Impact of locoregional treatment on the early-stage breast cancer patients: a retrospective analysis

Although adequate locoregional treatment improves local and regional control in early-stage breast cancer, uncertainty still exists about the role of locoregional therapy with respect to survival. To study the impact of surgery and radiotherapy on locoregional control and survival, we combined the data of three European Organisation for Research and Treatment of Cancer (EORTC) Breast Cancer Group trials including early-stage breast cancer patients with long-term follow-up. Risk ratios (RR) were estimated for locoregional recurrence and overall survival using Cox regression models. All analyses were adjusted for tumour size, nodal status, age, adjuvant radiotherapy, adjuvant chemotherapy and trial. The combined data-set consisted of 3648 patients. The median follow-up period was 11 years. 5.9% of the patients who underwent mastectomy and 10.8% of the patients who underwent breast-conserving therapy had a locoregional recurrence (P<0.0001). The risk of death after breast-conserving therapy was similar compared with mastectomy (RR 1.07, P=0.37). Adjuvant radiotherapy after mastectomy was associated with a lower risk for locoregional recurrence (RR 0.43, P<0.001) and death (RR 0.73, P=0.001). Patients with 1-3 positive nodes benefited the most from radiotherapy after mastectomy. Breast-conserving therapy was associated with an impaired locoregional control. However, breast-conserving therapy was not associated with a worse overall survival. Adjuvant radiotherapy in mastectomised patients was associated with both a significantly superior locoregional control and overall survival. The effect of adjuvant radiotherapy was most profound in patients who had 1-3 positive nodes.     

Regional Nodal Radiotherapy in Early-Stage Breast Cancer: Where Are We in 2016?

The goal of locoregional treatment in early-stage breast cancer patients is to eradicate residual locoregional microscopic disease in order to maximize locoregional control, to minimize seeding of distant metastatic sites, and ultimately to improve overall survival. Recently published landmark randomized trials demonstrate that the addition of regional nodal radiotherapy to breast conserving therapy or mastectomy in node positive or high-risk node negative women not only improves locoregional control but also decreases distant metastasis with a trend towards improved overall survival with a favorable toxicity profile. Certain node-positive early-stage breast cancer patients, however, have low rates of axillary recurrence and high rates of breast cancer-specific survival even with sentinel lymph node excision alone without axillary lymph node dissection. Herein, we review the recent developments in regional nodal management and reconcile the apparent conflict between the surgical and radiotherapy literature. In this context, we provide guidance as to the patients appropriate for regional nodal radiotherapy in 2016 and highlight important treatment considerations to minimize long-term toxicity.     

Survival and Pattern of Failure Following Locoregional Recurrence of Breast Cancer

This study analyzed prognostic factors at primary diagnosis and at first recurrence for impact on survival after isolated locoregional failure. The aims were: (1) assessment of prognostic factors for time to second locoregional failure, distant failure, and survival in isolated locoregional recurrence of breast cancer after mastectomy; and (2) investigation of the impact of a second locoregional failure on dissemination and survival.Between 1983 and 1985, 99 patients who had undergone mastectomy and then developed isolated local and/or regional recurrences, were treated with radical excision and radiotherapy; none of these patients had distant metastases. Survival and the times to second local failure and distant metastasis were analyzed according to potential prognostic factors.The median follow-up was 123 months; 38 patients were still alive. Median survival was 89 months and the 10-year survival rate was 38%, with no difference between local and regional recurrences. A total of 43 patients developed a second locoregional recurrence after a median of 73 months; primary tumour size and initial node status were significant independent prognostic factors. The annual hazard rates for recurrence were similar for patients developing local failure or systemic recurrence. The 10-year rate of dissemination was 49% for patients with locoregional control, compared with 51% for patients who had a second locoregional recurrence. The prognostic factors for survival were node status at mastectomy and haemoglobin level at first recurrence.The development of a second locoregional recurrence was not associated with an increased risk of dissemination or reduced survival. Differences in prognostic factors for locoregional control and distant metastases suggest that these recurrences represent different biological entities that require different treatment strategies. However, as the achievement of locoregional control had no influence on prognosis, the use of systemic adjuvant therapy may be warranted in a subset of these patients.     

The sequencing of radiation therapy and chemotherapy after mastectomy in premenopausal women with breast cancer

OBJECTIVE: The purpose of this study was to evaluate the prognostic importance of the sequencing of radiation therapy and chemotherapy after mastectomy in high-risk premenopausal women with breast cancer in addition to other known prognostic factors in the literature. METHODS: In this retrospective study, 176 premenopausal women with breast cancer were evaluated. The median age at referral was 39 years (range, 28-59 years); 106 patients had stage II and 70 had stage III disease. All were subjected to mastectomy. The median number of lymph nodes removed was 19. The influence of age, histological grade, number of nodes removed, number of positive nodes, tumor size, estrogen receptor status, lymphovascular invasion and sequencing of radiotherapy and chemotherapy on 5-year locoregional disease-free survival, 5-year systemic disease-free survival, 5-year disease-free survival and 5-year cancer-specific survival were studied. RESULTS: The 5-year locoregional disease-free survival was 94% for the entire patient population. Because of the small number of locoregional recurrences, none of the evaluated factors was prognostically significant for locoregional recurrence. The 5-year systemic disease-free, disease-free and cancer-specific survival rates were 72, 70 and 77%, respectively. On multivariate analysis of host, tumor and treatment-related factors, the number of positive nodes [RR 1.9 (95% CI: 1.36-2.63), RR 2 (1.46-2.84 ) and RR 1.8 (1.3-2.71), respectively], histopathological grade [RR 1.8 (95% CI: 1.24-2.65), RR 1.9 (1.34-2.88), RR 2.5 (1.65-4.07), respectively], estrogen receptor status [RR 3.5 (95% CI: 1.5-8.6), RR 3.9 (1.64-9.41), RR 2.5 (1.05-6.24), respectively] and the sequencing of radiotherapy and chemotherapy [RR 1.6 (95% CI: 1.17-2.39), RR 1.7 (1.25-2.54), RR 1.6 (1.14-2.43), respectively] were all significant independent predictors of outcome. CONCLUSIONS: Our results show that in addition to traditional prognostic factors, the sequencing of radiation therapy and chemotherapy also predict for increased risk of any type of recurrence or further tumor death.     

Clinical outcomes of post-operative locoregional radiotherapy in pre-menopausal and post-menopausal Chinese women with breast cancer.

BACKGROUND AND PURPOSES: Recent randomized studies from the West show that post-operative locoregional radiotherapy improves survival in lymph node (LN) positive pre-menopausal women with breast cancer but this benefit has not been established in the Chinese population. There is no published study on clinical outcomes (locoregional recurrence, survival and toxicities) of post-operative locoregional radiotherapy in Chinese women with breast cancer. MATERIALS AND METHODS: We conducted a retrospective study of 399 female Chinese patients with breast cancer who had received post-mastectomy locoregional radiotherapy in our center between 1984 and 1990. The patients were stratified according to tumor size, menopausal and LN status. We analyzed the incidence and pattern of locoregional recurrence, distant recurrence, survival rates and toxicity related to radiotherapy. RESULTS: Of the 399 patients 216 were pre-menopausal and 183 were post-menopausal. The mean age was 49.3 years (23-83). Distribution of tumor size and LN status of the two groups was similar. Median follow-up was 71.9 months. Locoregional recurrence occurred in 57 (14.3%) patients (pre-menopausal 24 (11.1%); post-menopausal 33 (18.3%) P=0.489). Recurrence was more common in LN positive patients (18.2%) than LN negative patients (9.2%). The pattern of locoregional recurrence was: chest wall 24, axilla LN 12, supraclavicular LN 10, chest plus LN 11. The distant recurrence rate was 39.6% for all patients and 75.4% for patients with locoregional recurrences. The overall 10-year survival rate for all patients was 54%. For LN positive patients the 10-year survival rate of pre-menopausal and post-menopausal women was 38 and 51%, respectively (P=0.207), and for LN negative patients the rate was 73 and 70%, respectively (P=0.603). Acute skin toxicity included redness (30.8%), dry desquamation (12.8%), and wet desquamation (6. 8%). Long-term toxicities included skin atrophy (0.3%), telangectasia (3.3%), pneumonitis (2.8%) and brachial plexus palsy (1.3%). CONCLUSIONS: In our series Chinese patients with node-positive breast cancer have a relatively high locoregional recurrence rate in spite of mastectomy and post-operative radiotherapy. Limited use of adjuvant system chemotherapy may account, at least in part, for this finding. Clinical outcomes of post-operative radiotherapy in pre-menopausal and post-menopausal breast cancer patients are similar.     

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.     

乳腺癌全乳房切除术后单纯区域复发的放疗和预后分析

目的 分析乳腺癌全乳房切除术后单纯区域复发(RR)患者的预后,探讨放疗的价值和靶区。方法 回顾性分析2001-2018年间 144例全乳房切除术后无辅助放疗、首次孤立性RR的乳腺癌患者,主要研究终点为再次局部区域复发(sLRR)、远处转移(DM)、无进展生存(PFS)和总生存(OS)。结果 RR后中位随访82.5个月,全组患者 5年sLRR、DM、PFS和OS分别为42.1%、71.9%、22.9%和62.6%。局部治疗+全身治疗是sLRR (P<0.001)和PFS (P=0.013)的独立影响因素。局部治疗时手术+放疗组的sLRR率最低(P<0.001)。手术+放疗组的 5年原RR部位再次复发率最低(P<0.001)。做和不做胸壁放疗患者的 5年胸壁复发率分别为12.1%和14.8%(P=0.873)。非锁骨上复发者,做和不做锁骨上放疗的 5年锁骨上复发率分别为9.9%和23.8%(P=0.206)。非腋窝或内乳复发者,无论放疗与否,腋窝或内乳的 5年复发率均<10%。结论 单纯RR患者有较高的 5年OS,推荐对复发部位行手术+放疗的局部治疗联合全身治疗。不建议常规对所有患者行胸壁、腋窝或内乳的预防放疗。锁骨上预防性放疗的价值需要进一步探讨。     

Radiotherapy to the chest wall following mastectomy for node-negative breast cancer: A systematic review

Background. Although nodal status is the major determinant of risk of locoregional relapse (LRR), other factors also contribute, and these assume a greater significance for those with node-negative breast cancer. Previous reviews of post-mastectomy radiotherapy have included studies using radiotherapy techniques or doses no longer considered clinically appropriate. Objectives. To determine the effectiveness of post-mastectomy radiotherapy in women with node-negative breast cancer with particular reference to those patient and tumour factors which contribute to an increased risk of LRR. Methods. A systematic literature review was conducted. Trials using inadequate or orthovoltage radiotherapy were excluded. Data linking potential risk factors, either individually or in combination, to the occurrence of LRR were handled qualitatively. Data from randomised trials of post-mastectomy radiotherapy were included in a meta-analysis. Results. Baseline risk of LRR is increased in the presence of lymphovascular invasion, a grade 3 tumour, tumours greater than 2 cm or a close resection margin and in patients who are pre-menopausal or aged less than 50. Those with no risk factors have a baseline risk of LRR of approximately 5% or less rising to a risk of 15% or more for those with two or more risk factors. In the meta-analysis of three randomised trials of mastectomy and axillary clearance (667 patients), the addition of radiotherapy resulted in an 83% reduction in the risk of LRR (P < 0.00001) and in a 14% improvement in survival (P = 0.16). Conclusion. The use of post-mastectomy radiotherapy for women with node-negative breast cancer requires re-evaluation. Radiotherapy should be considered for those with two or more risk factors.     

Valeur pronostique des sous-types moléculaires et du Ki67 pour les cancers du sein indemnes d’envahissement ganglionnaire après mastectomie : expérience de l’institut Curie–hôpital René-Huguenin et revue de la littérature

PurposeTo evaluate the prognostic value of Ki67 expression, breast cancer molecular subtypes and the impact of postmastectomy radiotherapy in breast cancer patients with pathologic negative lymph nodes (pN0) after modified radical mastectomy.Patients and methodsSix hundred and ninety-nine breast cancer patients with pN0 status after modified radical mastectomy, treated between 2001 and 2008, were identified from a prospective database in a single institution. Tumours were classified by intrinsic molecular subtype as luminal A or B, HER2+, and triple-negative using estrogen, progesterone, and HER2 receptors. Multivariate Cox analysis was used to determine the risk of locoregional recurrence associated with intrinsic subtypes and Ki67 expression, adjusting for known prognostic factors.ResultsAt a median follow-up of 56 months, 17 patients developed locoregional recurrence. Five-year locoregional recurrence-free survival and overall survival in the entire population were 97%, and 94.7%, respectively, with no difference between the postmastectomy radiotherapy (n = 191) and no-postmastectomy radiotherapy (n = 508) subgroups. No constructed subtype was associated with an increased risk of locoregional recurrence. A Ki67 above 20% was the only independent prognostic factor associated with increased locoregional recurrence (hazard ratio, 4.18; 95% CI, 1.11 to 15.77; P < 0.0215). However, postmastectomy radiotherapy was not associated with better locoregional control in patients with proliferative tumours.ConclusionKi67 expression but not molecular subtypes are predictors of locoregional recurrence in breast cancer patients with negative lymph nodes after modified radical mastectomy. The benefit of adjuvant radiotherapy in patients with proliferative tumours should be further investigated in prospective studies.     

Controversies in locoregional management of breast cancer with low volume pN0(i+) and pN1mi nodal disease

ABSTRACT

Introduction: The pathologic status of the axillary lymph nodes is an important prognostic factor in patients with breast cancer. With the transition from axillary lymph node dissection (ALND) to sentinel lymph node biopsy (SLNB) for patients with clinically node negative breast cancer, there has been an increase in detection of pN0(i+) breast cancer with isolated tumor cells and pN1mi disease with micrometastatic nodal involvement. The prognostic impact of small volume nodal involvement and the role of locoregional radiotherapy, especially in the era of modern systemic therapy, are unclear.

Areas covered: This review examines contemporary data evaluating the prognostic impact of pN0(i+) and pN1mi breast cancer on locoregional recurrence and survival outcomes, then discusses controversies related to the use of adjuvant locoregional radiation therapy in the presence of low volume nodal disease. Relevant papers were identified by searching multiple engines for articles published since 2000.

Expert opinion: Sentinel lymph node biopsy without completion ALND is a standard surgical option for patients with pN0(i+) and pN1mi disease. The available evidence does not support routine use of adjuvant locoregional radiation therapy in patients with pN0i+ or pN1mi disease, but locoregional radiotherapy should be considered in the presence of concomitant high-risk features and patient factors.     

High Tumour Stage and Margin Clearance are Still Important Prognostic Factors for Post-Mastectomy Locoregional Recurrence in Malaysia

Background: Locoregional recurrence after mastectomy for breast cancer may predict distant recurrence andmortality. This study examined the pattern and rates of post-mastectomy locoregional recurrence (PMLRR),survival outcome and prognostic factors for isolated PMLRR (ILR) in a breast cancer cohort in University ofMalaya Medical Center (UMMC). Methods: We studied 522 patients who underwent mastectomy between 1998and 2002 and followed them up until 2008. We defined PMLRR as recurrence to the axilla, supraclavicular nodesand or chest wall. ILR was defined as PMLRR occurring as an isolated event. Prognostic factors for locoregionalrecurrence were determined using the Cox proportional hazards regression model. Results: The overall PMLRRrate was 16.4%. ILR developed in 42 of 522 patients (8.0%). Within this subgroup, 25 (59.5%) remained diseasefree after treatment while 17 (40.5%) suffered disease progression. Univariate analyses identified race, age,size, stage, margin involvement, lymph node involvement, grade, lymphovascular invasion and ER status asprobable prognostic factors for ILR. Cox regression resulted in only Stage III disease and margin involvementas independent prognostic factors. The hazard of ILR was 2.5 times higher when the margins were involvedcompared to when they were clear (aHRR 2.5; 95% CI 1.3 to 5.0). Similarly, compared with stage I those withStage II (aHRR 2.1; 95%CI 0.6 to 6.8) and stage III (aHRR 4.6; 95%CI 1.4 to 15.9) had worse prognosis for ILR.Conclusion: Margin involvement and Stage III disease were identified to be independent prognostic factors forILR. Close follow-up of high risk patients and prompt treatment of locoregional recurrence were recommended.     

Evidence and controversies in the use of post-mastectomy radiation

Radiation after mastectomy is recommended for women with positive nodes, larger tumors, or positive margins. In addition to its role in reducing the risk for locoregional recurrence, it has an additive effect to the survival benefit seen with adjuvant systemic therapy. This article reviews the role of post-mastectomy radiation (PMRT) based on the recommendations in the 2007 NCCN Breast Cancer Clinical Practice Guidelines in Oncology and addresses the risk factors for recurrence after mastectomy. The data supporting both improvement in locoregional failure and survival are reviewed in detail. This article also discusses controversial areas in PMRT, including regional nodal radiation in women with 1 to 3 positive lymph nodes, PMRT in node-negative women with large tumors, and inclusion of internal mammary nodes. The final section discusses radiation field design and potential complications.     

Locoregional recurrence of pT3N0M0 breast cancer after mastectomy is not higher than that of pT1‐2N0M0: An analysis for radiotherapy

The purpose of this study was to investigate the value of post‐operative radiotherapy in the treatment of pT3N0M0 breast cancer after mastectomy. We analyzed the clinical data of 1390 patients with pT1‐3N0M0 breast cancer who were admitted and treated from 1998 to 2007 at the Sun Yat‐sen University Cancer Center. All patients underwent mastectomy and did not receive radiotherapy. The locoregional recurrence‐free survival, distant metastasis‐free survival and overall survival of different T stages of breast cancer were compared. The median follow‐up duration was 72 months. The 10‐year locoregional recurrence‐free survival patients with pT1N0, pT2N0 and pT3N0 breast cancers were 95.3, 91.9 and 93.6%, respectively (χ² = 2.550, P = 0.279). The 10‐year distant metastasis‐free survival rates of patients with pT1N0, pT2N0 and pT3N0 breast cancers were 88.1%, 81.0% and 78.4%, respectively (χ² = 8.254, P = 0.016). The 10‐year overall survival rates of patients with pT1N0, pT2N0 and pT3N0 breast cancers were 91.9%, 83.5% and 73.0%, respectively (χ² = 12.403, P = 0.002). Univariate analyses failed to identify any prognostic factors for locoregional recurrence in pT3N0 patients. Multivariate analysis showed that the T stage had no effect on locoregional recurrence. The locoregional recurrence rate in patients with pT3N0M0 breast cancer who underwent mastectomy and did not receive postoperative radiotherapy was not higher than that in patients with pT1‐2N0M0 breast cancer who received the same treatment, suggesting that routine adjuvant post‐operative radiotherapy should not be recommended in this patient population.     

Age-related variations in the use of axillary dissection: a survival analysis of 8038 women with T1-ST2 breast cancer

PURPOSE: The use of axillary dissection (AD) in women with invasive breast cancer is increasingly questioned. This study analyzes the survival in women with T1-2 breast cancer according to age and AD use. METHODS AND MATERIALS: Data from the Breast Cancer Outcomes Unit Database were analyzed for 8038 women aged 50-89 years referred to the British Columbia Cancer Agency between 1989 and 1998 with invasive T1-2,M0 breast cancer. Tumor and treatment characteristics were compared between women treated with and without AD (AD+ vs. AD-) according to three age groups: 50-64, 65-74 and 75+ years. Regional relapse and actuarial 5-year overall and breast cancer-specific survival were compared between AD+ and AD- women. Multivariate analysis of age, tumor and treatment factors, and adjusted hazard ratios with AD omission were performed. RESULTS: AD was omitted more frequently with advancing age (4% vs. 8% vs. 22% in women aged 50-64, 65-74, and 75+ years, respectively, p <0.0001). Tumor characteristics were more favorable in AD- women, with fewer having Grade III disease, T2 tumors, or lymphovascular invasion (all p <0.0001). Women treated without AD were also less likely to undergo radiotherapy after lumpectomy or mastectomy (both p <0.0001). Systemic therapy use and regional relapse rates were comparable between AD- and AD+ women in each age-specific cohort. Multivariate analysis identified age, tumor size, grade, lymphovascular invasion, estrogen receptor status, clinical nodal palpability, type of surgery, and radiotherapy use as independent variables affecting survival. Hazard ratios adjusted for these variables showed AD omission to be associated with lower overall survival in the entire cohort (hazard ratio 1.52, p <0.0001) and lower breast cancer-specific survival in women aged 65-74 years (hazard ratio 1.99, p = 0.02). CONCLUSION: AD was more frequently omitted with advancing age. The lack of differences in systemic therapy use, regional relapse, and breast cancer-specific survival among AD- compared with AD+ women aged 75+ years suggests that AD use may be selectively omitted in this elderly cohort. However, the lower survival associated with AD omission among women aged 65-74 years, and the lack of a survival advantage among AD- women aged 50-64 years despite more favorable tumor characteristics and comparable systemic therapy use support the hypothesis that definitive locoregional therapy has an impact on survival.     

Treatment guidelines and techniques in delivery of postmastectomy radiotherapy in management of operable breast cancer.

Radiation therapy has been shown to statistically significantly reduce the risk of locoregional recurrence in high-risk patients with operable breast cancer following mastectomy and systemic therapy. Recent trials have also demonstrated a significant survival benefit following radiotherapy in high-risk patients. Therefore, it is important to identify the patients who could potentially derive that survival benefit and to not offer treatment to those patients who are not at increased risk for failure. Established risk factors that predict for increased rates of locoregional recurrence include axillary lymph node involvement and T3 (or T4) disease. While treatment-related factors, such as the extent of the axillary dissection and extent of lymph nodal positivity, also undoubtedly affect locoregional recurrence, additional studies are needed to define the magnitude of their risk. Locoregional patterns of failure have identified the chest wall and supraclavicular/infraclavicular regions to be the most common sites of locoregional failure following mastectomy, which justifies treatment to these regions. While long-term complications are uncommon following locoregional radiotherapy, careful treatment planning is critical to minimize cardiac (and pulmonary) toxicity.     

Survival following locoregional recurrence of breast cancer: univariate and multivariate analysis.

Although prognostic variables for locoregional recurrence of breast cancer have been evaluated by univariate analysis, multifactorial analysis has not been previously performed. In the present study, survival following chest wall and/or regional lymphatic recurrence was determined in 230 patients with locoregionally recurrent breast cancer without evidence of distant metastases treated at the Radiation Oncology Center, Mallinckrodt Institute of Radiology and affiliated hospitals. Multifactorial analysis demonstrated that the site of recurrences correlated most strongly with overall survival (p = 0.001). The 5-year actuarial overall survival was 44-49% for patients with isolated chest wall, axillary, and internal mammary lymph node recurrence. Patients with either supraclavicular, multiple lymphatic, or concomitant chest wall and lymphatic recurrence had an 21-24% 5-year overall survival. The 5-year disease-free survival was 28-37% for patients with chest wall, axillary, or internal mammary recurrences compared to 4-13% for those with supraclavicular, chest wall and lymphatic, or those with multiple sites of lymphatic recurrence. Disease-free interval from mastectomy to recurrence was also found to be a significant prognostic factor for overall survival (p = 0.005). Fifty percent of patients with a disease-free interval of at least 2 years survived 5 years following locoregional relapse, compared to 35% for those with disease-free interval of less than 2 years. In the subset of patients with small chest wall recurrences (excised or less than 3 cm) and a disease-free interval of at least 2 years, the 5-year overall and disease-free survivals were 67% and 54%, respectively. These results suggest that subsets of patients with locoregional recurrence of breast cancer can survive for long periods of time. The conventional wisdom that chest wall and/or regional nodal recurrence following mastectomy uniformly confers a dismal prognosis is not necessarily true.     

Hypoxic regulation and prognostic value of LAMP3 expression in breast cancer

BACKGROUND:

LAMP3 is a newly described hypoxia regulated gene of potential interest in hypoxia‐induced therapy resistance and metastasis. The prognostic value of LAMP3 in breast cancer was investigated.

METHODS:

Expression levels of LAMP3 in breast cancer cell lines and patient tissues were determined by real‐time polymerase chain reaction and in a tissue microarray by immunohistochemistry. Immunofluorescent staining was used to evaluate the distribution of LAMP3 in tumor xenografts relative to pimonidazole. Kaplan‐Meier analysis as well as multivariate Cox regression survival analyses were performed.

RESULTS:

LAMP3 was variably expressed in breast cancer cell lines and induced in an oxygen concentration‐dependent manner. LAMP3 protein expression colocalized with hypoxic areas in breast cancer xenografts. LAMP3 mRNA was higher in breast tumors from patients with node‐positive (P = .019) and/or steroid hormone receptor‐negative tumors (P < .001). Breast cancer patients with high LAMP3 mRNA levels had more locoregional recurrences (P = .032 log‐rank). This was limited to patients treated with lumpectomy and radiotherapy as primary treatment (n = 53, P = .009). No association with metastasis‐free survival was found. In multivariate Cox regression analysis, LAMP3 remained as a statistically independent prognostic factor for locoregional recurrence (hazard ratio, 2.76; 95% confidence interval, 1.01‐7.5; P = .048) after correction for menopausal status, histologic grade, tumor size, nodal status, therapy, and steroid hormone receptor status. LAMP3 protein in breast cancer tissue proved also to be of prognostic relevance.

CONCLUSIONS:

Evidence was provided for an association of LAMP3 with tumor cell hypoxia in breast cancer xenografts. In the current breast cancer cohorts, LAMP3 had independent prognostic value. Cancer 2011;117:3670–3681. © 2011 American Cancer Society.     

A positive margin is not always an indication for radiotherapy after mastectomy in early breast cancer

OBJECTIVE: Postoperative radiotherapy is frequently employed among breast cancer patients with positive surgical margins after mastectomy but there is little evidence to support this practice. This study examined relapse and survival among women with node-negative breast cancer and positive surgical margins after mastectomy. METHODS: Among 2570 women diagnosed between 1989 and 1998 and referred to the British Columbia Cancer Agency with pathologic (p)T1-2, pN0 invasive breast cancer treated with mastectomy, 94 had positive surgical margins and formed the study cohort. Women with more established indications for postmastectomy radiotherapy (PMRT) including T3-4 tumors or node-positive disease were excluded. Demographic, tumor, and treatment factors; relapse patterns; and Kaplan-Meier 8-year locoregional relapse-free, breast cancer-specific, and overall survival rates were compared between women who were treated with (n = 41) and without (n = 53) PMRT. RESULTS: Median follow-up time was 7.7 years. The distributions of age, histologic grade, lymphovascular invasion (LVI), estrogen receptor status, and number of axillary nodes removed were similar between the two treatment groups. Six local chest wall recurrences (6.4%), 4 regional recurrences (4.3%), and 11 distant recurrences (11.7%) were identified. Local relapse rates were 2.4% vs. 9.4% (p = 0.23), and regional relapse rates were 2.4% vs. 5.7% (p = 0.63), with and without PMRT, respectively. Trends for higher cumulative locoregional relapse (LRR) rates without PMRT were identified in the presence of age <==50 years (LRR 20% without vs. 0% with PMRT), T2 tumor size (19.2% vs. 6.9%), grade III disease (23.1% vs. 6.7%), and LVI (16.7% vs. 9.1%). Statistical significance was not demonstrated in these differences (p > 0.10), possibly because of the small number of events. In patients with age >50 years, T1 tumors, grade I/II disease, and absence of LVI, no locoregional relapse occurred even with positive margins. PMRT did not improve distant relapse, 8-year breast cancer-specific and overall survival rates. CONCLUSION: This study suggests that not all patients with node-negative breast cancer with positive margins after mastectomy require radiotherapy. Locoregional failure rates approximating 20% were observed in women with positive margins plus at least one of the following factors: age <==50 years, T2 tumor size, grade III histology, or LVI. The absolute and relative improvements in locoregional control with radiotherapy in these situations support the judicious, but not routine, use of PMRT for positive margins after mastectomy in patients with node-negative breast cancer.     

Prognostic index score and clinical prediction model of local regional recurrence after mastectomy in breast cancer patients

PURPOSE: To develop clinical prediction models for local regional recurrence (LRR) of breast carcinoma after mastectomy that will be superior to the conventional measures of tumor size and nodal status. METHODS AND MATERIALS: Clinical information from 1,010 invasive breast cancer patients who had primary modified radical mastectomy formed the database of the training and testing of clinical prognostic and prediction models of LRR. Cox proportional hazards analysis and Bayesian tree analysis were the core methodologies from which these models were built. To generate a prognostic index model, 15 clinical variables were examined for their impact on LRR. Patients were stratified by lymph node involvement (<4 vs. >or =4) and local regional status (recurrent vs. control) and then, within strata, randomly split into training and test data sets of equal size. To establish prediction tree models, 255 patients were selected by the criteria of having had LRR (53 patients) or no evidence of LRR without postmastectomy radiotherapy (PMRT) (202 patients). RESULTS: With these models, patients can be divided into low-, intermediate-, and high-risk groups on the basis of axillary nodal status, estrogen receptor status, lymphovascular invasion, and age at diagnosis. In the low-risk group, there is no influence of PMRT on either LRR or survival. For intermediate-risk patients, PMRT improves LR control but not metastases-free or overall survival. For the high-risk patients, however, PMRT improves both LR control and metastasis-free and overall survival. CONCLUSION: The prognostic score and predictive index are useful methods to estimate the risk of LRR in breast cancer patients after mastectomy and for estimating the potential benefits of PMRT. These models provide additional information criteria for selection of patients for PMRT, compared with the traditional selection criteria of nodal status and tumor size.     

Imaging of the axilla before preoperative chemotherapy: Implications for postmastectomy radiation

Postmastectomy radiation therapy (PMRT) improves breast cancer survival in many women with lymph node‐positive disease who undergo surgery followed by adjuvant chemotherapy. The role of PMRT after women receive neoadjuvant chemotherapy (NAC) is less clear. The available data suggest that clinical extent of disease at presentation before NAC, pathologic residual disease (especially pathologically involved lymph nodes) after NAC, and response to NAC are key prognostic factors for locoregional recurrence. Therefore, accurate axillary staging before the initiation of NAC and assessment of response to chemotherapy are critically important. Here, the authors review the literature addressing the radiotherapy management of patients with breast cancer who received NAC and underwent mastectomy with a special focus on the imaging modalities used to assess axillary lymph node status. Cancer 2015;121:1187–1194. © 2014 American Cancer Society.