG and FMISO PET/CT scans before SBRT. PET images were acquired using a whole-body time-of-flight PET-CT scanner with respiratory gating. We classified them into recurrent and non-recurrent groups based on their clinical follow-ups and compared the groups' tumor diameters and PET parameters (i.e., maximum of the standardized uptake value (SUVmax), metabolic tumor volume, tumor-to-muscle ratio, and tumor-to-blood ratio). We performed univariate analysis to evaluate the impact of the PET variables on the patients' progression-free survival (PFS). We divided the patients by thresholds of FDG SUVmax and FMISO SUVmax obtained from receiver operating characteristic analysis for assessment of recurrence rate and PFS.ResultsThirty-two NSCLC patients (19 male and 13 females; median age, 83 years) were enrolled. All received SBRT. At the study endpoint, 23 patients (71.9%) were non-recurrent and nine patients (28.1%) had recurrent disease. Significant between-group differences were observed in tumor diameter and all the PET parameters, demonstrating that those were significant predictors of the recurrence in all patients. In the 22 patients with tumors > 2 cm, tumor diameter and FDG SUVmax were not significant predictors. Thirty-two patients were divided into three patterns from the thresholds of FDG SUVmax (6.81) and FMISO SUVmax (1.89); A, low FDG and low FMISO (n = 14); B, high FDG and low FMISO (n = 8); C, high FDG and high FMISO (n = 10). No pattern A patient experienced tumor recurrence, whereas two pattern B patients (25%) and seven pattern C patients (70%) exhibited recurrence. A Kaplan-Meier analysis of all patients revealed a significant difference in PFS between patterns A and B (p = 0.013) and between patterns A and C (p < 0.001). In the tumors > 2 cm patients, significant differences in PFS were demonstrated between pattern A and C patients (p = 0.002).ConclusionThe combination of FDG- and FMISO-PET can identify patients with a baseline risk of recurrence and indicate whether additional therapy might be performed to improve survival.

Prognostic Relevance of a Complete Pathologic Response in Liver Transplantation for Hepatocellular Carcinoma

BackgroundA complete pathologic response (CPR) after neoadjuvant treatment is reported to be associated with an exceptionally low risk of recurrence after liver transplantation for hepatocellular carcinoma (HCC). This study aimed to evaluate the prognostic role of CPR in liver transplantation for HCC.MethodsThis retrospective cohort study was based on 222 HCC transplant recipients. Incidence of recurrence and survival at 5 years were the primary and secondary outcome measures, respectively. Competing risk analyses were applied to evaluate recurrence incidence and its predictors. Propensity score matching was performed to compare the outcomes for patients after neoadjuvant treatment with and without CPR.ResultsNeoadjuvant treatment was performed for 127 patients, 32 of whom achieved CPR (25.2%). Comparison of baseline characteristics showed that the patients with CPR were at lowest baseline recurrence risk, followed by treatment-naïve patients and patients without CPR. Adjusted for potential confounders, CPR did not have any significant effects on tumor recurrence. No significant net reclassification improvement was noted after addition of CPR to existing criteria. Neoadjuvant treatment without CPR was associated with increased risk of recurrence in subgroups within the Milan criteria (p = 0.016), with alpha-fetoprotein concentration (AFP) model not exceeding 2 points (p = 0.021) and within the Warsaw criteria (p = 0.007) compared with treatment-naïve patients who were at risk similar to those with CPR. The 5-year incidences of recurrence in propensity score-matched patients with and without CPR were respectively 14.0% and 15.9% (p = 0.661), with corresponding survival rates of 73.2% and 67.4%, respectively (p = 0.329).ConclusionsThe findings showed that CPR is not independently associated with long-term outcomes after liver transplantation for HCC.

Abstract P3-12-04: Efficacy of extended adjuvant aromatase inhibitors in subgroups of women with early breast cancer

Abstract Background: Randomized trials (RCTs) have reported improvements in breast cancer outcomes from extending treatment with aromatase inhibitors (AIs) beyond the initial 5 years after diagnosis. It is uncertain whether this effect is consistent in different subgroups. Methods: We identified RCTs that compared extended AIs to placebo or no treatment using a systematic search of MEDLINE. The search was supplemented by a review of abstracts from the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium meetings between 2013 and 2016. Hazard ratios (HRs) and 95% confidence intervals (CI) for disease-free survival (DFS) were extracted or estimated from forest plots and included in a meta-analysis using generic inverse variance and random effects modelling. Pre-specified subgroups included age (&amp;lt;60 ± 5 years vs. ≥60 ± 5 years), tumor size (≤2 cm vs. &amp;gt;2 cm), nodal status (positive vs. negative), hormone receptor status (estrogen [ER] and progesterone receptor [PR] positive vs. ER or PR positive) and administration of adjuvant chemotherapy (yes vs. no). Results: Seven trials comprising 16,349 patients were analyzed. Studies designs and prior endocrine therapy are shown in Table 1 Table 1: Characteristics of included studies.TrialTreatment ArmsSample sizePrior endocrine treatmentABCSG 6aAnastrozole 3 years vs. none387/ 469Tamoxifen± aminoglutethimide: 100%, 5 yearsMA 17Letrozole 5 years vs. placebo2572/ 2577Tamoxifen: 100%, ∼5 yearsNSABP B-33Exemestane 5 years vs. placebo783/ 779Tamoxifen: 100%, ∼5 yearsDutch DATAAnastrozole 6 years vs,. anastrozole 3 years827/ 833Tamoxifen: 100%, 2-3 yearsIDEALLetrozole 5 years vs. letrozole 2.5 years903/ 898Any endocrine treatment (tamoxifen/AIs/sequence of tamoxifen+ AIs): 100%, 5 yearsMA.17RLetrozole 5 years vs. placebo959/ 959AIs: 100%, ∼5 years Prior tamoxifen: 79.3%NSABP B-42Letrozole 5 years vs. placebo1959/ 1964Any endocrine treatment (AIs/sequence of tamoxifen+ AIs): 100%, 5 years . The pooled effect of prolonged treatment with AIs in different subgroups is shown in the Table 2. Table 2: Intra-subgroup comparison of longer AIs treatment effect by subgroupsSubgroup ASubgroup BHR (95% CI) Subgroup AHR (95% CI) Subgroup BP for differenceAge &amp;lt;60 ± 5Age ≥60 ± 50.83 (0.70-0.99)0.85 (0.74-0.97)0.64T &amp;gt;2 cmT ≤2 cm0.77 (0.55-1.06)0.88 (0.68-1.13)0.44N positiveN negative0.72 (0.63-0.83)0.83 (0.64-1.08)0.22ER and PR positiveER or PR positive0.68 (0.44-1.04)1.03 (0.53-2.02)0.27Adjuvant chemotherapyNone0.71 (0.59-0.86)0.80 (0.65-0.98)0.51 Overall, the effect of prolonged AIs was similar in all subgroups. However, non-significantly greater effect sizes were seen in patient with larger tumors, nodal involvement, presence of both ER and PR expression and those treated with adjuvant chemotherapy. Conclusions: Extended treatment with adjuvant AIs is associated with similar relative improvements in DFS in all subgroups analyzed. The greater effect size seen in node positive and large tumor subgroups and the higher baseline risk of recurrence will likely translate to a higher absolute benefit from extended AIs in these groups. Citation Format: Goldvaser H, Algorashi I, Ribnikar D, Majeed H, Ocana A, Seruga B, Templeton AJ, Amir E. Efficacy of extended adjuvant aromatase inhibitors in subgroups of women with early breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-12-04.

Comparison of Residual Risk–Based Eligibility vs Tumor Size and Nodal Status for Power Estimates in Adjuvant Trials of Breast Cancer Therapies

Many large adjuvant clinical trials end up underpowered because of fewer than expected events in the control arm. Ensuring a minimum number of events would result in more informative trials. To calculate individualized residual risk estimates using residual risk prediction software and assess whether defining eligibility based on a minimum residual risk threshold could increase the reliability of clinical trial power calculations compared with eligibility criteria based on tumor size and nodal status. We estimated residual risk in 443 consecutive patients with early-stage breast cancer and assessed clinical trial power as a function of residual risk distribution among the accrued patients. We defined residual risk as the risk of recurrence that remains despite receipt of standard-of-care therapy; this risk is determined by baseline prognostic risk and by the improvement from adjuvant therapy. We performed trial simulations to examine how the power of a 2-arm, 1:1 randomized clinical trial would change as the residual risk distribution of the trial population that met eligibility criteria based on tumor size and nodal status changes. We also simulated trials that use a minimum residual risk value as eligibility criterion. Residual risk; clinical trial power as a function of residual risk distribution among the patients. In the 443 patients (mean [SD] age, 56.1 [12.3] years; range, 23-89 years), baseline prognostic and residual risks differed substantially: 328 (74%) patients had more than 20% baseline risk of recurrence; however, after adjustment for treatment effect only 12 (27%) had more than 20% residual risk. We assessed residual risk distribution in patient cohorts that met tumor size- and nodal status-based eligibility criteria for 3 currently accruing randomized adjuvant trials; the median residual risks were 28% (interquartile range [IQR], 25%-31%), 22% (IQR, 15%-28%), and 22% (IQR, 15%-28%), respectively, indicating that the power of these trials could vary unpredictably. Simulations showed that trials that use anatomical risk-based eligibility criteria can become underpowered if they accrue patients with low residual risk despite all participants meeting eligibility requirements. Using a minimum required residual risk threshold as eligibility criterion produced more reliable power calculations. When tumor size and nodal status are used to determine trial eligibility, the residual risk of recurrence can vary broadly, leading to unstable power estimates. The success of future adjuvant trials could be improved by defining patient eligibility based on a minimal residual risk of recurrence, and these trials can achieve a prespecified power with smaller sample sizes.

Prognostic factors for patients with early-stage uterine serous carcinoma without adjuvant therapy.

ObjectiveUterine serous carcinoma (USC) is an aggressive type 2 endometrial cancer. Data on prognostic factors for patients with early-stage USC without adjuvant therapy are limited. This study aims to assess the baseline recurrence risk of early-stage USC patients without adjuvant treatment and to identify prognostic factors and patients who need adjuvant therapy.MethodsSixty-eight patients with International Federation of Gynecology and Obstetrics (FIGO) stage I–II USC between 1997 and 2016 were included. All the cases did not undergo adjuvant treatment as institutional practice. Clinicopathological features, recurrence patterns, and survival outcomes were analyzed to determine prognostic factors.ResultsFIGO stages IA, IB, and II were observed in 42, 7, and 19 cases, respectively. Median follow-up time was 60 months. Five-year disease-free survival (DFS) and overall survival (OS) rates for all cases were 73.9% and 78.0%, respectively. On multivariate analysis, cervical stromal involvement and positive pelvic cytology were significant predictors of DFS and OS, and ≥1/2 myometrial invasion was also a significant predictor of OS. Of 68 patients, 38 patients had no cervical stromal invasion or positive pelvic cytology and showed 88.8% 5-year DFS and 93.6% 5-year OS.ConclusionCervical stromal invasion and positive pelvic cytology are prognostic factors for stage I–II USC. Patients with stage IA or IB USC showing negative pelvic cytology may have an extremely favorable prognosis and need not receive any adjuvant therapies.

Selection of Optimal Adjuvant Chemotherapy Regimens for Human Epidermal Growth Factor Receptor 2 (HER2) -Negative and Adjuvant Targeted Therapy for HER2-Positive Breast Cancers: An American Society of Clinical Oncology Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline.

A Cancer Care Ontario (CCO) guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer including adjuvant targeted therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancers was identified for adaptation. The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for adapting clinical practice guidelines developed by other organizations. The CCO guideline was reviewed for developmental rigor and content applicability. On the basis of the content review of the CCO guideline, the ASCO Panel agreed that, in general, the recommendations were clear and thorough and were based on the most relevant scientific evidence, and they presented options that will be acceptable to patients. However, for some topics addressed in the CCO guideline, the ASCO Panel formulated a set of adapted recommendations on the basis of local context and practice beliefs of the Panel members. Decisions regarding adjuvant chemotherapy regimens should take into account baseline recurrence risk, toxicities, likelihood of benefit, and host factors such as comorbidities. In high-risk HER2-negative populations with excellent performance status, anthracycline- and taxane-containing regimens are the standard of care. Docetaxel and cyclophosphamide for four cycles is an acceptable non-anthracycline regimen. In high-risk HER2-positive disease, sequential anthracycline and taxanes administered concurrently with trastuzumab or docetaxel, carboplatin, and trastuzumab for six cycles are recommended. An alternative regimen in a lower-risk, node-negative, HER2-positive population is paclitaxel and trastuzumab once per week for 12 cycles. Trastuzumab should be given for 1 year. Platinum salts should not be routinely administered in the adjuvant triple-negative population until survival efficacy data become available.

Making Decisions about Thromboprophylaxis in Pregnancy: Women’s Values and Preferences

Background: The risk of pregnancy-related venous thromboembolism (VTE) is increased in women with a history of thrombosis. Although antepartum low molecular weight heparin (LMWH) prophylaxis can reduce this risk; the baseline risk of recurrence and the absolute magnitude of the risk reduction with prophylaxis are uncertain. Further, LMWH prophylaxis is costly, burdensome, medicalizes pregnancy, and may increase the risk of bleeding. Therefore, uncertainty persists regarding the net benefit of thromboprophylaxis and recommendations about the use of antepartum LMWH should be sensitive to pregnant women’s values and preferences, which have not previously been studied.Methods: We undertook an international multicenter cross-sectional interview study that included women with a history of VTE who were pregnant, planning pregnancy, or might consider pregnancy in the future. Women were classified as high (5 to 10%) or low (1 to 5%) risk of recurrent antepartum VTE. We ascertained willingness to receive LMWH during pregnancy through direct choice exercises involving real-life scenarios using the participant’s estimated VTE (high or low) and bleeding risks, hypothetical scenarios (low, medium and high risk of recurrence) and a probability trade-off exercise. Study outcomes included the minimum absolute reduction in VTE risk at which women changed from declining to accepting LMWH, along with possible determinants of this threshold, and participant choice of management strategy in her real-life and the three hypothetical scenarios.Results: 123 women from seven centers in six countries participated. Using a fixed 16% VTE risk without prophylaxis, the mean threshold reduction in risk at which women were willing to use LMWH was 4.3% (95% CI, 3.5 – 5.1%). Pregnant women and those planning a pregnancy (compared to those who might consider pregnancy in the future) and those with less than 2 weeks of experience with using LMWH during pregnancy (compared to those with more experience) required a greater risk reduction to use prophylaxis. In the real life scenario, there was there a significant difference in the proportion of women choosing prophylaxis between those at high risk (87.1%) and low risk (60.0%) of recurrence (p=0.01). The proportion of women choosing to use LMWH prophylaxis was 65.1% for the low risk hypothetical scenario (4% risk of recurrence), 79.7% for the medium risk scenario (10% risk of recurrence) and 87.8% for the high risk scenario (16% risk of recurrence).Conclusions: Most women with prior VTE will choose prophylaxis during a subsequent pregnancy, regardless of whether they are categorized as high or low risk of recurrence. Nevertheless, 40% of lower risk women will decline LMWH, as will over 10% of high risk women. Thus, these results mandate individualized clinical decision-making for women considering LMWH use during pregnancy, and weak guideline recommendations for LMWH use that highlight the need for individualized decision-making. DisclosuresNo relevant conflicts of interest to declare.

Patients' perceptions of gene expression profiling in breast cancer treatment decisions.

Determining the likely benefit of adjuvant chemotherapy for early-stage breast cancer patients depends on estimating baseline recurrence risk. Gene expression profile (gep) testing of tumours informs risk prediction, but evidence of its clinical utility is limited. We explored patient perceptions of gep testing and the impact of those perceptions on chemotherapy decisions. We conducted one focus group (n = 4) and individual interviews (n = 24) with patients who used gep testing, recruited through clinics at two hospitals in Ontario. Data were analyzed using content analysis and constant comparison techniques. Patients' understanding of gep testing was variable, and misapprehensions were common. Patients valued the test because it provided them with certainty amidst confusion, with options and a sense of empowerment, and with personalized, authoritative information. They commonly believed that the test was better and fundamentally different from other clinical tests, attributing to it unique power and truth-value. This kind of "magical thinking" was derived from an amplified perception of the test's validity and patients' need for reassurance about their treatment choices. Despite misperceptions or magical thinking, gep was widely considered to be the deciding factor in treatment decisions. Patients tend to overestimate the truth-value of gep testing based on misperceptions of its validity. Our results identify a need to better support patient understanding of the test and its limitations. Findings illustrate the deep emotional investment patients make in gep test results and the impact of that investment on their treatment decisions.

The Role of Adjuvant Radiation Therapy for Stage I Endometrial Cancer: Does Meta-Analysis Reveal the Answer?

annual death rate from uterine cancer is much less than that from ovarian cancer and only modestly higher than that from cervical cancer, suggesting that high-risk endometrial cancer is actually a relatively rare disease (4). In Northern Europe, where most of the randomized trials were conducted, racial and other demographic characteristics differ from those in the United States, and highrisk endometrial cancer may be even less common. For example, in the Netherlands, home of the PORTEC trials, the annual death rate from endometrial cancer is about 3 per 100 000 women, compared with an annual rate of 5 per 100 000 women in the United States (4,5). We know from these data and from numerous clinical-pathologic analyses that uterine cancer has a heterogeneous presentation and that most of the recurrence (and death) risk, particularly for patients with stage I disease, resides in a relatively small subset of patients whose tumors exhibit multiple risk factors. Ideally, clinical trials would focus on these higher-risk patients for whom the margin for improvement is substantial. However, the desire to assure rapid accrual often leads investigators to broaden inclusion criteria. In fact, this has been one of the primary weaknesses of the endometrial cancer trials. Studies have tended to include large numbers of patients with low-grade or minimally invasive cancers—patients whose baseline risk of recurrence may be less than 5% to 10%. For these patients, even relatively minor side effects from radiation therapy (or lymphadenectomy or chemotherapy) will outweigh the most optimistic level of benefit from that treatment. If the proportion of patients with low-grade or minimally invasive cancers in a trial is large, treatment-related morbidity experienced by patients with low-risk tumors can easily obscure real benefits experienced by the smaller number of patients who have a greater margin for improvement. This phenomenon was well described by Kent and Haywood in their discussion of the potential pitfalls of summary statistics (6). The phenomenon is also clearly illustrated in the results of the GOG-99 trial (7). In that trial, subset analysis of a high-intermediate-risk subgroup suggested a fairly large potential benefit that was completely obscured when the entire group of patients, which on average was a relatively low-risk group, was

Radiotherapy in Older Women With Low-Risk Breast Cancer: Why Did Practice Not Change?

Radiotherapy after breast-conserving surgery reduces the risk of breast cancer recurrence and death as a result of breast cancer. In the most recent update of the Early Breast Cancer Trialists’ Group metaanalysis, radiotherapy lowered the risk of breast cancer recurrence by about one half and lowered the risk of breast cancer death by one sixth. 1,2 However, the absolute benefit of radiotherapy depended on the baseline risk of recurrence and was smaller in patients with a lower risk of recurrence. This concept raises the question of whether radiotherapy after breast-conserving surgery can be safely omitted if the absolute risk of recurrence is low. The CALGB 9343 trial directly addressed this question in the subset of older women with low-risk breast cancer. 2 This study enrolled more than 600 women age 70 years and older who had clinical stage 1 estrogen receptor–positive breast cancer and who were treated with breast-conserving surgery. Patients were randomly assigned to tamoxifen alone or tamoxifen plus radiotherapy. This study showed that there was no significant difference in the rates of subsequent mastectomy, distant metastases, or overall survival between the two groups. At the time of the initial study publication in 2004, the median follow-up was five years and the rate of local or regional recurrence was 1% in the group that received radiation and 4% in the group that did not. With longer follow-up of 10.5 years, the only significantly different outcome was local recurrence with a difference of 2% in the irradiated group and 9% in those women who did not receive adjuvant radiotherapy. 3 On the basis of these findings, the National Comprehensive

Abstract P5-11-15: Modeling for Response Predictive Factors in Adjuvant Endocrine Therapy: Impact on Preferential Benefits of Tamoxifen and Aromatase Inhibitors

Abstract Background: The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) observed significant improvements in breast cancer (BC) outcomes following adjuvant tamoxifen (TAM) and/or aromatase inhibitor (AI) therapy relative to natural history (NH) without endocrine therapy. In unselected populations, upfront AI for 5-years appears to be associated with improved disease-free survival (DFS) relative to 5-years of TAM alone. BC outcomes for TAM and AI in the EBCTCG meta-analyses, however, may reflect composite outcomes for heterogeneous sub populations of patients with varying responsiveness to TAM and AI's. A number of studies suggest that response to endocrine therapy (excellent vs poor) with TAM (TAM-excellent vs TAM-poor responders) and AI (AI-excellent vs AI-poor responders) may be related to TAM metabolizer status (non impaired vs impaired) and body mass index (normal vs high), respectively. This study examines the potential impact of these predictive factors on BC outcomes following TAM or AI therapy to determine the adjuvant endocrine monotherapy associated with improved BC outcomes for postmenopausal women with breast cancer. Methods: A generic state-transition model was developed to compute BC outcomes over a 10-year horizon in hypothetical cohorts of postmenopausal women receiving 5-years of adjuvant TAM (TAM cohort) or AI (AI cohort) or no endocrine therapy (NH cohort). We estimated DFS rates and cumulative life-years associated with NH, TAM and AI in unselected cohorts as well as sub-cohorts with varying responsiveness to TAM or AI. BC outcomes in the unselected cohorts were derived from the EBCTCG meta-analyses. BC outcomes in the sub-cohorts of TAM-excellent vs TAM-poor responders and AI-excellentvs AI-poor responders were based on varying combinations of responder proportions (excellent vs poor) and odd ratios (ORs) of BC outcomes in excellent vs poor responders that are plausible within the composite BC outcomes observed in the unselected TAM and AI cohorts. The model assumes that BC outcomes in poor responders could not be worse than BC outcomes for NH. Sensitivity analyses were conducted, and the impact of varying 10-year baseline recurrence risk without endocrine therapy was examined to reflect the natural spectrum of breast cancer disease encountered. Results: Two-way sensitivity analyses are provided for TAM and AI predictive factors to determine which adjuvant endocrine therapy (TAM vs AI) may be associated with improved BC outcomes based on the prevalence of the response predictive factors and their relative impact on BC outcomes. The plausible combinations of prevalence and OR for TAM excellent responders in the TAM cohort as well as AI poor responders in the AI cohort that predict improved BC outcomes with TAM relative to AI monotherapy are provided. Sensitivity analyses will be presented. Conclusions: Adjuvant endocrine monotherapy with TAM may be associated with improved BC outcomes in TAM-excellent responders compared to an unselected AI cohort or in an unselected TAM cohort compared to AI-poor responders. The choice of optimal adjuvant endocrine therapy may depend upon the prevalence of treatment predictive factors and their relative impact on BC outcomes. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-11-15.

Adjuvant hormone strategies in postmenopausal women with breast cancer: An economic evaluation based on the EBCTCG meta-analyses

6574 Background: Meta-analyses conducted by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) demonstrated significant improvements in breast cancer (BC) outcomes associated with tamoxifen (TAM) and/or aromatase inhibitor (AI) therapy. We conducted an economic evaluation, based on these meta-analyses, to examine the cost-effectiveness (CE) of adjuvant TAM, sequential TAM-AI and upfront AI in post menopausal (PM) women with BC. Methods: A generic model was developed to calculate cumulative costs and quality adjusted life year gains (QALYG) over 25-year horizon in hypothetical cohorts of PM women with BC undergoing 5-year treatment with TAM alone, upfront AI, or sequential TAM-AI. We examined different cohorts with varying 10-year baseline recurrence risk (RR) without adjuvant hormonal treatments to reflect the natural spectrum of breast cancer disease encountered (low = 25%; average = 38%; high = 50%; very high = 75%). The efficacy outcomes were derived from the EBCTCG meta-analyses, with 10-year duration of benefit assumed for all strategies. Costs and utilities were derived from the literature, and local resources. The analysis took a direct payer perspective and reports costs in 2008 Cdn$. Costs and benefits were discounted at 3%. CE was based on the $50,000/QALY gained threshold. Adverse events were not included in the primary analysis. Sensitivity analyses were conducted. Results: Adjuvant hormonal treatments with TAM and/or AI are CE strategies in PM women with BC. The costs and QALYG associated with hormonal treatments were dependent on the baseline RR: CE estimates were more favorable in cohorts with higher as opposed to lower RR. The baseline RR also influenced the choice of the optimal economic strategy. Upfront AI was associated with higher costs and more QALY gains compared to TAM-AI. CE however was favorable in patients with average to very high RR and unfavorable in patients with low RR. Conclusions: Adjuvant treatments with TAM and/or AI are associated with favorable CE in PM women with BC. The optimal CE strategies, however, are dependent on the baseline RR without hormonal treatment. A risk-tailored hormonal treatment choice could optimize the overall health system efficiency. [Table: see text]

Direct and indirect economic evaluation of upfront and sequential adjuvant treatment in postmenopausal women with breast cancer based on the BIG 1–98 trial

6594 Background: The monotherapy arms of the BIG 1–98 trial established the clinical superiority of upfront letrozole (LET) relative to tamoxifen alone (TAM) but direct comparison of sequential TAM-LET, LET-TAM and upfront LET did not establish a clinically superior strategy. We undertook an economic evaluation to identify an economically preferred strategy based on the relative cost-effectiveness (CE) of TAM, LET, TAM-LET, and LET-TAM in terms of cost per quality-adjusted life year gained (QALYG). Methods: A state-transition model was developed to calculate cumulative costs and QALYs over a 25yr horizon for hypothetical cohorts of postmenopausal women with HR+ breast cancer undergoing adjuvant hormonal treatment. As the sequential arms were not directly compared to TAM alone, it was not possible to directly compare all strategies. As such, the analysis conducted direct within-arm comparisons and an indirect between-arm comparison. DFS endpoints and relative DFS benefit were derived from the monotherapy and sequential arms of BIG 1–98. Adverse events were not included as these have not yet been reported. Sensitivity analyses were conducted for the key parameters and assumptions, including the baseline recurrence risk and the duration of carry-over benefit. Costs and utility weights were derived from the literature. The analysis took a Canadian direct payer perspective and drug costs were based on 2008 Canadian average wholesale prices. Costs and outcomes were discounted at 3%. Results: In the monotherapy arms LET had a CE of $16,650 relative to TAM. In the sequential arms LET-TAM had superior QALYGs and cost savings relative to LET and TAM-LET. In economic terms, LET-TAM dominated LET and TAM-LET. In the indirect comparison, LET-TAM dominated LET and TAM-LET and had superior QALYGs at increased cost relative to TAM for a CE of $178. Conclusions: Direct comparisons confirm the economic favourability of LET relative to TAM and establish the dominance of LET-TAM over LET and TAM-LET. These indirect comparisons support the strong economic favourability of LET-TAM relative to TAM in the indirect comparison. In the absence of superior clinical outcomes, economic evaluation is a useful in suggesting a preferred strategy. No significant financial relationships to disclose.