5-year Distant Disease-free Survival Research Articles

Favorable outcomes with de-escalated radiation therapy for limited-stage nodular lymphocyte-predominant Hodgkin lymphoma

AbstractRadiation fields for limited-stage nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) have shrunk over time; involved-site radiation therapy (ISRT) has replaced extended-field radiation therapy (EFRT) and involved-field radiation therapy (IFRT), but this has not been validated. The role of systemic therapy is unclear. We reviewed 71 stage I/II NLPHL patients and assessed progression-free survival (PFS), overall survival (OS), locoregional disease-free survival, and distant disease-free survival (DDFS). Median patient age was 39 years, and 61% had stage II disease. Thirty-six (51%) received radiation therapy (RT) only, 6 (8%) received systemic therapy only, and 29 (41%) received both. More patients receiving combined therapy had B symptoms (P = .035) and stage II disease (P = .001). In the RT-only group, 9 (25%) received EFRT, 13 (36%) received IFRT, and 14 (39%) received ISRT; in the combined-modality group, 3 (10%) received EFRT, 7 (24%) received IFRT, and 19 (66%) received ISRT. After a median follow-up of 6.2 years, 15 patients relapsed (13 distant, 2 locoregional). Five-year PFS and OS rates were 86% and 96% and did not differ by treatment. In the RT-only group, follow-up was shorter in the ISRT cohort (2.6 years vs 17.9 years [EFRT] and 8.5 years [IFRT], P < .01), but 5-year PFS did not differ by field size (P = .20). Locoregional control rates were 100% for the RT-only and combined groups, and corresponding 5-year DDFS rates were 93% and 95% (P = .95). Eight patients (11%) experienced a second malignancy (1 within RT field). Six patients died (1 from lymphoma). Use of limited ISRT fields does not appear to increase the risk of locoregional relapse, even when RT is given as single-modality therapy.

Co-mutation of TP53 and PIK3CA in residual disease after neoadjuvant chemotherapy is associated with poor survival in breast cancer.

The prevalence and clinical relevance of TP53 and PIK3CA mutations in pretreatment breast cancer have been previously reported. However, little is known regarding these mutations in residual tumor tissues after neoadjuvant chemotherapy. Here, we investigated the association between TP53 and PIK3CA mutations in residual disease and survival of breast cancers. TP53 and PIK3CA somatic mutations were examined in 353 post-neoadjuvant chemotherapy residual tumor tissues by Sanger sequencing. Survival curves of patients with TP53 and PIK3CA mutations were compared using the Kaplan-Meier method. Fifty-six (15.9%) of the 353 patients carried a TP53 somatic mutation and 79 patients (22.4%) carried a PIK3CA somatic mutation. A total of 18 patients carried co-mutation of TP53 and PIK3CA. Patients with somatic co-mutation were more likely to have high-grade tumors (35.3% vs. 10.6%, P = 0.010), estrogen receptor-negative tumors (55.6% vs. 26.7%, P = 0.009), progesterone receptor-negative tumors (61.1% vs. 30.5%, P = 0.008) and triple-negative tumors (35.3% vs. 13.3%, P = 0.025) compared with non-carriers. More importantly, co-mutation of TP53 and PIK3CA carriers had a significantly worse disease-free survival (DFS) and distant disease-free survival (DDFS) than non-carriers (5-year DFS: 58.0% vs. 83.2%, P < 0.001; 5-year DDFS: 70.3% vs. 86.4%, P = 0.024). Furthermore, in multivariate regression analysis, TP53 and PIK3CA co-mutation carriers showed a significantly worse DFS (adjusted hazard ratio = 3.70; 95% confidence interval, 1.79-7.63; P < 0.001). Patients with somatic co-mutation of TP53 and PIK3CA were associated with unfavorable survival compared with non-carriers. Co-mutation of TP53 and PIK3CA could be used as a potential prognosis marker in post-neoadjuvant chemotherapy breast cancer patients.

Abstract GS3-04: A prospective randomized multi-center open-label phase III trial of extending aromatase-inhibitor adjuvant therapy to 10 years - Results from 1697 postmenopausal women in the N-SAS BC 05 trial: Arimidex extended adjuvant randomized study (AERAS)

Abstract Background: Treatment with an aromatase inhibitor for 5 years as up-front monotherapy or after tamoxifen therapy for 2-3 years is the treatment of choice for hormone-receptor-positive breast cancer in postmenopausal women. Extending treatment with an aromatase inhibitor to 10 years may reduce the risk of breast cancer recurrence. Methods: We conducted a prospective randomized multi-center open-label phase III trial to assess the effect of the extended use of anastrozole for an additional 5 years. Postmenopausal patients with stageI-III, hormone-receptor-positive breast cancer, disease-free after 5 years of either anastrozole alone or tamoxifen 2-3 years followed by anastrozole 3-2 years were randomized to continual group with anastrozole for an additional 5 years or stop group without an additional anastrozole. Our primary end point was disease-free survival. Results: We enrolled 1697 women. After a median follow up of 4.9 years, there were 149 events involving disease recurrence or the occurrence of contralateral breast cancer (51 in continual group and 98 in stop group) and 7 deaths (3 in continual group and 4 in stop group). The 5-year disease-free survival rate was 91.9% (95% confidence interval [CI], 89.4 to 93.8) in continual group and 84.4% (95% CI: 80.0 to 88.0) in stop group (hazard ratio for disease-free survival,0.548 ;P=0.0004. by a two-sided log-rank test stratified according to nodal status, prior adjuvant chemotherapy, institution, and choice of anastrozole or tamoxifen). The rate of 5-year overall survival was 99.5% in continual group and 99.6% in stop group. (hazard ratio,1.389 ;P=0.665). The rate of 5-year distant disease-free survival was 97.2% in continual group and 94.3% in stop group (hazard ratio,0.514 ;P=0.0077). Bone-related adverse events were observed more frequently among patients in continual group than among patients in stop group, including a higher incidence of bone pain, stiff joints, bone fractures, and new-onset osteoporosis. Conclusion: The extension of treatment with an adjuvant aromatase inhibitor (anastrozole) to 10 years resulted in significantly higher rates of disease-free survival and distant disease-free survival than those with no additional anastrozole, but the rate of overall survival was not different between two groups. Our study shows that it is safe and beneficial for postmenopausal patients with hormone-receptor-positive breast cancer to take an anastrozole as adjuvant therapy for an additional 5 years after initial treatment. (UMIN:000000818) Citation Format: Ohtani S, Iijima K, Higaki K, Sato Y, Hozumi Y, Hasegawa Y, Takei H, Tanaka M, Yagata H, Masuoka H, Tanabe M, Egawa C, Komoike Y, Saji S, Nakamura T, Yanagita Y, Ohtsu H, Mukai H, Iwase T. A prospective randomized multi-center open-label phase III trial of extending aromatase-inhibitor adjuvant therapy to 10 years - Results from 1697 postmenopausal women in the N-SAS BC 05 trial: Arimidex extended adjuvant randomized study (AERAS) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS3-04.

A randomised study of tailored toxicity-based dosage of fluorouracil-epirubicin-cyclophosphamide chemotherapy for early breast cancer (SBG 2000-1)

Study aimRetrospective studies have demonstrated a worse outcome in breast cancer patients not developing leukopenia during adjuvant chemotherapy. The SBG 2000-1 is the first randomised trial designed to compare individually dosed chemotherapy without G-CSF support based on grade of toxicity to standard-dosed chemotherapy based on body surface area (BSA). MethodsPatients with early breast cancer were included and received the first cycle of standard FEC (fluorouracil 600 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 600 mg/m2). Patients with nadir leukopenia grade 0–2 after first cycle were randomised between either 6 additional courses of tailored FEC with increased doses (E 75–90 mg/m2, C 900–1200 mg/m2) or fixed treatment with 6 standard FEC. Patients with grade 3–4 leukopenia were registered and treated with 6 standard FEC. Primary end-point was distant disease-free survival (DDFS). ResultsThe study enrolled 1535 patients, of which 1052 patients were randomised to tailored FEC (N = 524) or standard FEC (N = 528), whereas 401 patients with leukopenia grade 3–4 continued standard FEC and formed the registered cohort. Dose escalation did not statistically significantly improve 10-year DDFS (79% and 77%, HR 0.87, CI 0.67–1.14, P = 0.32) or OS (82% and 78%, respectively, HR 0.89, CI 0.57–1.16, P = 0.38). Corresponding estimates for the registered group of patients were DDFS 79% and OS 82%, respectively. ConclusionsThe SBG 2000-1 study failed to show a statistically significant improvement of escalated and tailored-dosed chemotherapy compared with standard BSA-based chemotherapy in patients with low haematological toxicity, although all efficacy parameters showed a numerical advantage for tailored treatment.

Androgen Receptor in Stage I-II Primary Breast Cancer -Prognostic Value and Distribution in Subgroups.

The value of androgen receptor (AR) in breast cancer has gained renewed interest as a prognostic and treatment predictive biomarker. The aims of this work were to study the associations and the prognostic value of AR in patients from two clinical cohorts. Cohort 1 included 208 premenopausal, node-negative patients of whom 87% had received no adjuvant medical treatment; cohort 2 consisted of 263 patients with stage II disease who had all received 2 years of adjuvant tamoxifen. A semi-quantitative assessment of nuclear AR expression divided into five groups (0-1%, 2-10%, 11-50%, 51-75%, and 76-100%) was performed. Survival analyses, stratified by cohort, were performed using both a trend-test and a cut-off of >10% for positivity. A total of 76% of all patients were AR+, and 89%, 48%, and 23% of the estrogen receptor-positive, negative, and triple-negative, respectively. In Cox regression, stratified by cohort, AR divided into five groups was a prognostic factor for 5-year distant disease-free survival with a hazard ratio of 0.86 per step in fraction score (p=0.018). With a predefined cut-off at 10%, moderate evidence of an effect remained (Hazard Ratio=0.67, p=0.077). In multivariable analysis, AR did not retain an independent prognostic value. AR is a weak, however, not independent prognostic factor for distant metastasis. Although the prognostic value of AR may be questionable, the study identified a subset of AR-positive triple-negative patients as being potential candidates for AR-directed therapy for which further studies are warranted.

PTis and pT1a Ipsilateral Breast Tumor Recurrence Is Associated with Good Prognosis after Salvage Surgery

Objectives: Patients with ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery have a poor prognosis. There is little information regarding the prognostic impact of the tumor size in patients with IBTR. Methods: A total of 143 patients who had histologically confirmed IBTR without distant metastases and who underwent salvage surgery between 1989 and 2013 in our hospital were included. Distant disease-free survival (DDFS) was calculated according to the invasive tumor size of IBTR. The median follow-up period was 4.6 years. Results: Patients with pT1b or more advanced IBTR have a high (≥20%) 5-year distant recurrence risk. There were significant differences in DDFS between patients with pTis or pT1a and those with pT1b or a more advanced stage (5-year DDFS: 94.4 vs. 70.1%, respectively, p value = 0.006). This significance remained after adjusting for other clinicopathological factors (p value = 0.04). Conclusion: Patients with pTis or pT1a IBTR have a good prognosis after salvage surgery for IBTR, and the omission of adjuvant chemotherapy could be considered. Further research and validation studies are needed.

Effect of Tailored Dose-Dense Chemotherapy vs Standard 3-Weekly Adjuvant Chemotherapy on Recurrence-Free Survival Among Women With High-Risk Early Breast Cancer

Standard dosing of chemotherapy based on body surface area results in marked interpatient variation in pharmacokinetics, toxic effects, and efficacy. Whether tailored dosing can improve outcomes is unknown, as is the role of dose-dense adjuvant chemotherapy. To determine whether tailored dose-dense adjuvant chemotherapy improves the outcomes of early breast cancer compared with a standard 3-weekly chemotherapy schedule. A randomized, open-label, phase 3 trial of women aged 65 years and younger who had surgery for nonmetastatic node-positive or high-risk node-negative breast cancer at 86 sites in Sweden, Germany, and Austria between February 20, 2007, and September 14, 2011. Patients were randomized 1:1 either to 4 cycles of leukocyte nadir-based tailored and dose-dense adjuvant epirubicin and cyclophosphamide every 2 weeks followed by 4 cycles of tailored dose-dense docetaxel every 2 weeks, or to standard-interval chemotherapy with 3 cycles of fluorouracil and epirubicin-cyclophosphamide every 3 weeks followed by 3 cycles of docetaxel every 3 weeks. The primary end point was breast cancer recurrence-free survival (BCRFS). Secondary end points included 5-year event-free survival (EFS), distant disease-free survival (DDFS), overall survival (OS), and rates of grade 3 or 4 toxic effects. Among 2017 randomized patients (1006 in the tailored dose-dense group and 1011 in the control group; median [IQR] age, 51 [45-58] years; 80% with hormone receptor-positive tumors; 97% with node-positive disease), 2000 received study treatment (≥1 cycle of chemotherapy; 1001 in the tailored dose-dense group and 999 in the control group). After a median follow-up of 5.3 years (IQR, 4.5-6.1 years), 269 BCRFS events were reported, 118 in the tailored dose-dense group and 151 in the control group (HR, 0.79; 95% CI, 0.61-1.01; log-rank P = .06; 5-year BCRFS, 88.7% vs 85.0%). The tailored dose-dense group had significantly better EFS than the control group (HR, 0.79; 95% CI, 0.63-0.99; P = .04; 5-year EFS, 86.7% vs 82.1%). The groups did not differ in OS (HR, 0.77; 95% CI, 0.57-1.05; P = .09; 5-year OS, 92.1% vs 90.2%) or DDFS (HR, 0.83; 95% CI, 0.64-1.08; P = .17; 5-year DDFS, 89.4% vs 86.7%). Grade 3 or 4 nonhematologic toxic effects occurred in 527 (52.6%) in the tailored dose-dense group and 366 (36.6%) in the control group. Among women with high-risk early breast cancer, the use of tailored dose-dense chemotherapy compared with standard adjuvant chemotherapy did not result in a statistically significant improvement in breast cancer recurrence-free survival. Nonhematologic toxic effects were more frequent in the tailored dose-dense group. clinicaltrials.gov Identifier: NCT00798070; isrctn.org Identifier: ISRCTN39017665.

Impact of the response of primary tumor to preoperative chemotherapy and anti-HER2 therapy on survival of HER2-positive breast cancer patients

To study the impact of anti-HER2 therapy and response of primary tumor on distant disease free survival (DDFS) of the patients with HER2-positive breast cancer. The clinical data of the patients with HER2-positive breast cancer treated with neoadjuvant systemic therapy were analyzed retrospectively. Patients treated with preoperative anti-HER2 therapy and chemotherapy had a significant improved pathological complete response (pCR) rate (48.4%) compared with those treated with preoperative chemotherapy (17.2%) (P=0.000). The median follow-up period was 62(6-160) months. The 5-year DDFS in patients with anti-HER2 therapy and patients without anti-HER2 therapy was 93.5% and 83.3% respectively (P=0.006). The 5-year DDFS in patients achieving a pCR and patients not achieving a pCR was 94.7% and 82.6% respectively(P=0.001). Among patients achieving a pCR, anti-HER2 therapy did not improve DDFS significantly (P=0.960). Benefits of anti-HER2 therapy in DDFS among patients without a pCR achieved statistical significance (P=0.028). Combination of neoadjuvant anti-HER2 therapy and chemotherapy resulted in a higher pCR rate in HER2-overexpressing primary breast cancer. Patients treated with neoadjuvant systemic therapy who achieved a pCR have excellent outcome regardless of whether they received anti-HER2 therapy.

Safety of breast-conserving treatment for triple-negative breast cancer

To investigate the effect of risk factors on ipsilateral breast tumor recurrence (IBTR) and distant disease-free survival (DDFS) for patients with triple-negative breast cancer (TNBC) who underwent breast-conserving treatment (BCT). A series of 1 835 patients with primary breast cancer treated with BCT in a single institute between December 1999 and August 2010 were analyzed retrospectively. Totally 1 614 patients, whose characteristics were intact, were analyzed to compare their outcomes with respect to the incidence of IBTR, DDFS and disease-free survival (DFS). All of patients were female. Median age was 47 years (ranging 21 to 92 years, interquartile range 14 years). According to the immunohistochemical results of the patients, 1 614 cases were divided into TNBC group (n=308) and non-TNBC group (n=1 306). The risk factors of relapse after breast-conserving treatment (age at diagnosis, spread to axillary lymph nodes, hormone receptor status, neoadjuvant chemotherapy, and maximal tumor diameter, human epidermal growth factor receptor 2 (HER-2) status, preoperative MRI, the location and extent of the tumor bed defined by CT scans for electron boost planning as part of breast radiotherapy) were studied.χ(2) test was used to compare the distribution of baseline characteristics among subtypes. The probability of survival (or relapse occurrence), and DDFS were calculated using the Kaplan-Meier method. Cumulative incidence functions were used to describe the cumulative hazard from LR, IBTR and DDFS in the presence of competing risks. A total of 1 614 women with primary breast cancer underwent a breast-conserving surgery followed by radiotherapy. The median follow-up period was 77 months (interquartile range 36 months). One hundred and forty patients (8.6%) were lost to follow-up. Overall 5-year IBTR rate was 3.1% (95% CI: 2.2% to 4.0%), 5-year DDFS rate was 95.8% (95% CI: 94.9% to 96.7%) and 5-year DFS rate was 93.8% (95% CI: 92.7% to 94.9%). Lymph nodal involvement (HR=3.03, 95% CI: 1.66 to 5.51, P=0.000) and use of CT information in boost field planning (HR=0.40, 95% CI: 0.20 to 0.80, P=0.010) were associated significantly with IBTR in Cox multivariable analysis. Multivariable analysis showed that TNBC doesn't have a significantly increased risk of IBTR compared with the non-TNBC subtype (HR=0.90, 95% CI: 0.50 to 1.76, P=0.78). TNBC was not an independent risk factor for DDFS or DFS. The multivariable model showed significant effect of nodal status and age at diagnosis on 5-year DDFS rate and 5-year DFS rate. Breast-conserving treatment for TNBC is not associated with increased IBTR compared with non-TNBC subtype. Use of CT information in boost field planning can reduce the risk of ipsilateral breast tumor recurrence for patients undergoing BCT.

Immunohistochemical subtypes predict the clinical outcome in high-risk node-negative breast cancer patients treated with adjuvant FEC regimen: results of a single-center retrospective study.

BackgroundAnthracycline-based adjuvant chemotherapy improves survival in patients with high-risk node-negative breast cancer (BC). In this setting, prognostic factors predicting for treatment failure might help selecting among the different available cytotoxic combinations.MethodsBetween 1998 and 2008, 757 consecutive patients with node-negative BC treated in our institution with adjuvant FEC (5FU, epirubicin, cyclophosphamide) chemotherapy were identified. Data collection included demographic, clinico-pathological characteristics and treatment information. Molecular subtypes were derived from estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status and Scarff-Bloom-Richardson (SBR) grade. Disease-free survival (DFS), distant disease-free survival (DDFS) and overall survival (OS) were estimated using the Kaplan-Meier Method, and prognostic factors were examined by multivariate Cox analysis.ResultsAfter a median follow-up of 70 months, the 5-year DFS, DDFS and OS were 90.6 % (95 % confidence interval (CI): 88.2–93.1), 92.8 % (95 % CI: 90.7–95) and 95.1 % (95 % CI, 93.3–96.9), respectively. In the multivariate analysis including classical clinico-pathological parameters, only grade 3 maintained a significant and independent adverse prognostic impact. In an alternative multivariate model where ER, PR and grade were replaced by molecular subtypes, only luminal B/HER2-negative and triple-negative subtypes were associated with reduced DFS and DDFS.ConclusionsNode-negative BC patients receiving adjuvant FEC regimen have a favorable outcome. Luminal B/HER2-negative and triple-negative subtypes identify patients with a higher risk of treatment failure, which might warrant more aggressive systemic treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1746-3) contains supplementary material, which is available to authorized users.

Postoperative intensity-modulated radiation therapy provides favorable local control and low toxicities in patients with soft tissue sarcomas in the extremities and trunk wall

PurposeTo investigate the efficacy and toxicity of postoperative intensity-modulated radiation therapy (IMRT) for patients with soft tissue sarcomas (STSs) in the extremities and trunk wall.Patients and methodsEighty patients with localized STSs in the extremities and trunk wall treated with function-conserving surgery and postoperative IMRT were analyzed. The primary locations were in the extremities in 51 patients and in the trunk wall in 29 patients. The margins were positive in nine patients and negative in 71 patients. The median dose of IMRT was 64 Gy.ResultsAt a median follow-up time of 38 months, eight patients developed local recurrences. The 5-year local control (LC) rate was 88.1%. The patients with negative margins exhibited much better LC than did those with positive margins (90% vs 64.8%, P=0.023). Multivariate analysis revealed that positive margin was an independent risk factor for LC. The 5-year distant metastasis-free survival, disease-free survival, and overall survival rates were 75.2%, 72.6%, and 83.6%, respectively. Large tumor size (>5 cm) was significantly associated with poor overall survival. Edema and joint stiffness were observed in 17.6% and 9.8% of patients with extremity STSs, respectively.ConclusionIMRT provides excellent LC and low toxicity for patients with STSs in the extremities and trunk wall.

Change in estrogen receptor, HER2, and Ki-67 status between primary breast cancer and ipsilateral breast cancer tumor recurrence

IntroductionChanges in the biological marker status between primary and recurrent tumors are observed in breast cancer. However, their clinical significance is still uncertain, especially for patients with ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery. Patients and methodsA total of 117 patients with IBTR without distant metastases were enrolled in this study. All patients were examined for estrogen receptor (ER), HER2, and Ki-67 in both the primary tumors and paired IBTR. We evaluated the impact of changes in these biomarkers between primary tumors and IBTR on the prognosis after IBTR. ResultsThere were no associations of changes in the ER, HER2 status with distant disease-free survival (DDFS) after surgical resection of IBTR, whereas the change in the Ki-67 status between the primary tumors and IBTR was significantly correlated with DDFS (unadjusted: p = 0.0094; adjusted: p = 0.013). Patients in the “increased or remained high” Ki-67 group had a significantly shorter DDFS than those in the “decreased or remained low” Ki-67 group (5-year DDFS: 55.5 vs. 79.3%, respectively, p = 0.0084 by log-rank test). ConclusionAn increased or persistently high Ki-67 status in the IBTR was significantly correlated with a poorer prognosis after IBTR.

Systemic Therapy of Locoregional Recurrence of Breast Cancer

Historically, locoregional recurrence (LRR) of breast cancer comprised the recurrence of breast cancer following mastectomy occurring in the skin of the chest wall, the surgical scar, the axilla, or in other regional lymph nodes such as the ipsilateral supraclavicular, infraclavicular, and internal mammary nodes. With the establishment of breast-conserving surgery (BCS) as an effective alternative to mastectomy, ipsilateral breast tumor recurrence (IBTR) was added as a potential site of LRR in patients undergoing BCS. While LRR sometimes presents concurrently with distant metastatic disease, it most often occurs as isolated locoregional recurrences (ILRRs). ILRRs are associated with a high risk of subsequent distant metastatic disease and ultimately death from metastatic breast cancer. Risks are higher with ILRR following mastectomy than with ILRR following BCS. A review of the literature reporting prognosis after LRR demonstrated an overall 5-year disease-free survival (DFS) of 30% and 5-year overall survival (OS) of 35% in patients initially treated with mastectomy. In patients treated with BCS, the overall 5-year DFS following LRR was 59%, and the 5-year OS was 68%. The National Surgical Adjuvant Breast and Bowel Project (NSABP) evaluated prognosis following LRR as a first event across 5 large adjuvant trials conducted in women with node-positive breast cancer treated with BCS and defined the risks following IBTR and following LRR in other sites (oLRR). The 10-year cumulative incidences of IBTR and oLRR were 8.7% and 6.0%, respectively. The 5-year distant DFS following IBTR and oLRR was 51.4% and 18.8%, respectively, indicating a better prognosis in

Prognostic Value of Bone Marrow Micrometastasis in Patients with Operable Esophageal Squamous Cell Carcinoma: A Long-Term Follow-Up Study

Detection of bone marrow micrometastasis (BMM) has been focused on as a prognostic parameter in various malignant neoplasms recently. This study was designed to evaluate the prognostic significance of BMM detection in patients with operable esophageal squamous cell carcinoma (ESCC) after long-term follow-up. In 61 consecutive patients with ESCC who had undergone radical surgical resection, BMM was detected through reverse transcriptase-polymerase chain reaction (RT-PCR). Correlation between BMM detection and prognosis of the 61 patients was analyzed. BMM was found in 13 patients (21.3%). No significant correlation between BMM detection and tumor, node, metastasis (TNM) stage was found. The median survival time, 5-year overall survival rate, 5-year disease-free survival rate, and 5-year distant disease-free survival rate for cases with positive BMM were 13.0 months, 15.4%, 7.7%, and 34.2%, respectively, compared with that of 66.0 months, 59.7%, 49.1%, and 60.6% for cases with negative BMM (p < 0.05). In multivariate analysis, BMM were found to be an independent factor in the prediction of overall survival (odds ratio [OR] 3.928, p = 0.001), disease-free survival (OR 4.285, p < 0.001), and distant disease-free survival (OR 3.270, p = 0.013). BMM is an independent prognostic factor in the prediction of the subsequent development of metastatic disease and disease outcome for operable ESCC patients, and may be a useful adjunct to conventional tumor staging. Further studies are required to evaluate the value of neoadjuvant or adjuvant systemic therapy in ESCC patients with BMM.

Sentinel lymph node biopsy in melanoma: final results of MSLT-I.

In 1994 an international randomized controlled clinical trial, MSLT-I, opened to study the utility of sentinel lymph node biopsy (SLNB) for patients with clinically localized melanoma. This trial compared outcomes of patients treated with wide local excision (WLE) and SLNB (followed by immediate completion lymph node dissection [CLND] for those with a positive sentinel node [SN]) with outcomes of patients treated with WLE alone and CLND upon the development of clinically apparent disease. In February 2014 the final analysis of long-term outcomes data was published. Importantly, these data showed that the rates of nodal positivity were the same between the two arms of the trial. Although no difference in 10-year melanoma-specific survival was noted between the two arms, this was not entirely surprising as the overall rate of nodal disease within the trial was 20.8%, meaning that 79.2% of patients could not derive a benefit from SLNB. Subset analysis was performed to determine the impact of early intervention for those patients most likely to have a benefit from early detection. This analysis showed that for patients with nodal disease and intermediate-thickness melanoma (defined as 1.2-3.5-mm Breslow depth), early treatment following positive SLNB was associated with improved 10-year distant disease-free survival and improved 10-year melanoma-specific survival.

Association between the HER2 Ile655Val polymorphism and response to trastuzumab in women with operable primary breast cancer

Human epidermal growth factor receptor 2 (HER2) Ile655Val polymorphism may affect the efficacy of trastuzumab treatment of breast cancer. HER2 Ile655Val polymorphism was determined in 4167 patients with primary breast cancer using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. We investigated the associations between the HER2 Ile655Val polymorphism and clinical outcomes in women with HER2-negative breast cancer and with HER2-positive breast cancer who received trastuzumab or who did not. At a median follow-up of 44 months, HER2 Ile655Val polymorphism was not significantly associated with survival either in the entire study population of 4167 patients or in 2976 HER2-negative breast cancer patients. Among 816 HER2-positive patients who received adjuvant chemotherapy and/or endocrine therapy without trastuzumab treatment, patients with the Val/Ile or the Val/Val genotype had a significantly worse disease-free survival (DFS) and distant DFS (DDFS) than those with the Ile/Ile genotype (DFS, adjusted hazard ratio [HR] 1.5; 95% confidence interval [CI] 1.0-2.3; P = 0.037; DDFS, adjusted HR 1.9; 95% CI 1.2-2.9 P = 0.005). In contrast, among 212 HER2-positive patients who received chemotherapy in combination with trastuzumab treatment, patients with the Val/Ile or the Val/Val genotype had a significantly better DFS and DDFS than those with the Ile/Ile genotype (5-year DFS, 100% versus 83%; P = 0.008; 5-year DDFS, 100% versus 89%; P = 0.031). HER2 Ile655Val polymorphism affects the function of HER2 gene only restricted in HER2-positive breast cancers. HER2-positive breast cancer patients with the Val variant have an aggressive phenotype, but are sensitive to trastuzumab treatment.

Abstract P1-08-06: Low tumor CD68 mRNA content (intratumoral macrophages) is predictive for benefit from adjuvant trastuzumab in HER2-positive breast cancer: An analysis of the FinHER trial

Abstract Background: Tumor immune cell infiltrates influence prognosis of node negative breast cancer (BC), and intratumoral B-cells and T-cells are of importance for achieving response to chemotherapy in triple negative BC. The role of tumor infiltrating macrophages remains unclear, but they might promote tumorigenesis. We investigated the prognostic value of CD68 mRNA levels within the luminal, HER2-positive and triple negative subtypes in the FinHer trial patient population, and evaluated their predictive value on survival outcomes achieved with adjuvant trastuzumab and chemotherapy in early breast cancer. Methods: RNA was extracted from formalin-fixed paraffin-embedded (FFPE) tumor tissue of 917 (90.8%) patients out of the 1010 patients who participated in the FinHer trial. Intratumoral macrophage infiltration was assessed by measuring breast tumor CD68 mRNA content using RT-qPCR from representative FFPE tissue samples. Breast cancer molecular subtypes (luminal, HER2 positive and triple-negative) were approximated using immunohistochemistry (IHC) and central CISH testing data obtained from the FinHer trial datafile. Prognostic significance of CD68 on distant disease-free survival (DDFS) was assessed using Kaplan-Meyer analysis and log-rank test. Results: Tumor CD68 mRNA expression was normally distributed with median expression of 33.56 (dCt). CD68 mRNA levels correlated weakly with estrogen receptor (ER) mRNA expression and ER protein levels (r = 0.11 and r = 0.15, respectively; p&amp;lt;0.0001), but not with tumor HER2 mRNA level or IHC/CISH status (r = -0.06, p = 0.12; and r = 0.01, p = 0.92, respectively). The median tumor CD68 mRNA content was not prognostic for DDFS in the subset of luminal cancers (ER+, HER2-; n = 533, 5-year DDFS 88% versus 88%; p = 0.92), but a lower than the median CD68 level tended to be associated with favorable DDFS in triple negative cancer (n = 143; 81% vs. 70%; p = 0.11) and was significantly associated with favorable DDFS in HER2-positive cancer (n = 191; 86% vs. 67%; p = 0.001). In the subset of HER2-positive cancer with tumor CD68 mRNA expression level lower than the median, patients treated with trastuzumab benefitted from addition of trastuzumab to chemotherapy (5-year DDFS 93% with trastuzumab vs. 79% without trastuzumab; p = 0.02), whereas no benefit from trastuzumab was observed when tumor CD68 content was higher than the median (67% vs. 68%; p = 0.92). Conclusions: The study validates tumor CD68 concentration as a prognostic biomarker in HER2-positive early breast cancer. Patients with HER2-positive cancer and few tumor macrophages (low tumor CD68 mRNA content) benefitted from addition of trastuzumab to chemotherapy, whereas patients with HER2-positive BC with high tumor macrophage content derived no benefit from adjuvant trastuzumab. Trastuzumab may be effective only for macrophage-poor HER2-positive cancers that are prone to antibody-dependent cellular cytotoxicity (ADCC), whereas it may have little efficacy for cancers that progress despite or due to high intratumoral macrophage content that interferes with ADCC. Other agents, such as T-DM1, might work better than trastuzumab in the subset of women who have HER2-positive BC with a high tumor macrophage content. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-06.

The Prognostic Value of Mitotic Activity Index (MAI), Phosphohistone H3 (PPH3), Cyclin B1, Cyclin A, and Ki67, Alone and in Combinations, in Node-Negative Premenopausal Breast Cancer

Proliferation, either as the main common denominator in genetic profiles, or in the form of single factors such as Ki67, is recommended for clinical use especially in estrogen receptor-positive (ER) patients. However, due to high costs of genetic profiles and lack of reproducibility for Ki67, studies on other proliferation factors are warranted. The aim of the present study was to evaluate the prognostic value of the proliferation factors mitotic activity index (MAI), phosphohistone H3 (PPH3), cyclin B1, cyclin A and Ki67, alone and in combinations. In 222 consecutive premenopausal node-negative breast cancer patients (87% without adjuvant medical treatment), MAI was assessed on whole tissue sections (predefined cut-off ≥10 mitoses), and PPH3, cyclin B1, cyclin A, and Ki67 on tissue microarray (predefined cut-offs 7th decile). In univariable analysis (high versus low) the strongest prognostic proliferation factor for 10-year distant disease-free survival was MAI (Hazard Ratio (HR)=3.3, 95% Confidence Interval (CI): 1.8-6.1), followed by PPH3, cyclin A, Ki67, and cyclin B1. A combination variable, with patients with MAI and/or cyclin A high defined as high-risk, had even stronger prognostic value (HR=4.2, 95%CI: 2.2-7). When stratifying for ER-status, MAI was a significant prognostic factor in ER-positive patients only (HR=7.0, 95%CI: 3.1-16). Stratified for histological grade, MAI added prognostic value in grade 2 (HR=7.2, 95%CI: 3.1-38) and grade 1 patients. In multivariable analysis including HER2, age, adjuvant medical treatment, ER, and one proliferation factor at a time, only MAI (HR=2.7, 95%CI: 1.1-6.7), and cyclin A (HR=2.7, 95%CI: 1.2-6.0) remained independently prognostic. In conclusion this study confirms the strong prognostic value of all proliferation factors, especially MAI and cyclin A, in all patients, and more specifically in ER-positive patients, and patients with histological grade 2 and 1. Additionally, by combining two proliferation factors, an even stronger prognostic value may be found.

Serum levels of CEA and CA15-3 in different molecular subtypes and prognostic value in Chinese breast cancer

The prognostic significance of preoperative carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) levels in breast cancer is controversial. This study evaluated the prognostic value of preoperative serum CEA and CA15-3 levels in Chinese breast cancer patients. A total of 470 patients with breast cancer had preoperative CEA and CA15-3 concentrations measured. The relationships between preoperative concentration and clinicopathological factors and outcomes were determined. CEA and CA15-3 levels were increased in 34 (7.2%) and 58 (12.3%) patients, respectively. Elevations of serum CEA and CA-15-3 levels correlated with the primary tumor size and axillary lymph node status. CEA levels were lower in patients with triple-negative breast cancer than in those with other subtypes (P = 0.002). The 5-year distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) of CEA-negative vs. CEA-positive patients were 84.1% vs. 54.5% (P < 0.001), 82.7% vs. 54.8% (P < 0.001), and 89.7% vs. 78.5% (P = 0.007), respectively. The 5-year DMFS, DFS, and OS of CA15-3-negative vs. CA15-3-positive patients were 84.0% vs. 69.6% (P = 0.002), 83.0% vs. 66.2% (P < 0.001), 90.9% vs. 74.2% (P = 0.005), respectively. Multivariate analysis of prognosis indicated that CEA and CA15-3 levels were independent prognostic factors for DMFS (P = 0.021) and DFS (P = 0.032), and DFS (P = 0.014) and OS (P = 0.032), respectively. Serum levels of CEA and CA15-3 may differ in breast cancer molecular subtypes and preoperative levels of CEA and CA15-3 have a significant effect on prognosis in Chinese women with breast cancer.

St Gallen molecular subtypes in primary breast cancer and matched lymph node metastases - aspects on distribution and prognosis for patients with luminal A tumours: results from a prospective randomised trial

BackgroundThe St Gallen surrogate molecular subtype definitions classify the oestrogen (ER) positive breast cancer into the luminal A and luminal B subtypes according to proliferation rate and/or expression of human epidermal growth factor receptor 2 (HER2) with differences in prognosis and chemo-responsiveness. Primary tumours and lymph node metastases might represent different malignant clones, but in the clinical setting only the biomarker profile of the primary tumour is used for selection of adjuvant systemic treatment. The present study aimed to classify primary breast tumours and matched lymph node metastases into luminal A, luminal B, HER2-positive and triple-negative subtypes and compare the distributions.MethodsEighty-five patients with available tumour tissue from both locations were classified. The distribution of molecular subtypes in primary tumours and corresponding lymph node metastases were compared, and related to 5-year distant disease-free survival (DDFS).ResultsThe St Gallen molecular subtypes were discordant between primary tumours and matched lymph node metastases in 11% of the patients (p = 0.06). The luminal A subtype in the primary tumour shifted to a subtype with a worse prognostic profile in the lymph node metastases in 7 of 45 cases (16%) whereas no shift in the opposite direction was observed (0/38) (p = 0.02). All subtypes had an increased hazard for developing distant metastasis during the first 5 years after diagnosis in both primary breast tumours and matched lymph node metastases, compared with the luminal A subtype.ConclusionThe classification according to the St Gallen molecular subtypes in primary tumours and matched lymph node metastases, implicates a shift to a more aggressive subtype in synchronous lymph node metastases compared to the primary breast tumour. The selection of systemic adjuvant therapy might benefit from taking the molecular subtypes in the metastatic node into account.