High Risk Of Locoregional Recurrence Research Articles

The 21-gene recurrence score and locoregional recurrence in breast cancer patients.

Although the 21-gene recurrence score (RS) assay has been validated to assess the risk of distant recurrence in hormone receptor-positive breast cancer patients, the relationship between RS and the risk of locoregional recurrence (LRR) remains unclear. The purpose of this study was to determine if RS is associated with LRR in breast cancer patients and whether this relationship varies based on the type of local treatment [mastectomy or breast-conserving therapy (BCT)]. 163 consecutive estrogen receptor-positive breast cancer patients at our institution had an RS generated from the primary breast tumor between August 2006 and October 2009. Patients were treated with lumpectomy and radiation (BCT) (n = 110) or mastectomy alone (n = 53). Patients were stratified using a pre-determined RS of 25 and then grouped according to local therapy type. Median follow-up was 68.2 months. Patients who developed an LRR had stage I or IIA disease, >2 mm surgical margins, and received chemotherapy as directed by RS. While an RS > 25 did not predict for a higher rate of LRR, an RS > 24 was associated with LRR in our subjects. Among mastectomy patients, the 5-year LRR rate was 27.3 % in patients with an RS > 24 versus 10.7 % (p = 0.04) in those whose RS was ≤ 24. RS was not associated with LRR in patients who received BCT. Breast cancer patients treated with mastectomy for tumors that have an RS > 24 are at high risk of LRR and may benefit from post-mastectomy radiation.

Locoregional Outcomes in Clinical Stage IIB Breast Cancer After Neoadjuvant Therapy and Mastectomy With or Without Radiation

Low rates of locoregional recurrence (LRR) in patients with clinical stage IIB breast cancer (cT2N1 or cT3N0) who undergo neoadjuvant therapy (NAT) and mastectomy have been reported. We aimed to quantify the risk of LRR and the relationship between LRR and potential risk factors in this subset of patients.We conducted a retrospective review of 116 patients with clinical IIB breast cancer who underwent NAT followed by mastectomy +/− postmastectomy radiotherapy (PMRT) between 2000 and 2009. We estimated the rate of LRR by cumulative incidence. The effect of prognostic factors was examined by Gray's test and Fine and Gray's test.Median follow-up: 63 months. Median age: 49. 28.4% cT2N1 and 71.6% cT3N0. 62.1% of tumors were ER+, 22.6% HER2+, 19% triple negative (TN). All patients underwent NAT and mastectomy. The majority of patients (87%) received PMRT; 32.3% were treated to chest wall (CW) only, and 67.7% to CW plus supraclavicular (SCV) field.Compared to cT2N1, patients with cT3N0 disease were more likely to be pN0 (60% vs 27%, P = 0.005). There was no significant relationship between risk of LRR and pathologic complete response (pCR), use of PMRT, RT to SCV field, or TN status, but there was higher risk of LRR in cT2N1 than cT3N0 (HR 6.03, P = 0.015).LRR was more common in cT2N1 than in cT3N0 disease, emphasizing the negative prognostic implication of clinically node-positive presentation.

Development and validation of a gene profile predicting benefit of postmastectomy radiotherapy in patients with high-risk breast cancer: a study of gene expression in the DBCG82bc cohort.

To identify genes predicting benefit of radiotherapy in patients with high-risk breast cancer treated with systemic therapy and randomized to receive or not receive postmastectomy radiotherapy (PMRT). The study was based on the Danish Breast Cancer Cooperative Group (DBCG82bc) cohort. Gene-expression analysis was performed in a training set of frozen tumor tissue from 191 patients. Genes were identified through the Lasso method with the endpoint being locoregional recurrence (LRR). A weighted gene-expression index (DBCG-RT profile) was calculated and transferred to quantitative real-time PCR (qRT-PCR) in corresponding formalin-fixed, paraffin-embedded (FFPE) samples, before validation in FFPE from 112 additional patients. Seven genes were identified, and the derived DBCG-RT profile divided the 191 patients into "high LRR risk" and "low LRR risk" groups. PMRT significantly reduced risk of LRR in "high LRR risk" patients, whereas "low LRR risk" patients showed no additional reduction in LRR rate. Technical transfer of the DBCG-RT profile to FFPE/qRT-PCR was successful, and the predictive impact was successfully validated in another 112 patients. A DBCG-RT gene profile was identified and validated, identifying patients with very low risk of LRR and no benefit from PMRT. The profile may provide a method to individualize treatment with PMRT.

Does biologic subtype and pathologic response after neoadjuvant chemotherapy predict locoregional recurrence?

65 Background: The relative contribution of biological subtype and response to neoadjuvant chemotherapy (NAC) to locoregional recurrence (LRR) is uncertain. We aim to determine if these factors identify a high risk population for LRR. Methods: 233 patients received anthracycline/taxane-based NAC, mastectomy and postmastectomy radiation therapy (PMRT) in 2000-2009 for Stage II-III breast cancer. 53% (n=123) were HR+ (ER or PR+/HER2-), 23% (53) HER2+ (HER2+/HR+ or HR-), and 24% (57) TN (HR-/HER2-). 76% of HER2+ received trastuzumab. Median PMRT dose was 50 Gy to chest wall and regional nodes. Pathologic complete response (pCR) rates were compared using Fisher's exact test. Rates of LRR and distant recurrence (DR) were estimated by Kaplan-Meier methods. Cox regression analysis was performed. Results: Median follow-up was 62 months (range 7-161) with 21 LRR, 84 DR and 58 deaths. pCR rate and 5-year LRR rates were 14% and 7% in the entire cohort, respectively. Significantly more TN and HER2+ patients achieved pCR than HR+ patients (Table 1, p=0.003). TN patients had higher 5-year LRR rate compared to HR+ and HER2+ patients (18% vs. 4% and 6%, p=0.02). The 5-year LRR rate was 0% in pCR patients versus 9% in non-pCR patients (p=0.06). In patients without pCR, TN subtype was associated with increased LRR (23% at 5-year vs. 4% HR+ and 7% HER2+; p=0.001). TN patients without pCR were also associated with increased DR (48% at 5-year vs. 29% HR+ and 30% HER2+, p=0.02). On univariate analysis, TN subtype (HR=2.0, p=0.008), pathologic stage (HR=2.2, p=0.02), and pN+ status (HR=9.3, p=0.03) were associated with increased LRR. Conclusions: Although response to NAC strongly correlates with breast cancer subtype, patients with HR+ and HER2+ breast cancer had favorable rates of LRR regardless of response to NAC, perhaps because of additional postoperative targeted therapy. In contrast, while no LRR was seen in TN patients with pCR, those with poor response to NAC had significantly higher LRR risk, underscoring the need for potential new treatment strategies to improve local control in this population. [Table: see text]

Rates and Patterns of Recurrence after Curative Intent Resection for Gastric Cancer: A United States Multi-Institutional Analysis

Reports on recurrence and outcomes of US patients with gastric cancer are scarce. The aim of this study was to determine incidence and pattern of recurrence after curative intent surgery for gastric cancer. Using the multi-institutional US Gastric Cancer Collaborative database, we identified 817 patients undergoing curative intent resection for gastric cancer between 2000 and 2012. Patterns and rates of recurrence along with associated risk factors were identified using adjusted regression analysis. Recurrences were classified as locoregional, peritoneal, or hematogenous. Median patient age was 65.8 years (interquartile range [IQR] 56.4, 74.7); the majority of patients were male (n = 462, 56.6%) and white (n = 511, 62.5%). At the time of surgery, the majority of patients underwent a partial gastrectomy (n = 481, 59.2%) with a complete R0 resection achieved in 91.6% (n = 748) of patients. At the time of last follow-up, 244 (29.9%) of 817 patients developed a recurrence; 163 (66.8%) patients had recurrence at only a single site; the remaining 81 (33.2%) had multiple sites of initial recurrence. Among patients who recurred at a single site, recurrence was most common at a distant location and included hematogenous (n = 57, 23.4%) or peritoneal (n = 47, 19.3%) only metastasis. Tumors at the gastroesophageal junction (odds ratio [OR] 3.18, 95% CI 1.08 to 9.40; p = 0.04) were associated with higher risk of locoregional recurrence, while the presence of multiple lesions (OR 10.82, 95% CI 3.56 to 32.85; p < 0.001) remained associated with an increased risk of distant hematogenous recurrence after adjusted analysis. Recurrence was associated with worse survival, with a median recurrence-free survival of 10.8 months (IQR 8.9, 12.8) among those who experienced a recurrence. Nearly one-third of patients experienced recurrence after gastric cancer surgery. The most common site of recurrence was distant.

Relationship between the prognostic and predictive value of the intrinsic subtypes and a validated gene profile predictive of loco-regional control and benefit from post-mastectomy radiotherapy in patients with high-risk breast cancer

Background. Breast cancer is characterized by great molecular heterogeneity demonstrated, e.g. by the intrinsic subtypes. Administration of post-mastectomy radiotherapy (PMRT) does, however, not reflect this heterogeneity. A gene profile (DBCG-RT profile) has recently been developed and validated, and has shown prognostic impact in terms of loco-regional failure and predictive impact for PMRT. Reports have also shown predictive value in terms of benefit of PMRT from intrinsic subtypes and derived approximations. The aim of this study was to examine: 1) the agreement between various methods for determining the intrinsic subtypes; and 2) the relationship between the prognostic and predictive impact of the DBCG-RT profile and the intrinsic subtypes.Material and methods. Intrinsic subtypes and the DBCG-RT profile was determined from microarray analysis based on fresh frozen tissue from 191 patients included in the Danish Breast Cancer Cooperative Group (DBCG) 82bc trial. Corresponding formalin-fixed, paraffin-embedded tissue was available from 146 of these patients and from another 890 DBCG82bc patients. Estrogen receptor, progesterone receptor, HER2, CK5/6, Ki-67 and EGFR were combined into immunohistochemical approximations of the intrinsic subtypes. Endpoint considered was loco-regional recurrence (LRR).Results. The DBCG-RT profile identified a group of patients with low risk of LRR and no additional benefit from PMRT among all subtypes. Combining six immunohistochemical markers identified a subgroup of triple negative patients with high risk of LRR and significant benefit from PMRT. Agreement in the different assignments of tumors to the subtypes was suboptimal, and the clinical outcome and predicted benefit from PMRT varied according to the method used for assignment.Conclusion. The prognostic and predictive information obtained from the DBCG-RT profile cannot be substituted by any approximation of the tumors intrinsic subtype. The predictive value of the intrinsic subtypes in terms of PMRT was influenced by the method used for assignment to the intrinsic subtypes.

Recent advances and clinical implications of the micropapillary histological subtype in lung adenocarcinomas.

Micropapillary (MIP) histologic subtype included in the classification of lung adenocarcinomas (ADCs) is associated with both size- and stage-independent poor prognoses. MIP pattern in lung ADCs, even at small, early stages, correlates with high lymphovascular invasion, visceral pleural invasion and lymph node metastases. Recently, we reported that patients with a MIP component are at a higher risk of locoregional recurrence after limited resection. Identification of a MIP pattern is only possible with permanent pathologic sections; preoperative imaging, cytology or intraoperative frozen section specimens remain unreliable. The intermixed, heterogenous morphology of lung ADC presents a technical challenge in investigating the molecular biology of cells with MIP morphology. A comprehensive understanding of the biology of MIP morphology is vital for therapeutic interventions.

Proliferative index activity in oral squamous cell carcinoma: indication for postoperative radiotherapy?

The predictive value of the Ki-67 labelling index and its relationship with radiosensitivity in oral squamous cell carcinoma (SCC) remains controversial. We sought to evaluate whether the expression of Ki-67 antigen found in SCC of the tongue and the floor of the mouth is an indication for postoperative radiotherapy (PORT). The first study group included 34 patients who were treated only with primary surgery, while the second group included 26 patients who underwent primary surgery combined with PORT. The correlation between Ki-67 expression and loco-regional recurrence, as well as the 5-year disease-specific survival, was assessed in the two groups. Cases of high-proliferative tumours showed a significantly higher risk of loco-regional recurrence (P=0.018) and a poorer prognosis (P=0.001) only in the 34 patients treated with surgery alone. In multivariate Cox regression analysis, high Ki-67 expression was an independent predictor of loco-regional recurrence (HR 5.42, P=0.029) and disease-specific survival (HR 9.02, P=0.004). The correlation between Ki-67 expression and the risk of loco-regional recurrence in SCC of the tongue and the floor of the mouth may be useful in the selection of patients at a higher risk of recurrence who would benefit from PORT, despite adequate margins of resection and early stage of the disease.

Lymph node ratio influence on risk of head and neck cancer locoregional recurrence after initial surgical resection: Implications for adjuvant therapy

The purpose of this study was to determine if lymph node ratio is associated with locoregional recurrence for patients with oral cavity or laryngeal cancer treated with initial surgical management. The study included 350 patients with oral cavity (73%) or laryngeal cancer (27%) who underwent initial surgery. All analyses were multivariable, adjusting for primary site, pathologic prognostic factors, and adjuvant therapy. Lymph node ratio was significantly associated with locoregional recurrence, in which each 1% increase in lymph node ratio had an adjusted hazard ratio (HR) for locoregional recurrence of 1.02 (95% confidence interval [CI], 1.002-1.042; p = .05). Lymph node ratio was also associated with OS, in which each 1% increase in lymph node ratio had an adjusted HR for death of 1.028 (95% CI, 1.012-1.045; p = .001). Adjusting for pathologic factors and adjuvant therapy, lymph node ratio was found to be an independent prognostic factor for locoregional recurrence and overall survival (OS). Patients with lymph node ratio ≥20% are at high risk of locoregional recurrence and death, and may be considered for adjuvant chemoradiation.

Clinical significance of intraparotid lymph node metastasis in primary parotid cancer

The clinical utility of intraparotid lymph node metastasis in primary parotid cancer is unknown, and this study was undertaken to address this gap in knowledge. A medical chart review was performed on 86 patients who underwent parotidectomy with neck dissection (39 cN+ and 47 cN0). The disease-specific mortality and locoregional recurrence (LRR) were correlated with intraparotid lymph node metastasis status. Using intraparotid lymph node metastasis status to predict cervical nodal metastasis resulted in a sensitivity and specificity of 70% and 90.6%, respectively (positive predictive value [PPV] of 87.3%). Patients with positive intraparotid lymph node metastasis had a worse 3-year disease-specific mortality compared with patients with negative intraparotid lymph node metastasis (p = .0037). Patients with cN0 neck but positive intraparotid lymph node metastasis were more likely to develop locoregional recurrence than patients without intraparotid lymph node metastasis (p = .08). In patients with cN0 neck but positive intraparotid lymph node metastasis, intraparotid lymph node metastasis presence was strongly associated with a worse disease-specific survival and placed them at a higher risk of locoregional recurrence.

Post-mastectomy radiotherapy for breast cancer patients with t1-t2 and 1-3 positive lymph nodes: a meta-analysis.

BackgroundThe role of post-mastectomy radiotherapy (PMRT) in patients with T1-2 and 1-3 positive lymph nodes remains controversial. The aim of this study is to investigate the possible benefits of PMRT for this subgroup.MethodsThree electronic databases were systematically quarried (Cochrane Library, MEDLINE, and EMBASE) for published studies evaluating the effects of PMRT on breast cancer patients with T1-T2 tumors with 1-3 positive lymph nodes. Of the 334 studies identified, information was available for 3432 patients from 10 clinical studies. Pooled relative risk estimates (RR) and overall survival (OS) were calculated using the inverse variance weighted approach, publication bias and chi-square test were also calculated. ResultsFrom the 10 studies, the pooled RR (RRs) for locoregional recurrence (LRR) with PMRT was 0.348 (95% CI = 0.254 to 0.477), suggesting a significant benefit for PMRT to decrease the risk of LRR in patients with T1-T2 tumors and 1-3 positive nodes (p<0.05). Reporting bias ( Begg’s p = 0.152; Egger’s p = 0.107) or significant heterogeneity (Cochran’s p = 0.380; I2 = 6.7%) were not detected. For further subset analysis, the RR for T1, N1-3+ tumors was 0.330 (95% CI = 0.171 to 0.639); for T2, N1-3+ tumors the RR was 0.226 (95% CI = 0.121 to 0.424). The pooled RR for overall survival (OS) was not significantly different between PMRT and no-PMRT group (1.051, 95% CI =1.001 to 1.104).ConclusionsOur pooled analysis revealed that PMRT significantly reduces the risk of LRR in patients with TI-T2 tumors with 1-3 positive nodes, and the magnitude of the LRR risk reduction is slightly greater for larger tumors. Our results suggest that PMRT should be considered for patients with T1/T2 tumors with 1-3 positive nodes to decrease the relatively high risk of LRR.

Risk factors for locoregional recurrence in patients with resected N1 non-small cell lung cancer: a retrospective study to identify patterns of failure and implications for adjuvant radiotherapy

BackgroundMeta-analysis of randomized trials has shown that postoperative radiotherapy (PORT) had a detrimental effect on overall survival (OS) in patients with resected N1 non–small cell lung cancer (NSCLC). Conversely, the locoregional recurrence (LR) rate is reported to be high without adjuvant PORT in these patients. We have evaluated the pattern of failure, actuarial risk and risk factors for LR in order to identify the subset of N1 NSCLC patients with the highest risk of LR. These patients could potentially benefit from PORT.MethodsWe conducted a retrospective study on 199 patients with pathologically confirmed T1–3N1M0 NSCLC who underwent surgery. None of the patients had positive surgical margins or received preoperative therapy or PORT. The median follow-up was 53.8 months. Complete mediastinal lymph node (MLN) dissection and examination was defined as ≥3 dissected and examined MLN stations; incomplete MLN dissection or examination (IMD) was defined as <3 dissected or examined MLN stations. The primary end point of this study was freedom from LR (FFLR). Differences between patient groups were compared and risk factors for LR were identified by univariate and multivariate analyses.ResultsLR was identified in 41 (20.6%) patients, distant metastasis (DM) was identified in 79 (39.7%) patients and concurrent LR and DM was identified in 25 (12.6%) patients. The 3- and 5-year OS rates in patients with resected N1 NSCLC were 78.4% and 65.6%, respectively. The corresponding FFLR rates were 80.8% and 77.3%, respectively. Univariate analyses identified that nonsmokers, ≤23 dissected lymph nodes, visceral pleural invasion and lymph node ratio >10% were significantly associated with lower FFLR rates (P < 0.05). Multivariate analyses further confirmed positive lymph nodes at station 10 and IMD as risk factors for LR (P < 0.05). The 5-year LR rate was highest in patients with both these risk factors (48%).ConclusionsThe incidence of LR in patients with surgically resected T1–3N1M0 NSCLC is high. Patients with IMD and positive lymph nodes at station 10 have the highest risk of LR, and may therefore benefit from adjuvant PORT. Further investigations of PORT in this subset of patients are warranted.

Chemoradiation for resected pancreatic adenocarcinoma with or without intraoperative radiation therapy boost: Long-term outcomes

Background/objectivesTo analyze prognostic factors associated with long-term outcomes in patients with pancreatic cancer treated with chemoradiation therapy (CRT) and surgery with or without intraoperative electron beam radiotherapy (IOERT). Patients and methodsFrom January 1995 to December 2012, 60 patients with adenocarcinoma of the pancreas and locoregional disease (clinical stage IB [n = 13; 22%], IIA [n = 16; 27%], IIB [n = 22; 36%], IIIC [n = 9; 15%]) were treated with CRT (45–50.4 Gy before surgery [n = 19; 32%] and after surgery [n = 41; 68%]) and curative resection (R0 [n = 34; 57%], R1 [n = 26, 43%]). Twenty-nine patients (48%) also received a pre-anastomosis IOERT boost (applicator diameter size, 7–10 cm; dose, 10–15 Gy; beam energy, 9–18 MeV). ResultsWith a median follow-up of 15.9 months (range, 1–182), 5-year overall survival (OS), disease-free survival (DFS), and locoregional control were 20%, 13%, and 58%, respectively. Univariate analyses showed that R1 margin resection status (HR, 3.17; p = 0.04), not receiving IOERT (HR, 7.33; p = 0.01), and postoperative CRT (HR, 5.12; p = 0.04) were associated with a higher risk of locoregional recurrence. In the multivariate analysis, only margin resection status (HR, 3.0; p = 0.05) and not receiving IOERT (HR, 6.75; p = 0.01) retained significance with regard to locoregional recurrence. Postoperative mortality and perioperative complications were 3% (n = 2) and 43% (n = 26). ConclusionsAlthough local control is good in the radiation-boosted area, OS remains modest owing to high risk of distant metastases. Intensified locoregional treatment needs to be tested in the context of more efficient systemic therapy.

Impact of endocrine therapy in early-stage breast cancer on time to locoregional recurrence.

64 Background: Locoregional recurrence (LR) remains a major source of morbidity and mortality in breast cancer. Our primary aim was to evaluate the impact of endocrine therapy (ET) on time to LR. Methods: A retrospective chart review of breast cancer patients (pts) treated with lumpectomy and locoregional radiation from 1999-2005 at the Princess Margaret Cancer Centre was carried out. LR was defined as ipsilateral breast or lymph node recurrence. Kaplan-Meier estimates of survival and univariate analyses were performed for age, menopausal status, tumor and nodal stage, grade, receptor status, adjuvant chemotherapy (AC) and ET. Results: Of 440 pts evaluated, the mean age at primary resection was 56 years (yrs) (range 40-79), and 67% were postmenopausal. The majority had ductal carcinomas (87%) and grade 1-2 (68%) tumors. Tumor distribution was 315 (72%) T1, 120 (27%) T2, 4 (1%) T3; 138 (31%) were node positive. Receptor status was ER/PR+HER2- 206 (47%), ER+PR+HER2unknown 80 (18%), ER-PR-HER2unknown 41 (9%), and triple negative 37 (8%). AC was used in 190 (43%). ET (tamoxifen and/or aromatase inhibitors) was initiated in 294 (84%) eligible pts, and 267/294 (91%) completed a minimum duration of ≥2 yrs. Overall, LR occurred in 24 (5%) pts, and 8/24 (33%) pts with LR also had distant metastases. Average time from surgery to LR was 5.4 yrs (range 8 months-12 yrs). The average duration of ET in pts with LR was 4.3 yrs (range 0-8), and 5.8 yrs (range 0-12) without LR. Of ER/PR+ pts with LR, 3/15 (20%) did not receive ET. At the time of LR, 5 (33%) pts were receiving ET. After stopping ET, 2 (13%) recurred 0-2 yrs, 3 (20%) at 4-5 yrs, and 2 (13%) at 7-8 yrs. Treatment with at least 2 yrs of ET predicted for fewer recurrences: at 2 yrs LR-free rate was 100% vs 90% for &lt;2 yrs ET; at 5 yrs 99.6% vs 84%; and at 8 yrs 98.2% vs 84% (p=0.0092). ER/PR+HER2- pts had lower LR risk (p=0.028), and ER-/PR-/HER+ had higher LR risk (p=0.029). The remaining variables were not associated with risk of LRs. Survival post-LR was 90% (95%CI 64-97%) at 2 yrs and 65% (95%CI 34-84%) at 5 yrs. Conclusions: Pts who completed at least 2 yrs of ET had significantly lower risk of LR. The average time to LR was 5.4 years, and pts with LR had decreased survival at 5 yrs post-recurrence.

Pre-chemotherapy 18F-FDG PET/CT upstages nodal stage in stage II–III breast cancer patients treated with neoadjuvant chemotherapy

In breast cancer patients treated with neoadjuvant chemotherapy (NAC) the number of tumor-positive nodes can no longer reliably be determined. Furthermore, ultrasound (US) seems suboptimal for the detection of N3-disease. Therefore we assessed the proportion of breast cancer patients treated with NAC in which pre-chemotherapy 18F-FDG PET/CT detected ≥4 axillary nodes or occult N3-disease, upstaging nodal status and changing risk estimation for locoregional recurrence (LRR). Conventional regional staging consisted of US with fine needle aspiration and/or sentinel lymph node biopsy. Patients were classified as low-risk (cT2N0), intermediate-risk (cT0N1, cT1N1, cT2N1, cT3N0), or high-risk (cT3N1, cT4, cN2-3) for LRR. The presence and number of FDG-avid nodes were evaluated and the proportion of patients that would be upstaged by PET/CT, based on detection of ≥4 FDG-avid axillary nodes defined as cN2(4+) or occult N3-disease, was calculated. In total, 87 of 278 patients were considered high-risk based on conventional staging. PET/CT detected occult N3-disease in 5 (11 %) of 47 low-risk patients. In 144 intermediate-risk patients, PET/CT detected ≥4 FDG-avid nodes in 24 (17 %) patients and occult N3-disease in 22 (15 %) patients, thereby finally upstaging 38 (26 %) of intermediate-risk patients. Of 43 (23 %) upstaged patients, 18 were ypN0, 12 were ypN1, and 13 were ypN2-3. Pre-chemotherapy PET/CT is valuable for selection of breast cancer patients at high risk for LRR. In our population, 23 % of patients treated with NAC were upstaged to the high-risk group based on PET/CT information, potentially benefiting from regional radiotherapy.

The Importance of Adequate Primary Tumor Excision Margins and Sentinel Node Biopsy in Achieving Optimal Locoregional Control for Patients With Thick Primary Melanomas

This study sought to investigate the impact of histopathologically measured excision margins and SNB on local and locoregional disease control in patients with primary cutaneous melanomas more than 4 mm thick. Most current guidelines recommend at least a 2-cm surgical margin (which corresponds to a 16-mm histopathologic margin). These guidelines are based on limited evidence, mostly obtained in patients who did not have an SNB. Histopathologic tumor excision margins for clinically lymph node-negative patients with melanomas more than 4 mm thick, treated at Melanoma Institute Australia (1992-2009), were determined. Clinicopathologic predictors of local and locoregional disease-free survival were investigated. There were 632 patients eligible for the study; of these, 397 (62.8%) had an SNB. The median histopathologic excision margin was 15 mm (interquartile range, 11.0-19.5 mm). After a median follow-up of 37 months, local and locoregional recurrences were observed in 48 (7.6%) and 159 (25.2%) patients, respectively. Excision margin as a continuous variable was a significant predictor of local [hazard ratio (HR), 0.91; P < 0.001) and locoregional (HR, 0.97; P = 0.042) tumor control on multivariate analyses. Patients with histopathologic margins 16 mm or less had worse local disease-free survival (HR, 2.41; P = 0.01). Patients who did not have an SNB were at higher risk of locoregional recurrence (HR, 1.67; P = 0.003). Histopathologically determined primary tumor excision margins more than 16 mm, corresponding to 2-cm surgical margins, were associated with better local control in patients with melanomas more than 4 mm thick. Patients achieved the best local and locoregional control when SNB was coupled with a more than 16-mm histologic excision margin.

Locoregional Recurrence Following Accelerated Partial Breast Irradiation for Early-Stage Invasive Breast Cancer: Significance of Estrogen Receptor Status and Other Pathological Variables

Understanding risk factors for locoregional recurrence (LRR) after accelerated partial breast irradiation (APBI) can help to guide patient selection for treatment with APBI. Published findings to date have not been consistent. More data are needed as these risk factors continue to be defined. A total of 277 women with early-stage invasive breast cancer underwent lumpectomy and were treated adjuvantly at our institution with APBI using high-dose rate brachytherapy. APBI was delivered using multicatheter interstitial brachytherapy (91%) or single-entry catheter brachytherapy (9%) to a dose of 32-34Gy in 8-10 twice daily fractions. Failure patterns and risk factors for recurrence were analyzed. With a median follow-up of 61months, the 5-year locoregional control rate was 94.4%. Negative estrogen receptor (ER) status was strongly associated with LRR on multivariate analysis (p<0.005). Lobular histology, the presence of an extensive intraductal component, and lymphovascular invasion also were significant but to a lesser degree than ER-negative status. Patients with multiple risk factors were at highest risk for LRR. Age was not significantly associated with increased risk for LRR. The presence of specific pathological features, particularly ER negative status, was associated with increased risk of LRR in this cohort of women treated with APBI. Further investigation is warranted to determine whether patients with adverse pathological risk factors are at higher risk of LRR after APBI than after conventional whole breast irradiation (WBI), as these same features also may place women at risk for LRR after WBI.

Circulating tumor cells in head and neck cancer: clinical impact in diagnosis and follow-up

Metastasis and the associated loss of function of vital organs in the course of the disease is one of the main causes of death in head and neck cancer patients. An earlier and more reliable determination of metastasis and recurrence than currently obtained by common imaging methods could improve therapy and therefore the prognosis of head and neck cancer patients. The detection of tumor cells, which circulate in the blood of cancer patients, known as circulating tumor cells and those that can be found in the bone marrow, called disseminated tumor cells (DTC) provides a diagnostic source especially for those patients at high risk of locoregional recurrence or distant failure. Circulating tumor cells (CTC) have been identified as a prognostic factor in different solid tumors. In head and neck squamous cell carcinoma, there are data for a similar prognostic relevance. The methods of detection of CTC/DTC, the role in diagnosis and follow-up in head and neck cancer are summarized in this review. Furthermore, the future technical and clinical challenges to be addressed to establish CTC/DTC in clinical routine are being critically discussed.

The number of positive lymph nodes in the central compartment has prognostic impact in papillary thyroid cancer

Central compartment lymph node (CCLN) metastasis in papillary thyroid cancer (PTC) is associated with higher risk of loco-regional recurrence and distant metastasis. This study evaluated the prognostic implication of the number of metastatic CCLN in PTC. Prospective data collection on 91 patients with PTC who underwent total thyroidectomy and CCLN dissection with or without lateral neck dissection between January 2005 and December 2010 was made. Number of positive CCLN was correlated with known prognostic factors (age, gender, tumour size, extrathyroidal extension and lateral node metastasis). Patients were divided into three groups according to the number of positive CCLN: group A = 0 (n = 35); B = 1-2 nodes (n = 32) and C = >3 nodes (n = 24). The risk of lateral compartment disease increased in parallel with the number of positive CCLN (31 vs. 50 vs. 75 % in groups A-B-C, respectively; p < 0.004). Gender/age/tumour size/extrathyroidal extension did not correlate with number of positive CCLN. The increasing number of positive CCLN did not influence post-ablation iodine uptake (1.25 vs. 1.14 vs. 2.63 %) and correlated with mean thyroglobulin values at 1-year post-ablation (12.3 vs. 42.3 vs. 91.48 μg/L) CONCLUSIONS: The number of CCLN metastasis is a risk factor for lateral compartment disease with no correlation with other prognostic markers.

Abstract P3-04-03: A seven-gene profile predicting benefit of postmastectomy radiotherapy independently of nodal status in high risk breast cancer

Abstract Background: Recommendations for postmastectomy radiotherapy (PMRT) are well established in patients estimated to have a high risk of loco-regional recurrence (LR) (e.g. tumor size &amp;gt; 5 cm or ≥ 4 positive lymph nodes). International recommendations for patients with 1–3 positive lymph nodes suggest that PMRT should be restricted to younger patients and patients with other poor prognostic features. However, large randomized trials, including the DBCG82 trials (Danish Breast Cancer Cooperative Group), have previously shown a substantial overall survival benefit after PMRT in patients with low risk of LR, and shown that the largest translation of LR reduction into breast cancer mortality reduction occurs within the most favorable prognosis group. Our hypothesis is that a more refined partitioning of patients likely to benefit from PMRT can be established through identification of genes whose transcription interacts with PMRT to modify the hazard of LR. Material and methods: The DBCG82bc cohort constitutes high risk patients (tumor size &amp;gt; 5 cm and/or positive nodes and/or invasion in skin or pectoral fascia) diagnosed between 1983–89, treated with mastectomy and partial axillary lymph nodes dissection and randomized to +/− PMRT. From 267 DBCG82bc patients, frozen tumor samples were available. Whole genome arrays (Applied Biosystem Human Genome Survey Microarray v2.0®, Applied Biosystem, Foster City, USA) were successful in 195 samples. Genes, whose expression levels interacted with PMRT on the association with LR, were identified through a two step Cox Proportional Hazard model with lasso penalty. 11 node negative patients were excluded from the subsequent analysis of 184 node positive patients (1–3 pos. nodes: 102 pts, ≥ 4 pos. nodes: 82 pts). Results: Seven genes were identified whose expression interact with the effect of PMRT, and a specialized index was generated based on the expression levels of these genes. Patients were ranked according to the size of the index, and divided into quartiles with 25% of the patients designated as having a “high index” and 75% a “low index”. Among patients not receiving PMRT, a low index was in both nodal groups (1–3 vs. ≥ 4 positive nodes) associated with a significantly higher risk of LR compared to patients with a high index. In both nodal groups, PMRT significantly reduced the risk of LR in patients with a low index; equalizing the risk to patients with a high index, who showed no additional LR reduction by PMRT. In the group of 1–3 positive nodes, PMRT raised the local control rate (LCR) after 10 years from 47.5 % to 91.8% in the low index group (p = 0.0001), whereas the change in the high index group was non-significant (92.3% vs. 100.0%). In the group of patients with ≥ 4 positive nodes, PMRT raised LCR from 16.6% to 80.0% in the low index group (p = 0.0001), and no effect on LCR was seen in the high index group (83.3% vs. 87.5%, n.s.). Conclusion: A seven gene-profile attaining prognostic and predictive impact, irrespective of number of positive nodes, was identified. The profile allowed the identification of 25% of the patients not showing any additional benefit from PMRT in terms of LR. The gene-profile may provide a method to identify patients expected to benefit from PMRT. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-04-03.