Benefit Of Postmastectomy Radiotherapy Research Articles

The Role of Adjuvant Radiotherapy in the Treatment of Breast Cancer.

The role of postmastectomy radiotherapy and regional nodal irradiation after radical mastectomy is defined in high-risk patients with locally advanced tumors, positive margins, and unfavorable biology. The benefit of postmastectomy radiotherapy in intermediate-risk patients (T3N0 tumors) remains a matter of controversy. It has been demonstrated that radiotherapy after breast-conserving surgery lowers the locoregional recurrence rate compared with surgery alone and improves the overall survival rate. In patients with four or more positive lymph nodes or extracapsular extension, regional lymph node irradiation is indicated regardless of the surgery type (breast-conserving surgery or mastectomy). Despite the consensus that patients with more than three positive lymph nodes should be treated with radiotherapy, there is controversy regarding the recommendations for patients with one to three involved lymph nodes. In patients with N0 disease with negative findings on axillary surgery, there is a trend to administer regional lymph node irradiation in patients with a high risk of recurrence. In patients treated with neoadjuvant systemic therapy and mastectomy, adjuvant radiotherapy should be administered in cases of clinical stage III and/or ≥ypN1. In patients treated with neoadjuvant systemic therapy and breast-conserving surgery, postoperative radiotherapy is indicated irrespective of pathological response.

The Predictive Effect of the 8th AJCC Pathological Prognostic Staging on the Benefit of Postmastectomy Radiotherapy in N2/N3 Breast Cancer.

BackgroundThe role of the 8th American Joint Committee on Cancer (AJCC) pathological prognostic staging (PPS) on treatment-decision making of breast cancer (BC) remains unclear. This study aimed to investigate the predictive effect of the 8th AJCC PPS on the benefit of postmastectomy radiotherapy (PMRT) in N2/N3 BC.MethodsWe included women with stage N2/3 BC diagnosed between 2010 and 2018 from the Surveillance, Epidemiology, and End Results database. The effect of PMRT on breast cancer-specific survival (BCSS) was evaluated using the multivariate Cox proportional-hazards models.ResultsA total of 13,445 patients were identified, including 10,547 (78.4%) patients treated with PMRT. All patients had reassigned stages based on the 8th AJCC PPS. There were 7102 patients (52.8%) that had stage changed, including 1160 patients (8.6%) were upstaged and 5942 patients (44.2%) were downstaged from the 7th AJCC anatomical staging (AS) to the 8th AJCC PPS. Regarding the 7th AJCC AS, 7603 (56.5%), 948 (7.1%), and 4895 (36.4%) were stage IIIA, IIIB, and IIIC diseases, respectively. Using the 8th AJCC PPS, 3525 (26.2%), 460 (3.4%), 1335 (9.9%), 3457 (25.7%), 2169 (19.1%), and 2100 (15.6%) patients were restaged as IB, IIA, IIB, IIIA, IIIB, and IIIC diseases, respectively. The PPS displayed increased prognostic accuracy and improved model fit with respect to BCSS compared to the 7th AS (C-index, 0.731 vs 0.605, P < 0.001; Akaike Information Criterion, 42141 vs 43118). Regarding the AS, the receipt of PMRT was associated with a better BCSS in those with stage IIIA (P = 0.004), IIIB (P = 0.003), and IIIC (P < 0.001) diseases. Using the PPS, the receipt of PMRT was not associated with a better BCSS among patients with stage IB (P = 0.446), IIA (P = 0.140), and IIB (P = 0.248) disease, while the receipt of PMRT was associated with a better BCSS for those with stage IIIA (P = 0.009), IIIB (P < 0.001), and IIIC (P < 0.001) disease.ConclusionThe 8th AJCC staging provides superior risk stratification and a better tool to predict the benefit of PMRT in N2/3 BC.

Is it beneficial for patients with pT1‐2N1M0 breast cancer to receive postmastectomy radiotherapy? An analysis based on RecurIndex assay

The benefit of postmastectomy radiotherapy (PMRT) for pT1-2N1M0 breast cancer patients currently remains controversial. This study was conducted to investigate whether pT1-2N1M0 breast cancer patients could benefit from PMRT based on RecurIndex assay. The clinical data of 213 pT1-2N1M0 breast cancer patients were retrospectively analyzed. Through RecurIndex assay, 81 cases were assessed as the low risk, and 132 as the high risk. Compared to low-risk patients, high-risk patients especially those not receiving PMRT had a significantly increased risk of recurrence and metastasis, and worse 7-year local-regional recurrence-free interval (LRFI), distance recurrence-free interval (DRFI) and recurrence-free survival (RFS) rates. PMRT-based subgroup analysis indicated no significant differences between the low-risk patients with and without PMRT in 7-year LRFI, DRFI, RFS and overall survival (OS) rates, but apparent differences were all shown between the high-risk patients with and without PMRT in 7-year LRFI, DRFI, RFS and OS rates. Overall, for pT1-2N1M0 breast cancer patients at low risk of recurrence and metastasis stratified by RecurIndex assay, there may be a phenomenon of no PMRT benefits, while for those at high risk, use of PMRT may produce survival benefits.

A Prognostic Risk Stratification Model to Identify Potential Population Benefiting From Postmastectomy Radiotherapy in T1-2 Breast Cancer With 1-3 Positive Axillary Lymph Nodes.

Background and ObjectivesTo establish a prognostic stratification nomogram for T1–2 breast cancer with 1–3 positive lymph nodes to determine which patients can benefit from postmastectomy radiotherapy (PMRT).MethodsA population-based study was conducted utilizing data collected from the Surveillance, Epidemiology, and End Results database. Chi-square test or Fisher exact test was used to compare the distribution of characteristics. Cox analysis identified significant prognostic factors for survival. A prognostic stratification model was constructed by R software. Propensity score matching was applied to balance characteristics between PMRT cohort and control cohort. Kaplan-Meier method was performed to evaluate the performance of stratification and the benefits of PMRT in the total population and three risk groups.ResultsThe overall performance of the nomogram was good (3-year, 5-year, 10-year AUC were 0.75, 0.72 and 0.67, respectively). The nomogram was performed to excellently distinguish low-risk, moderate-risk, and high-risk groups with 10-year overall survival (OS) of 86.9%, 73.7%, and 62.7%, respectively (P<0.001). In the high-risk group, PMRT can significantly better OS with 10-year all-cause mortality reduced by 6.7% (P = 0.027). However, there was no significant survival difference between PMRT cohort and control cohort in low-risk (P=0.49) and moderate-risk groups (P = 0.35).ConclusionThe current study developed the first prognostic stratification nomogram for T1–2 breast cancer with 1–3 positive axillary lymph nodes and found that patients in the high-risk group may be easier to benefit from PMRT.

Tolerance and outcome of hypofractionated post-mastectomy radiotherapy among elderly breast cancer patients in a specialized center in Nigeria.

BackgroundThe incidence of breast cancer rises dramatically with age, and numerous studies have reported the benefits of post mastectomy radiotherapy in both young and elderly breast cancer patients. The limited numbers of radiotherapy machines and the conventional fractionation schedule which are of long duration make access to radiotherapy more difficult especially among the elderly in Nigeria. Hypo fractionated radiotherapy offers an alternative option (with a shorter duration and comparable side effects and outcomes) to conventional radiotherapy as reported in western literatures. Such studies are grossly lacking in a sub-Saharan African country like Nigeria, hence the need for this study.MethodsIn this retrospective study, the records of 83 elderly patients with stages II and III breast cancer that were treated with radiotherapy in the Radiotherapy and Oncology Department of UDUTH, Sokoto, Nigeria, from January 2015 to February 2019 were evaluated. Radiotherapy was given at a dose of 45 Gy in 18 fractions of 2.5 Gy to the chest wall and the regional lymph nodes over a period of 3.5 weeks. The end point was freedom from any grade 3 or higher toxicities and disease free survival at 2 years.ResultsMajority, 67 (80.7%) of the 83 patients had invasive ductal carcinoma which were not otherwise specific. About two-thirds of the patients (69.9%) had the disease located in the right breast. After a 24 month follow up, there were no grade 3 or 4 toxicities. Forty-two (50.6%) and 16 (19.2%) patients had grade 2 skin and nausea/vomiting toxicities respectively. Eighty (96.4%) were disease free at 24 months, 3 (3.6%) patients had local recurrence, while 1 (1.2%) had distant metastasis to the lungs. The two years overall survival rate was 90%.ConclusionsHypofractionated radiotherapy in elderly breast cancer patients proved to be comparable to conventional radiotherapy in terms of toxicities and outcome in our center.

Post-mastectomy Radiotherapy in T1-2 Breast Cancer Patients With One to Three Lymph Node Metastases: A Propensity Score Matching Analysis.

Background and Objectives: Whether post-mastectomy radiotherapy (PMRT) could improve prognosis for T1-2 breast cancer patients with one to three lymph node metastases remains controversial. The present study aimed to determine the significance of PMRT in patients with T1-2N1M0 breast cancer.Methods: Data of 45,646 patients from the Surveillance, Epidemiology, and End Results (SEER) database were analyzed; 12,585 matched patients were divided into a PMRT group and non-radiotherapy group (no-PMRT), respectively, using the propensity score matching method. Univariate and multivariate analyses were performed to determine the prognostic factors of breast cancer, and subgroup analysis was performed according to the number of lymph node metastases.Results: With the median follow-up of 62 months, 5-year cancer-specific survival was 91.48% in the PMRT group and 91.88% in the no-PMRT group (P = 0.405). PMRT did not improve the breast cancer-specific survival (BCSS) in patients with stage T1-2N1M0 (HR = 0.99, 95% CI = 0.92–1.06, P = 0.715). In subgroup analysis, radiotherapy improved the BCSS in patients with three nodes positive, with the 5-year BCSS at 88.5% in the radiation group and 86.6% in the no-radiation group (HR = 0.78, 95% CI = 0.65–0.90, P < 0.001). In patients with two nodes positive, 5-year BCSS was 90.3% in the PMRT group and 89.5% in the no-PMRT group, with no significant difference between the two groups (HR = 0.96, 95% CI = 0.85–1.09, P = 0.552). In patients with one node positive, 5-year BCSS was higher in the no-PMRT group (92.1%) than that in the PMRT group (90.8%); radiotherapy increased the cancer-related death compared with those who did not receive it (HR = 1.21, 95% CI = 1.08–1.36, P = 0.002).Conclusion: The benefit of PMRT in T1-2N1M0 patients was obviously different, and the recommendation of PMRT for this population should be individualized. PMRT should be considered for patients with three nodes positive, should be suggested cautiously in those with two nodes positive, and could be omitted in those with one node positive.

Post-mastectomy radiotherapy is associated with improved overall survival in T3N0 patients who do not receive chemotherapy

Background and purposeThere is limited retrospective evidence addressing the utility of post-mastectomy radiotherapy (PMRT) in patients with T3N0 breast cancer. We performed a retrospective analysis of the National Cancer Database (NCDB) comparing overall survival (OS) in T3N0 patients treated with mastectomy alone (MTX) or with PMRT. Materials and methodsWe performed a matched-cohort analysis of NCDB breast cancer patients with pT3N0 disease who did not receive NAC, or cT3N0 patients who received NAC treated between 2006 and 2014. Patients were matched for all available baseline characteristics using propensity scores with inverse probability of treatment weighting (IPTW) with stabilized weights. ResultsWe identified 13,901 eligible patients. In the pT3N0 cohort, median follow-up was 47 months for the MTX group and 50 months for the PMRT group. In the cT3N0 cohort, median follow-up was 44 months for the MTX group and 46 months for the PMRT group. OS was higher in pT3N0 patients treated with PMRT compared to MTX: 7-year OS of 74% vs. 65% (P < 0.001). Doubly robust multivariable analysis showed an association between PMRT and improved OS (HR 0.78, 95% CI 0.68–0.89, P < 0.001). There was no benefit to PMRT in patients who received adjuvant chemotherapy (AC). In the NAC cohort, PMRT did not change OS, with 7-year OS of 78% with MTX and 79% with PMRT. There was a trend of improved OS with PMRT in patients with residual disease in the breast and lymph nodes (HR 0.70, 95% CI 0.46–1.07). ConclusionPMRT improves OS in patients with pT3N0 disease, but the benefit appears limited to those who do not receive AC. PMRT does not improve OS in patients with cT3N0 disease who receive NAC, but there might be a benefit in patients with a poor response to chemotherapy. However, longer follow-up may be needed to make a definitive conclusion about the benefit of PMRT in patients who receive chemotherapy.

Effect of postmastectomy radiotherapy on triple-negative breast cancer with T1-2 and 1-3 positive axillary lymph nodes: a population-based study using the SEER 18 database.

There is consensus on the routine use of postmastectomy radiotherapy (PMRT) in patients with four or more positive axillary lymph nodes. However, the benefits of PMRT in patients with T1-2 and 1-3 involved lymph nodes still remain controversial. Data from the Surveillance, Epidemiology, and End Results Program (SEER) of the United States between 2010 and 2012 were used to analyze the outcomes of 675 triple-negative breast cancer (TNBC) patients with T1-2 and 1-3 lymph nodes involved. Those patients were subdivided into radiotherapy (RT) (312) and no-RT groups (363). After a median follow-up time of 37 months, Kaplan-Meier analysis showed that PMRT significantly improved overall survival (OS) but not breast cancer-specific survival (BCSS) in the total cohort of 675 patients (P=0.033 and P=0.063). And it was demonstrated that PMRT were independently associated with increased OS according to univariate and multivariate analyses. However, no significant differences in BCSS or OS were observed between the groups stratified by the number of positive lymph nodes. In conclusion, PMRT significantly improved OS for TNBC patients with T1-2 and 1-3 lymph nodes involved. Additional prospective studies are needed to provide a stronger evidence base for choosing patients for PMRT.

The Benefit of Post-Mastectomy Radiotherapy in ypN0 Patients after Neoadjuvant Chemotherapy According to Molecular Subtypes.

PurposeThe benefit of post-mastectomy radiation therapy (PMRT) in patients with breast cancer who achieve ypN0 following neoadjuvant chemotherapy (NAC) has not yet been established. This study aimed to identify the role of PMRT in patients who achieve ypN0 according to molecular subtype.MethodsWe identified patients initially suspected with axillary disease who achieved ypN0 following NAC. From 13 institutions of the Korean Radiation Oncology Group between 2005 and 2011, a total of 189 patients were included in the analysis. Effects of PMRT on loco-regional control (LRC), disease-free survival (DFS), and overall survival (OS) were evaluated for different molecular subtypes.ResultsIn all patients, the prognostic effect of PMRT on LRC, DFS, or OS was not significant. Subgroups analysis showed that the effect of PMRT on LRC was different according to molecular subtype (p for interaction = 0.019). PMRT was associated with greater LRC in the luminal subtype (p = 0.046), but not in other subtypes.ConclusionIn patients who achieve ypN0 following NAC and mastectomy, PMRT shows no additional survival benefits for any molecular subtype.

The Role of Postmastectomy Radiation Therapy for Clinical Stage II-III Breast Cancer Patients With Pathological Complete Remission of Axillary Lymph Nodes After Neoadjuvant Chemotherapy

With the increasing use of neoadjuvant chemotherapy (NAC), patients with pathologically involved nodes had a great chance to be found as pathologically node negative at the time of definitive surgery. Several retrospective studies addressed that there were no survival benefits in those patient with pathologically complete remission (pCR) of axillary lymph node who treated with postmastectomy radiotherapy (PMRT) after NAC. We aim to retrospectively evaluate the role of PMRT in clinical stage II-III breast cancer patients with pathological nodes negative (ypN0) after NAC. We retrospectively identified 946 breast cancer patients with clinical stage II-III who underwent NAC in our center between 2003 and 2013. There were 290 patients achieved ypN0 after mastectomy and the clinical outcomes of the patients had been elucidated. The effects of PMRT on locoregional recurrence-free survival (LRRFS), disease-free survival (DFS) and overall survival (OS) were evaluated by Kaplan-Meier method and compared using the log-rank test. Prognostic factors associated with survival were evaluated by univariate and multivariate analysis. The median age was 50 years old (range, 25-80 years). All patients received 2-8 cycles (median, 4 cycles) of preoperative chemotherapy contained with anthracycling and paclitaxel and mastectomy. Of the 290 patients, 217 (74.8%) underwent PMRT and 73 (25.2%) did not. With a median follow-up time of 63 month, 12 patients developed LRR and 39 developed distant metastasis. The 5-year LRRFS, DFS and OS was 94.2%, 79.3% and 91.8% in no-PMRT group and 95.9%, 84.3% and 92.4% in PMRT group, respectively (p=NS). There was no significant difference between the patients with PMRT and without PMRT in terms of survival outcome, even for the subgroup of patients with clinical stage III disease or with residual disease in breast after NAC. On univariate and multivariate analysis, there were no benefits of PMRT on LRRFS (hazard ratio [HR], 0.714; 95% confidence interval [CI], 0.193-2,634; p =0.612), DFS (HR 0.908; 95%[CI], 0.477-1.734; p = 0.773) or OS (HR, 0.829; 95% [CI], 0.291-2.359; p =0.725). Age at diagnosis，ER and LVI status, adjuvant chemotherapy were independent prognostic factors for LRRFS （p＜0.01）, primary tumor response to NAC was marginally significant with poor LRRFS (hazard ratio [HR] 0.109; 95% CI, 0.011-1.098; p=0.06). Advanced Clinical T stage (T3-T4) was independently associated with decreased DFS and OS. Patients who achieved ypN0 after NAC without PMRT had similar outcomes compared with patients treated with PMRT, regardless of clinical stage and primary tumor response. PMRT might not be necessary for ypN0 patients. Prospective randomized study is needed to identify whether it is safe to omit PMRT in patients with clinical stage II-III disease and achieved ypN0 after NAC and mastectomy

Oncotype Score and Benefit of Post-Mastectomy Radiotherapy in T1-2 N1 Breast Cancer

Oncotype Score and Benefit of Post-Mastectomy Radiotherapy in T1-2 N1 Breast Cancer

Neoadyavant chemotherapy and postoperative irradiation in breast cancer: interrelation and prospects

In 2005 the Oxford meta-analysis of individual patient data from many trials showed no benefit to postmastectomy radiotherapy in node-negative breast cancer patients but reduced 5-year local recurrence and 15-year breast cancer mortality in patients with node-positive disease who underwent axillary lymphnode dissection. Despite these data, there is still some debate over the appropriateness of postmastectomy radiotherapy in patients with 1 to 3 involved lymph nodes. Neoadjuvant chemotherapy leads to clinical and pathological response in a certain proportion of patients. So far, the universal approach was to ignore the information on response to chemotherapy and recommend postmastectomy radiotherapy based on pre-chemo clinical disease status. The main goal of this article is first to summarize the evidence for the use of postmastectomy radiotherapy in a more traditional treatment sequence, and then show new evidence that highlights how information about the response to chemotherapy can be incorporated into the decision regarding the need and benefit of postmastectomy radiotherapy in the context of neoadjuvant chemotherapy.

Trends in the Application of Postmastectomy Radiotherapy for Breast Cancer With 1 to 3 Positive Axillary Nodes and Tumors ≤5 cm in the Modern Treatment Era: A Retrospective Korean Breast Cancer Society Report.

Despite high-level evidence, the benefit of postmastectomy RT in these patients in recent years has not been fully elucidated. We investigated postmastectomy radiotherapy (RT) use and evaluated clinicopathologic and treatment factors influencing RT use in Korean women with pT1-2N1 breast cancer.We identified women diagnosed with pT1-2N1 breast cancer between 1994 and 2009 using the Korean Breast Cancer Registry. Factors associated with RT use were evaluated using logistic regression analysis. The median follow-up was 95 months.Of the 6196 women, 11.9% underwent postmastectomy RT. RT was applied more frequently in women with 3 positive lymph nodes (adjusted odds ratio [OR], 2.69) and larger tumors (OR per centimeter, 1.10). RT use was not significantly associated with well-established risk factors (e.g., tumor grade, hormone receptor status, and lymphovascular space invasion). Although RT utilization increased gradually during the study period (OR per year, 1.07), factors associated with RT were similar over time. The estimated 5-year overall survival increased significantly from 84.1% in 1994 to 2000 to 94.6% in 2005 to 2009.This population-based analysis revealed that the indications for postmastectomy RT in pT1-2N1 breast cancer in Korea are based solely on conventional anatomical factors, although their survival has increased significantly in the modern treatment era. There is a significant unmet need for better risk stratification in these patients and for tailored RT with the incorporation of tumor biology-associated factors.

Highlights of This Issue

The tricarbocylic acid (TCA) cycle is essential to maintenance of oxidative phosphorylation and an important source of biosynthetic precursors in cancer cells. CPI-613 is a novel inhibitor of 2 key TCA cycle enzymes. Pardee and colleagues report on the results a phase I clinical trial of CPI-613, demonstrating that it was well tolerated and several patients had dramatic and sustained responses. Gene expression profiling of the responding versus nonresponding patients suggested increased immune activation in the responders. This study is the first demonstration of activity and safety of an agent that inhibits the TCA cycle and represents an exciting new weapon in the war on cancer.The benefit of postmastectomy radiotherapy (PMRT) is suspected to be heterogeneous. Tramm and colleagues have identified a gene profile attaining prognostic and predictive impact from microarray-analysis and fresh frozen tissue from 191 high-risk, breast cancer patients randomized to +/− PMRT. The gene profile identified a subgroup of patients not benefiting from radiotherapy in terms of locoregional recurrence. The gene profile was transferred to formalin-fixed, paraffin-embedded material (FFPE) and qRT-PCR, and hereafter independently validated in FFPE from another set of patients. This study is the first to present a gene profile predictive of benefit from PMRT, and the gene profile may potentially assist in individualizing PMRT.Rising prostate-specific antigen (PSA) levels after radical prostatectomy (RP) can indicate prostate cancer recurrence years before clinical metastasis. The time interval between PSA recurrence and metastasis can be so long that patients may die of other causes before metastasis; in these cases, recurrence is overdetected and salvage treatments cannot provide benefit. By using established datasets on time from PSA recurrence to metastasis and competing mortality among RP patients, Xia and colleagues quantify the probability that a recurrence is overdetected given patient and tumor characteristics. The results provide practical information for patients and providers when deciding whether to initiate salvage treatment.Altered epigenetic gene regulation and cell function through aberrant long noncoding RNA (lncRNA) appears important in human cancer. However, little is known about these lncRNAs in many tumors, including bladder cancer. Peter and colleagues examined the expression of 39,000 lncRNAs and mRNAs in a cohort of normal and malignant urothelial tissues. They identified generalized upregulation of many lncRNAs, which appeared distinct to the more balanced up and down regulation seen for mRNAs. Thirty-two lncRNAs were associated with disease progression. Functional analysis implicated the lncRNA AB074278 for the maintenance of proliferation and apoptosis avoidance in cancer, possibly through targeting the tumor suppressor EMP1.

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.

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.

460 A Seven-gene Signature Predicting Benefit of Postmastectomy Radiotherapy in High Risk Breast Cancer

460 A Seven-gene Signature Predicting Benefit of Postmastectomy Radiotherapy in High Risk Breast Cancer

Effect of Breast Cancer Radiotherapy and Cigarette Smoking on Risk of Second Primary Lung Cancer

Prior studies have found that postmastectomy radiotherapy (PMRT) for breast cancer (BC) increases the risk of lung cancer (LC). We explored the joint effects of cigarette smoking and PMRT on LC risk. We conducted a population-based nested case-control study among women registered in the Connecticut Tumor Registry diagnosed with nonmetastatic BC between January 1, 1965 and December 31, 1989. Patient cases developed a LC >or= 10 years after BC diagnosis. Controls were matched to patient cases on age, year of BC diagnosis, and length of survival. Medical records were reviewed for pathology, BC therapy, and smoking history. We used conditional logistic regression to estimate odds ratios for the independent and joint effects of smoking and PMRT on risk of overall, ipsilateral, and contralateral LC. Among 113 second primary LC patient cases and 364 controls, compared with nonsmoking women who did not receive PMRT, nonsmoking women who received PMRT had no higher risk of LC; adjusted odds ratios were 5.9 (95% CI, 2.7 to 12.8) for ever-smokers who did not receive PMRT and 18.9 (95% CI, 7.9 to 45.4) for ever-smokers who received PMRT. Adjusted odds ratios for the joint effects of smoking and PMRT were 10.5 (95% CI, 2.9 to 37.8) for the contralateral lung and 37.6 (95% CI, 10.2 to 139.0) for the ipsilateral lung. Smoking and PMRT were associated with increased risk for all histologic types of LC. PMRT after a diagnosis of BC sharply increased the risk of second primary LC, especially in the ipsilateral lung, among ever-smokers. Clinicians should consider including smoking history in their discussions with patients about the risks and benefits of PMRT.

Postmastectomy radiotherapy in intermediate-risk patients: The gray zone

Postmastectomy radiotherapy continues to be one of the most controversial issues in breast radiotherapy. At the crux of the controversy lies the lack of conclusive studies that specifically address the risk-benefit ratio of postmastectomy radiotherapy for patients at intermediate risk of developing locoregional recurrence. A well-designed phase III trial was initiated, but the trial failed to accrue and was closed prematurely, leaving the issue unresolved. Recent data confirm that postmastectomy radiotherapy yields a clear benefit in breast cancer-specific survival. Furthermore, the risk of cardiac morbidity that historically has offset the benefit of postmastectomy radiotherapy appears to be lessening with modern radiotherapy approaches. However, newer, more efficacious systemic therapy regimens may decrease the risk of locoregional recurrence and increase the risk of toxicity from combined-modality therapy. Recent studies attempt to better stratify patients into risk categories based on disease factors and to estimate the benefit of postmastectomy radiotherapy when traditional risk estimates, such as nodal status, are obscured by neoadjuvant systemic therapy. Nonetheless, a clear consensus on the role of postmastectomy radiotherapy remains elusive for patients who are at intermediate risk of locoregional recurrence after mastectomy.

Lymphedema secondary to postmastectomy radiation: incidence and risk factors.

Postmastectomy radiotherapy (PMRT) has proven benefits for certain patients with breast cancer; however, one of its complications is lymphedema. This study examines the incidence of and risk factors associated with lymphedema secondary to PMRT. The charts of patients treated with mastectomy at Roswell Park Cancer Institute between January 1, 1995, and April 20, 2001, who received PMRT were reviewed. Univariate analysis of patient, disease, and treatment variables was conducted. Multivariate analysis was performed on variables found to be significant in univariate analysis. One hundred five patients received PMRT. The incidence of lymphedema was 27%. Patient age, body mass index, disease stage, positive lymph nodes, nodes resected, postoperative infection, duration of drainage, chemotherapy, and hormonal therapy were not associated with lymphedema. Total dose (P =.032), posterior axillary boost (P =.047), overlap technique (P =.037), radiotherapy before 1999 (P =.028), and radiotherapy at Roswell Park Cancer Institute (P =.028) were significantly associated with lymphedema. Increased lymphedema was noted with supraclavicular, internal mammary, mastectomy scar boost, and chest wall tangential photon beam radiation, but the associations were not statistically significant. The high incidence and debilitating effects of lymphedema must be weighed against the benefits of PMRT. Efforts to prevent lymphedema should be emphasized.