Adjuvant Treatment Guidelines Research Articles

Adjuvant Therapy for Hepatocellular Carcinoma After Curative Treatment: Several Unanswered Questions.

Most patients with hepatocellular carcinoma (HCC) have a poor prognosis. Hepatectomy and local ablation are the main curative treatments for HCC. Nevertheless, the recurrence rate after hepatectomy or ablation is up to 70%, which seriously affects patient prognosis. Several adjuvant therapies have been explored to reduce postoperative recurrence. However, although a variety of adjuvant therapies have been shown to reduce the recurrence rate and improve overall survival, a standard consensus of national HCC guidelines for adjuvant treatment is lacking. Therefore, there are significant differences in the recommendations for adjuvant therapy for HCC between the Eastern and Western guidelines. A variety of adjuvant treatment methods, such as antiviral therapy, transarterial chemoembolization or traditional Chinese medicine, are recommended by the Chinese HCC guidelines. However, Western guidelines make few recommendations other than antiviral therapy. Adjuvant immune checkpoint inhibitors are recommended only in the recently updated American Association for the Study of Liver Diseases guidelines. This review summarized the existing adjuvant therapy options after curative hepatectomy or ablation and discusses several important dilemmas of adjuvant treatments.

Survival and prognostic factors for postoperative primary appendiceal cancer: a retrospective cohort study based on the Surveillance, Epidemiology, and End Results database.

The factors affecting the postoperative survival of patients with primary appendiceal cancer (PAC) have yet to be fully explored. And there are no clear guidelines for adjuvant treatment after appendectomy. Whether chemotherapy can prolong patient survival after appendectomy, is critical in guiding postoperative medications. The majority of studies on appendiceal cancer are single case reports, and they focused on the incidence of appendiceal cancer. The present study aimed to investigate the survival characteristics of patients with primary appendiceal cancer after surgery using the Surveillance, Epidemiology, and End Results (SEER) database. The data of 2,891 cases of primary appendiceal cancer between 2004 to 2015 were obtained from the SEER database and subjected to survival analysis using the Kaplan-Meier method and Cox proportional-hazards model. The annual percentage change (APC) was calculated using the weighted least squares method. The overall age-adjusted incidence rate per 100,000 population steadily increased from 0.58 in 2004 to 1.63 in 2015. For patients who received chemotherapy, the median overall survival (OS) was 65 months and the 5-year OS rate was 51.9%, and for patients who did not receive chemotherapy or whose chemotherapy status was unknown, the median OS was not reached and the 5-year OS rate was 78.9%. Age [35< age <69: hazard radio (HR) =2.147; 95% confidence interval (CI): 1.442-3.197, P<0.001; age >69: HR =5.259; 95% CI: 3.485-7.937, P<0.001], race (White race: HR =0.728; 95% CI: 0.590-0.899, P=0.003), histologic type (mucinous neoplasm: HR =0.690; 95% CI: 0.580-0.821, P<0.001; malignant carcinoid: HR =0.657; 95% CI: 0.536-0.806, P<0.001), grade (II: HR =1.794; 95% CI: 1.471-2.187, P<0.001; III: HR =2.905; 95% CI: 2.318-3.640, P<0.001; IV: HR =3.128; 95% CI: 2.159-4.533, P<0.001), and stage (localized: HR =0.236; 95% CI: 0.194-0.287, P<0.001; regional: HR =0.425; 95% CI: 0.362-0.499, P<0.001) were identified as independent predictors of survival. And after adjusting for known factors (age, sex, race, tumor size, marital status, histologic type, grade, stage), chemotherapy (HR =1.220; 95% CI: 1.050-1.417, P=0.009) was revealed to be an independent indicator of poor prognosis. There was an increasing trend in the incidence of appendiceal cancer in the United States between 2004 and 2015. Chemotherapy was revealed to be an independent indicator of poor prognosis, which provide valuable insight into the therapy of primary appendiceal cancer. Large clinical trials of chemotherapy and targeted therapy for appendiceal cancer are urgently needed.

Association Between Adherence to Clinical Practice Guidelines for Adjuvant Therapy for Breast Cancer and Survival in a Resource-Limited Setting.

PURPOSEAddressing unwarranted clinical variation in oncology practices is expected to lead to improved cancer outcomes. Particularly, the application and impact of treatment guidelines on breast cancer outcomes are poorly studied in resource-limited settings. We measured adherence to a set of locally developed adjuvant treatment guidelines in a middle-income setting. Importantly, the impact of guidelines adherence on survival following breast cancer was determined.METHODSData of 3,100 Malaysian women with nonmetastatic breast cancer diagnosed between 2010 and 2017 were analyzed. Adherence to the Malaysian Clinical Practice Guidelines for Management of Breast Cancer second Edition was measured. Outcomes comprised overall survival and event-free survival.RESULTSGuideline adherence for chemotherapy, radiotherapy, hormonal therapy, and targeted therapy were 61.7%, 79.2%, 85.1%, and 26.2%, respectively. Older age was generally associated with lower adherence to guidelines. Compared with patients who were treated according to treatment guidelines, overall survival and event-free survival were substantially lower in patients who were not treated accordingly; hazard ratios for all-cause mortality were 1.69 (95% CI, 1.29 to 2.22), 2.59 (95% CI, 1.76 to 3.81), 3.08 (95% CI, 1.94 to 4.88), and 4.48 (95% CI, 1.98 to 10.13) for chemotherapy, radiotherapy, hormone therapy, and targeted therapy, respectively. Study inferences remain unchanged following sensitivity analyses.CONCLUSIONOur study findings appear to suggest that adherence to treatment guidelines that have been adapted for resource-limited settings may still provide effective guidance in improving breast cancer outcomes.

The role of molecular tests for adjuvant and post-surgical treatment in gynaecological cancers

The adjuvant and post-surgical treatment of gynaecological cancers has historically been guided by the estimation of relapse risk based on clinicopathological factors determined at the time of cancer diagnosis. The recent advancement of genomic and molecular characterisation of gynaecological cancers has begun to shift paradigms in the selection of adjuvant treatment strategy. Recent data regarding the predictive and/or prognostic value of molecular tests in the treatment of advanced ovarian cancer as well as early stage endometrial cancer have been the first such examples to enter adjuvant treatment guidelines for these diseases. In this article, we discuss the current state and future development of molecular assays for gynaecological cancers and how they impact upon treatment selection for ovarian, endometrial and cervical cancers in the post-surgical setting.

Consistent multimodality approach to oral cavity and high-risk oropharyngeal cancer in veterans

PurposeHigh-risk oropharyngeal squamous cell carcinoma (OPSCC) associated with tobacco exposure remains difficult to treat due to high rates of locoregional recurrence similar to oral cavity squamous cell carcinoma (OCSCC). Current NCCN guidelines allow for surgical management of this disease, but oncologic and functional data in the modern era remain scarce. We sought to compare and contrast oncologic and functional considerations for surgical management of OPSCC and OCSCC in a cohort of Veterans. Materials and methodsWe conducted a retrospective review of patients treated at the Michael E. DeBakey Veterans Affairs Medical Center between 2017 and 2020, treated using a homogenous, multi-modality algorithm. ResultsOPSCC tumors presented with a higher rate of perineural invasion (p < 0.05) and extranodal extension (p = 0.02) compared to OCSCC tumors. Compliance with NCCN guidelines for adjuvant treatment were lower for OPSCC patients primarily due to a higher rate of previous irradiation; re-irradiation could be delivered in 75% of patients when recommended by NCCN guidelines. Total glossectomy was accompanied by concomitant total laryngectomy in 100% of OPSCC patients and 0% of OCSCC. ConclusionSurgical resection and free flap reconstruction of high-risk OPSCC generates oncologic outcomes comparable to OCSCC with comparable complication rates but a lower overall functional status. Reconstruction focused on rapid healing allows for high-rates of re-irradiation and minimal treatment delays.Level of evidence: level 4.

Adjuvant therapy of histopathological risk factors of retinoblastoma in Europe: A survey by the European Retinoblastoma Group (EURbG).

Advanced intraocular retinoblastoma can be cured by enucleation, but spread of retinoblastoma cells beyond the natural limits of the eye is related to a high mortality. Adjuvant therapy after enucleation has been shown to prevent metastasis in children with risk factors for extraocular retinoblastoma. However, histological criteria and adjuvant treatment regimens vary and there is no unifying consensus on the optimal choice of treatment. Data on guidelines for adjuvant treatment in European retinoblastoma referral centres were collected in an online survey among all members of the European Retinoblastoma Group (EURbG) network. Extended information was gathered via personal email communication. Data were collected from 26 centres in 17 countries. Guidelines for adjuvant treatment were in place at 92.3% of retinoblastoma centres. There was a consensus on indication for and intensity of adjuvant treatment among more than 80% of all centres. The majority of centres use no adjuvant treatment for isolated focal choroidal invasion or prelaminar optic nerve invasion. Patients with massive choroidal invasion or postlaminar optic nerve invasion receive adjuvant chemotherapy, while microscopic invasion of the resection margin of the optic nerve or extension through the sclera are treated with combined chemo- and radiotherapy. Indications and adjuvant treatment regimens in European retinoblastoma referral centres are similar but not uniform. Further biomarkers in addition to histopathological risk factors could improve treatment stratification. The high consensus in European centres is an excellent foundation for a common European study with prospective validation of new biomarkers.

RADT-27. ASSOCIATION BETWEEN ADJUVANT RADIATION THERAPY AND OVERALL SURVIVAL IN PLEOMORPHIC XANTHOASTROCYTOMA

Abstract Pleomorphic Xanthoastrocytoma (PXA) is a low-grade central nervous system (CNS) tumor with a generally favorable prognosis. However, due to its rarity, optimal adjuvant treatment guidelines have not been established by large scale studies. In this study, we investigated the effect of adjuvant radiation therapy (RT) on overall survival (OS) in adult patients with PXA to help address this unanswered question. The National Cancer Database (NCDB) was used to identify adult patients (age 18 years old) diagnosed with histologically confirmed PXA (2004-2016). Patient demographics, tumor characteristics, and treatment information were collected. Kaplan-Meier curves were generated to study OS, and factors that affected OS were identified using a multivariate Cox proportional hazards (CPH) model. A total of 546 patients were identified. The average age of patients at diagnosis was 36.6 years old, and overall median survival was 128.6 months. RT was used to treat 179 (33.3%) patients. Those who received RT had a shorter median OS (33.3 months) compared to those who did not (&amp;gt; 128.6 months, p &amp;lt; 0.001). Our multivariate model demonstrated receiving RT was independently associated with a significantly higher risk of death (hazard ratio [HR]=4.28, 95% confidence interval [CI] = 1.77-10.38, p = .0013). Patients ≥ 65 years of age also demonstrated significantly higher risk of death (HR = 2.20, CI = 1.54-4.16, p = 0.006) and had a decreased median OS (26.0 months). In adults with PXA, treatment with RT is independently associated with a significantly higher risk of mortality. The routine use of this modality in treating PXA warrants further study.

Association between adjuvant radiation therapy and overall survival in Pleomorphic Xanthoastrocytoma

BackgroundPleomorphic Xanthoastrocytoma (PXA) is a low-grade central nervous system (CNS) tumor with a generally favorable prognosis. However, due to its rarity, optimal adjuvant treatment guidelines have not been established by large scale studies. In this study, we investigated the effect of adjuvant radiation therapy (RT) on overall survival (OS) in adult patients with PXA to help address this unanswered question. MethodsThe National Cancer Database (NCDB) was used to identify adult patients (age ≥ 18 years old) diagnosed with histologically confirmed grade II PXA (2004–2016). Patient demographics, tumor characteristics, and treatment information were collected. Kaplan-Meier curves were generated to study OS, and factors that affected OS were identified using a multivariate Cox proportional hazards (CPH) model. ResultsA total of 546 patients were identified. The average age of patients at diagnosis was 36.6 years old, and overall median survival was 128.6 months. RT was used to treat 179 (33.3 %) patients. Those who received RT had a shorter median OS (33.3 months) compared to those who did not (>128.6 months, p < 0.001). Our multivariate model demonstrated receiving RT was independently associated with a significantly higher risk of death (hazard ratio [HR] = 4.28, 95 % confidence interval [CI] = 1.77−10.38, p = .0013). Patients ≥65 years of age also demonstrated significantly higher risk of death (HR = 2.20, CI = 1.54−4.16, p = .006) and had a decreased median OS (26.0 months). ConclusionIn adults with PXA, treatment with RT is independently associated with a significantly higher risk of mortality. The routine use of this modality in treating PXA warrants further study.

Evaluation of oncologic outcomes in head and neck cancer patients ≥80 years old based on adherence to NCCN guideline for postoperative adjuvant treatment

There is a paucity of literature characterizing outcomes in older adult patients with head and neck cancer (HNC). This study aims to describe patients from this group, their adherence to National Comprehensive Cancer Network (NCCN) adjuvant treatment guidelines, and the impact of guideline adherence on overall survival (OS). In this retrospective cohort study, we reviewed all patients ≥80 years old with HNC who underwent surgery with curative intent from 2008 to 2016. Adherence to NCCN guidelines was determined in blinded fashion, and quality metrics and OS were compared. One hundred fifty-nine patients met inclusion criteria. The majority of patients (n = 94, 59%) underwent treatment in accordance with NCCN recommendations while 65 (41%) deviated from NCCN guidelines. The two cohorts did not demonstrate a difference in 2-year OS (62% vs 66%, P = .50). Older adult patient outcomes were not different when treatment deviated from NCCN guidelines.

Comorbidity-dependent adherence to guidelines and survival in breast cancer-Is there a role for guideline adherence in comorbid breast cancer patients? A retrospective cohort study with 2137 patients.

In the treatment of breast cancer, decisions on adjuvant treatment reflect individual patient characteristics like age and comorbidity. This study assessed the association between adherence to guidelines for adjuvant treatment and survival while taking into account age at diagnosis and comorbidities. We collected the Charlson comorbidity index at baseline for 2179 women treated for primary breast cancer from 1992 to 2008 who participated in a German retrospective multicenter cohort study. We assessed subsequent adjuvant therapy guideline adherence and survival in relation to baseline comorbidities. Guidelines for adjuvant chemotherapy and radiotherapy were more often violated in patients with higher Charlson score. Patients with higher Charlson scores received chemotherapy and radiotherapy less often and had higher rates of mastectomy. Irrespective of comorbidity (Charlson score 0, 1-2, ≥3), patients with 100% guideline-adherent adjuvant treatment showed better overall and disease-free survival (DFS) compared to patients with guideline violations (GVs). Controlling for age, comorbidity and tumor characteristics, the hazard ratio for at least one GV was 1.65 (95% confidence interval [CI]: 1.33-2.07) for overall survival and 1.84 (95% CI: 1.53-2.22) for DFS. Guideline-adherent treatment was significantly less frequent in comorbid patients, although guideline adherence was strongly associated with improved survival, irrespective of severity, and number of comorbid diseases.

Compliance with adjuvant treatment guidelines in endometrial cancer: room for improvement in high risk patients

ObjectivesCompliance of physicians with guidelines has emerged as an important indicator for quality of care. We evaluated compliance of physicians with adjuvant therapy guidelines for endometrial cancer patients in the Netherlands in a population-based cohort over a period of 10years. MethodsData from all patients diagnosed with endometrial cancer between 2005 and 2014, without residual tumor after surgical treatment, were extracted from the Netherlands Cancer Registry (N=14,564). FIGO stage, grade, tumor type and age were used to stratify patients into risk groups. Possible changes in compliance over time and impact of compliance on survival were assessed. ResultsPatients were stratified into low/low-intermediate (52%), high-intermediate (21%) and high (20%) risk groups. Overall compliance with adjuvant therapy guidelines was 85%. Compliance was highest in patients with low/low-intermediate risk (98%, no adjuvant therapy indicated). The lowest compliance was determined in patients with high risk (61%, external beam radiotherapy with/without chemotherapy indicated). Within this group compliance decreased from 64% in 2005–2009 to 57% in 2010–2014. In high risk patients with FIGO stage III serous disease compliance was 55% (chemotherapy with/without radiotherapy indicated) and increased from 41% in 2005–2009 to 66% in 2010–2014. ConclusionWhile compliance of physicians with adjuvant therapy guidelines is excellent in patients with low and low-intermediate risk, there is room for improvement in high risk endometrial cancer patients. Eagerly awaited results of ongoing randomized clinical trials may provide more definitive guidance regarding adjuvant therapy for high risk endometrial cancer patients.

De-intensification of adjuvant therapy in human papillomavirus-associated oropharyngeal cancer.

Current adjuvant treatment guidelines for oropharyngeal squamous cell carcinoma treated with primary surgery are based on studies that predate the human papillomavirus (HPV) era. HPV-associated oropharynx carcinoma (HPV-OPC) has a much more favorable prognosis compared to HPV-unassociated cancer and is increasingly considered to be a distinct disease entity due to its unique etiology, presentation, and behavior. Currently, there is significant interest in adjuvant treatment de-intensification of HPV-OPC patients in order to reduce treatment-related toxicity while maintaining excellent clinical outcomes. Here, we review the evidence and rationale underlying the ongoing prospective trials of adjuvant treatment de-intensification for HPV-OPC patients.

HER2 status and disparities in luminal breast cancers.

National Comprehensive Care Network guidelines for adjuvant treatment of invasive breast cancer are based on HER2 and hormone receptor (HR) status, where HR+ disease encompasses all estrogen receptor (ER)+ and/or progesterone receptor (PR)+ tumors. We sought to explore clinical and demographic differences among patients with HR+ breast cancer subtypes, and the role of HER2 status, age, race/ethnicity, and socioeconomic status (SES) in disease risk. We evaluated breast cancer subtype distribution, defined by HR and HER2 status, using patient clinical, demographic, and socioeconomic characteristics. Differences in HR categories by demographic and tumor characteristics were examined using chi‐squared tests. Multinomial logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) to quantify associations between breast cancer HR status and demographic factors. We found that differences in HR+ (ER−/PR+ vs. ER+/PR− or ER+/PR+) tumor biology are likely clinically significant and may play a role in breast cancer, regardless of HER2 status. While clinical and patient characteristics differed within each luminal subtype, we found disparities in SES only among Luminal A (HR+/HER2−) tumors. Among HR+/HER2− cases, we observed that ER−/PR+ patients tend to live in areas of higher poverty (OR = 1.20, 95% CI = 1.03–1.40) and are 70% more likely to be aged 50 years or older. However, this pattern was not found in women with Luminal B (HR+/HER2+) disease (Poverty OR = 0.98, 95% CI = 0.76–1.27; Age OR = 1.01, 95% CI = 0.81–1.26). Racial/ethnic disparities among non‐Hispanic black and Hispanic women persisted across HR+/HER2− cases compared to non‐Hispanic white women. Our findings suggest that while race/ethnicity and SES are correlated, each plays an independent role in contributing to disease among Luminal A tumors. Further study is needed to investigate how tumor biology, race/ethnicity, and socioeconomic disparities among HR+/HER2− cases may contribute to poorer patient prognosis.

No clear effect of postoperative radiotherapy on survival of breast cancer patients with one to three positive nodes: a population-based study

In published radiotherapy trials, the failure rate in the control arm among patients with one to three positive nodes is high compared with that seen with modern adjuvant treatments. Therefore, the generalizability of the results has been questioned. The aim of the present study was to compare relative survival in breast cancer patients between two Swedish regions with screening mammography programs and adjuvant treatment guidelines similar with the exception of the indication of radiotherapy for patients with one to three positive nodes. Between 1989 and 2006, breast cancer patients were managed very similarly in the west and southeast regions, except for indication for postoperative radiotherapy. In patients with one to three positive nodes, postmastectomy radiotherapy was generally given in the southeast region (89% of all cases) and generally not given in the west region (15% of all cases). For patients with one to three positive nodes who underwent breast-conserving surgery, patients in the west region had breast radiotherapy only, while patients in the southeast region had both breast and lymph nodes irradiated. The 10-year relative survival for patients with one to three positive lymph nodes was 78% in the west region and 77% in the southeast region (P = 0.12). Separate analyses depending on type of surgery, as well as number of examined nodes, also revealed similar relative survival. Locoregional postoperative radiotherapy has well-known side-effects, but in this population-based study, there was little or no influence of this type of radiotherapy on survival when one to three lymph nodes were involved.

Detection of potential actionable targets in appendiceal cancer detected by immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), and mutational analysis.

469 Background: Appendiceal cancers are rare and there are no established guidelines for adjuvant treatment and metastatic disease. Methods: Samples were identified from &gt; 60,000 global tumors analyzed at a referral molecular profiling CLIA certified laboratory (Caris Life Sciences) for biomarkers of drug sensitivity, under an approved protocol. 285 samples with primary tumor sites of appendix were identified (M/F ratio of 38%/62%; mean age of 55). Approximately 80% of samples were adenocarcinomas, 10% carcinoids, and 10% of indeterminate histology. IHC assays (n=273) were performed with up to 30 biomarkers; FISH (n=39) for c-Myc, cMET, EGFR, HER2 and/or TOPO2A gene copy amplifications; and sequencing done ( n= 223) for KRAS, EGFR, PIK3CA, and BRAF. Results: Targets on IHC: 97% high BCRP; 16% high KIT; 80% high COX-2; 50%high EGFR; 30% low MGMT, 81% high MRP1, 35% high PDGFR, 82% low PTEN, 27% high RRM1, 39% high SPARC; 67% high TLE3, 27% high TOPO2A ; 63% high TOPOI, and 99% negative TS. Targets on FISH: 5% amplified EGFR and 0% amplified Her2/Neu. Sequencing results: 53% mutated KRAS and 2% mutated BRAF. Conclusions: The high levels of drug resistance proteins (BCRP and MRP1) highlights the difficulty in treating these tumors. The incidence of KRAS mutations (53%) and low expression of TS (99%) is noteworthy, and points towards using 5FU/capecitabine as a backbone of therapy. Therapeutic options are varied and options include TOPO1 inhibitors (irinotecan/topotecan), EGFR inhibitors (erlotinib, cetuximab), PDGFR antagonists (regorafenib, axitinib), MGMT (temazolamide), BRAF inhibitors (vemurafenib, dabrafenib) and SPARC (nab-paclitaxel). These findings indicate the need to evaluate patient samples for patterns in marker expression and alteration, in order to better understand the molecular biology and formulate a personalized therapy approach in these difficult to treat cancers, and to pursue whole genomic sequencing. Supported by a grant from Caris Life Sciences.

Colorectal signet-ring cell carcinoma: Responsive to adjuvant chemotherapy but still a poor prognosis.

529 Background: Colorectal signet-ring cell carcinoma (SRCC) has been associated with a poor survival compared to mucinous adenocarcinoma (MC) and the common adenocarcinoma (AC). Prognostic impact of tumor localization is unknown and efficacy of adjuvant chemotherapy in SRCC has never been assessed. This study analyses prognostic impact of SRCC and determines whether SRCC patients benefit from adjuvant chemotherapy for colon cancer equally compared with AC. Methods: Data on 196,757 patients with CRC in the Netherlands in the period 1989 and 2010 was included in this nationwide population-based study. Five-year relative survival estimates were calculated and multivariate relative survival analyses using a multiple regression model of relative excess risk (RER) were performed. Results: SRCC was found in 1.0% of CRC patients. SRCC patients presented more frequently with stage III or IV disease than AC (75.2% versus 43.6%, P&lt;0.0001) and SRCC was more frequently found in the proximal colon (57.7% versus 32.0%, P&lt;0.0001). SRCC patients had a poor 5-year relative survival of 31% in colon and 20% in the rectum compared to 57% and 59% in AC (P&lt;0.0001). This poorer survival for SRCC was found in stage II, III and IV. In comparison with AC, there was no significant interaction between SRCC and adjuvant chemotherapy (RER 1.10, 95% CI 0.81-1.51), suggesting a comparable benefit from adjuvant chemotherapy in AC and SRCC. Conclusions: Prognostic impact of SRCC is dismal in both colon and rectal cancer patients, but colonic SRCC patients seem to benefit from adjuvant chemotherapy equally compared with AC. Reduced efficacy of adjuvant chemotherapy therefore does not seem to explain the poor outcome in SRCC patients. We recommend to adhere to adjuvant treatment guidelines for all histological subtypes, but encourage clinical trials to take histological subtype into account for stratification.

Anticipating the Clinical Use of Prognostic Gene Expression–Based Tests for Colon Cancer Stage II and III: Is Godot Finally Arriving?

According to current recommendations for adjuvant treatment, patients with colon cancer stage II are not routinely offered chemotherapy, unless considered to have a high risk of relapse based on specific clinicopathological parameters. Following these criteria, it is challenging to identify the subgroup of patients that will benefit the most from adjuvant treatment. Contrarily, patients with colon cancer stage III are routinely offered chemotherapy, but due to expected adverse effects and frailty, elderly patients are often excluded from standard protocols. Colon cancer is a disease of the elderly and accordingly, there is a large subgroup of patients for which guidelines for adjuvant treatment remain less clear. In these two clinical settings, improved risk stratification has great potential impact on patient care, anticipating that high-risk patients will benefit from chemotherapy. However, microsatellite instability is the only molecular prognostic marker recommended for clinical use. In this perspective, we provide an updated view on the status and clinical potential of the many proposed prognostic gene expression-based tests for colon cancer stage II and III. The main limitation for clinical implementation is lack of prospective validation. For patients with stage II, highly promising tests have been identified and clinical trials are ongoing. For elderly patients with stage III, the value of such tests has received less focus, but promising early results have been shown. Although awaiting results from prospective trials, improved risk assessment for patients with stage II and III is likely to be achieved in the foreseeable future.

P5-14-09: Malignant Calcification Is an Important Prognostic Factor in Women with Invasive Breast Cancer – Suggestion for Regarding It as High-Risk Factor in Current Staging and Adjuvant Treatment Guidelines.

Abstract Purpose: To investigate whether calcification is a prognostic factor for breast cancer. Methods: A total of 804 patients with invasive breast cancer diagnosed between 2001 and 2003 were recruited and divided into two groups based on whether they had malignant calcification on mammogram. The association of calcification with lymph node status, grade, tumor size, ER, PR and Her2 status, 8-year disease-free survival (DFS) and overall survival (OS) was evaluated. Survival difference was analyzed by Kaplan-Meier technique. The relative importance of each of the potentially prognostic variables was tested using Cox regression analysis. Results: The incidence of malignant calcification in all breast cancer was 41.5%. Compared with tumor without calcification, those with calcification had a larger size (2.6cm vs 2.1cm, P=0.000), higher axillary lymph node (LN) positive rate (40.1% vs 31.5%, P=0.012), more LN involvement (14.8% vs 9.2%, P=0.000), lower ER (54.3% vs 65.1%, P=0.002) and PR (42.7% vs 60.6%, P=0.000) expression and higher Her2 expression (27.3% vs 14.7%, P=0.000). The 8-year DFS was lower for patients with calcification than those without (89.9% vs. 76.8%, P=0.000). The 8-year OS for tumor with calcification was 82.2%, compared with 92.8% for those without (P=0.000). Subgroup analysis showed that the shorter survival and higher relapse rate for tumors with calcification could be found in both LN- and LN+ patients, also could be found in T1, T2, Grade II, ER+, PR+ and Her2- patients. The existence of calcification, LN stage, tumor size, ER status, and grade were significantly associated with survival in univariate analysis. Further Cox regression analysis demonstrated that calcification and LN stage maintained their prognostic significance in both DFS and OS. The hazard ratios of these factors are listed in Table 1. Conclusions: The existence of calcification is a poor prognostic factor for patients with invasive breast cancer. Its prognostic value is only second to LN status and is higher than the other factors evaluated, including tumor size, grade, and ER, PR status. Thus, breast cancer with calcification should be regarded as a high-risk factor when determining cancer stage and selecting the adjuvant treatment. Discussion: Given the strong prognostic value of calcification revealed in this research, the biological mechanism of its formation and related cell signal pathway should be investigated. Further adjuvant clinical trial should be done to select certain sensitive chemotherapeutic agent or regimen. Some biomarkers have been found to have a role in the formation of calcification and may be targets for treatment. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-09.

Abstract P5-13-11: Medico-Economic Assessment of the Genomic Grade Index on Adjuvant Treatment Strategy in Elston-Ellis Grade 2, Estrogen Receptor Positive, HER2 Negative, Node Negative, Small Size Breast Carcinomas

Abstract Background: Elston-Ellis grading (EE) is one of the key criteria for adjuvant therapy decision in ER+/HER2-/pN0/pT1 -2 tumors. The genomic grade index (GGI) is a 97-gene micro-array assay able to identify tumors of high or low genomic grade. GGI has been developed in order to improve the prognosis determination, especially in EE2 tumors which represent a significant proportion of breast carcinomas and where the inter-assessor variability is the highest. The aim of the present study was to model the influence of the GGI on adjuvant treatment decision in EE2 patients, using a cohort of ER+/HER2-/pN0/pT1-2 tumors. Methods: A randomly selected series of pT1-2, pN0 breast cancers from the Institut Curie 1995-1996 cohort was profiled using Affymetrix HGU133 Plus 2.0 gene chips. The GGI was calculated using Ipsogen Mapßuant Dx®. Treatment decisions were made for EE2 cases based on the Institut Curie adjuvant treatment guidelines (www.curie.fr). The treatment decision algorithm was firstly run using the grade as defined by Elston Ellis, and secondly using the GGI (undetermined cases were classified as grade2). Results: Out of 72 EE2 tumors, 35 were classified as GGI-1 (49%) and 13 (18%) as GGI-3. Based on EE, 7% of patients would have received adjuvant chemotherapy (ACT) alone (all were ER-/PR-), 50% adjuvant hormonal therapy (AHT) alone, and 43% both. Using the GGI, 7% (n=5) of patients would have been spared AHT and 10% (n=7) ACT. In the ER+/HER2- subgroup of 62 pts, 58% of patients would have received AHT alone and 42% AHT+ACT based on EE; GGI would have lead to a 14% reduction in AHT prescription and to a 26% reduction in ACT prescription. Conclusion: Applying the Genomic Grade Index instead of the Elston Ellis Grade to determine the adjuvant treatment strategy in a series of EE2/ER+/HER2-/pN0/pT1-2 breast carcinomas would lead to a 14% and 27% reduction in the administration of, respectively, adjuvant hormone-therapy and chemotherapy. Adjuvant treatment decision: models based on Elston-Ellis or Genomic Grading Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-13-11.

Comorbidities' impact on survival after treatment for early breast cancer.

584 Background: Guidelines for adjuvant treatment of breast cancer are based on results of randomized clinical trials and we apply these guidelines on the general population of women with early breast cancer without taking such comorbidity into consideration. Methods: With the aim of studying comorbidity, we used the Danish Breast Cancer Cooperative Group database to identify all women diagnosed with early breast cancer between 1990 and through 2006. We obtained information on somatic comorbidity and cause of death, by linkage to the national Hospital Discharge Registry and the national Death Registry through the unique personal identification number. Comorbidity was categorized according to the Charlson Comorbidity Index (CCI) score 0, 1, 2 and 3+. Cox proportional hazard regression was performed to determine the hazards of death, breast cancer specific mortality and non-breast cancer mortality, adjusting for: age, stage, year at diagnosis, receptor status, fascial invasion, vascular invasion, type of surgery and treatment. Results: Among 55,139 women, with a median estimated potential follow-up of 7.4 years, 18,537 had died, including 14,076 deaths from breast cancer and 4,461 deaths from other causes. Compared with women with no comorbidity (CCI=0) the risk of dying from breast cancer, as well as other causes, increased significantly with increasing CCI (Table). Conclusions: Having adjusted for other prognostic factors, comorbidity significantly increases risk of dying both from breast cancer and other causes. Hazard ratios with 95% confidence intervals Breast cancer-specific mortality Non-breast cancer mortality All-cause mortality CCI n Adjusted HR 95% CI Adjusted HR 95% CI Adjusted HR 95% CI 0 44,313 1 Reference 1 Reference 1 Reference 1 5,838 1.30 1.23-1.37 1.97 1.81-2.13 1.44 1.38-1.51 2 3,211 1.34 1.25-1.44 2.24 2.03-2.47 1.55 1.47-1.64 3+ 1,777 1.72 1.59-1.88 3.55 3.16-3.99 2.12 1.98-2.27 * All p values < 0.0001. No significant financial relationships to disclose.