Isolated Locoregional Recurrence Research Articles

A prediction model for distant metastasis after isolated locoregional recurrence of breast cancer

PurposeThe impact of progesterone receptor (PR) status on the prognosis of breast cancer after isolated locoregional recurrence (ILRR) remains unclear. This study evaluated the impact of clinicopathologic factors, including PR status of ILRR, on distant metastasis (DM) after ILRR.MethodsWe retrospectively identified 306 patients with ILRR diagnosed at the National Cancer Center Hospital between 1993 and 2021 from the database. Cox proportional hazards analysis was performed to examine factors associated with DM after ILRR. We developed a risk prediction model based on the number of detected risk factors and estimated survival curves using the Kaplan–Meier method.ResultsDuring a median follow-up time of 4.7 years after ILRR diagnosis, 86 patients developed DM, and 50 died. Multivariate analysis revealed that seven risk factors were associated with poor distant metastasis-free survival (DMFS): estrogen receptor-positive/PR-negative/human epidermal growth factor receptor 2-negative ILRR, short disease-free interval, recurrence site other than ipsilateral breast, no-resection of ILRR tumor, chemotherapy for the primary tumor, nodal stage in the primary tumor, and no endocrine therapy for ILRR. The predictive model classified patients into 4 groups based on the number of risk factors: low-, intermediate-, high-, and the highest-risk groups with 0 to 1, 2, 3 to 4, and 5 to 7 factors, respectively. This revealed significant variation in DMFS among the groups. A higher number of the risk factors was associated with poorer DMFS.ConclusionOur prediction model, which considered the ILRR receptor status, may contribute to the development of a treatment strategy for ILRR.

The Role of Chemotherapy in Patients With HER2-Negative Isolated Locoregional Recurrence of Breast Cancer: A Multicenter Retrospective Cohort Study.

Background: The role of chemotherapy for isolated locoregional recurrence (iLRR) of breast cancer has not been firmly established after local therapies.Methods: We performed a multicenter, retrospective analysis to evaluate the clinical implications of chemotherapy in breast cancer patients with HER2-negative iLRR.Results: Of a total of 277 patients, 146 (52.7%) received chemotherapy for iLRR. Median follow-up duration was 56.1 months. Eighty-six (31.0%) patients had luminal B-like and 100 (36.1%) had TNBC iLRR. There was a trend of longer disease free survival (DFS) in the chemotherapy group (4-year DFS: 70.4 vs. 59.5%, HR = 0.68, 95% CI 0.45–1.02, log-rank p = 0.059). When adjusted with clinically relevant factors, DFS was significantly prolonged with chemotherapy (adjusted HR = 0.61, 95% CI 0.40–0.94, p = 0.023). Subgroup analyses for DFS showed patients with disease free interval (DFI) <5 years or prior chemotherapy had a benefit from chemotherapy (adjusted HR = 0.57, p = 0.018; adjusted HR = 0.51, p = 0.005, respectively). Regarding the molecular subtypes, a longer DFS with chemotherapy was observed both in luminal B-like (4-year DFS: 77.8 vs. 55.0%, HR = 0.51, 95% CI 0.27–0.99, log-rank p = 0.048) and in TNBC patients (4-year DFS: 61.9 vs. 42.8%, HR = 0.49, 95% CI 0.24–1.02, log-rank p = 0.056), but not in luminal A-like.Conclusions: The chemotherapy for iLRR of breast cancer should be individualized for each patient, considering DFI, prior chemotherapy, and molecular subtypes.

Identifying Long-Term Survival Candidates among Patients with Isolated Locoregionally Recurrent Breast Cancer: Implications of the Use of Systemic Chemotherapy.

PurposeWe aimed to investigate the clinicopathologic factors associated with distant metastasis (DM) and post-recurrence overall survival (OS) after salvage treatments for isolated locoregional recurrence (ILRR) of breast cancer and identify long-term surviving patients for providing a more personalized therapy.MethodsWe analyzed 125 patients who underwent salvage local treatments for ILRR after initial curative breast surgery.ResultsFifty-two (41.6%) patients experienced secondary recurrence or disease progression, of which 20 (38.5%) experienced a secondary locoregional recurrence and 40 (76.9%) experienced DM as the first site of failure. In multivariate analysis of distant metastasis free survival (DMFS) and post-recurrence OS, the initial pN2-3 stage, a disease-free interval of < 36 months, and non-curative resection for recurrent disease were independently poor prognosticators. The score for patients stratified according to the number of risk factors increased from 0 to 3; the corresponding 5-year DMFS rates were 91.4%, 53.0%, 35.9%, and 0% and the 5-year OS rates were 97.3%, 70.4%, 32.7%, and 25.0%, respectively (p < 0.001). Systemic chemotherapy reduced DM in patients with a score of 2–3, but it did not in those with a score of 0-1.ConclusionOur collective stratification can help with prognosis prediction for ILRR of breast cancer. Depending on the DM risk of patients, the potential combination of systemic therapy should be discussed further.

Risk stratification system for groups with a low, intermediate, and high risk of subsequent distant metastasis and death following isolated locoregional recurrence of breast cancer.

This study aimed to identify prognostic factors for long-term outcomes among patients with isolated locoregional recurrence (ILRR) of breast cancer as their first failure event. Many prognostic tools have been developed to inform systemic treatment choices in the adjuvant setting, but tools for predicting post-ILRR prognosis are scarce. A total of 495 patients who experienced ILRR after primary surgery at the Asan Medical Center between 1989 and 2008 were included. All patient information and tumor characteristics at the initial surgery were retrieved from our retrospectively collected database, and ILRRs were categorized as local recurrence or regional recurrence (RR). Distant metastasis-free survival (DMFS), breast cancer-specific survival (BCSS), and overall survival post-ILRR were calculated. The median follow-up from the ILRR was 65months (range 1-249months), and the 5-year post-ILRR DMFS rate was 58.9%. We found three factors-lymph node metastasis, a disease-free interval < 30months, and RR as the ILRR type-that were independent prognostic factors for both DMFS [hazard ratio (HR) = 2.08, 1.60, and 1.59; P < 0.001, 0.002, and 0.003, respectively] and BCSS (HR = 2.28, 1.99, and 1.48; P < 0.001, < 0.001, and 0.016, respectively) post-ILRR. Patients were classified into four groups according to the presence these three prognostic indicators: the low-, intermediate-, high-, and extremely high-risk groups. The 5-year post-ILRR DMFS rates were 79.4%, 68.1%, 47.6%, and 36.0%, respectively. This risk stratification system for subsequent distant metastases after ILRR can be used to make more informed decisions regarding prognosis-based local or systemic management strategies.

Therapy of isolated locoregional recurrent carcinoma of the breast.

Thereis widespread consent that isolated locoregional recurrence (ILRR) in breast cancer should be treated surgically. On searching literature and guidelines most studies include ipsilateral recurrence in breast tissue or on thoracic wall post-mastectomy, recurrence in scar tissue as well as in ipsilateral axillary lymph nodes. Some studies discuss metachronous contralateral breast cancer as ILRR. About 10-35% of women with primary breast cancer suffer from ILRR. The existing data concerning the role of systemic therapy in the treatment of ILRR are insufficient. We investigated the influence of chemotherapy on disease-free- (DFS) and overall-survival (OS). Retrospective analysis of all patients with ILRR and without distant metastasis was done, which were treated at the Department of Gynecology, Obstetrics and Reproductive Medicine, Saarland University between 2005 and 2013. Data collection used patients' database system and was followed via patient questionnaires. In total, we collected data of 93 patients with locally recurrent breast cancer and observed a 72.6% questionnaire response rate. Average timeline accounted for 99months between primary diagnosis and local recurrence; average age of patients at diagnosis of local recurrence was 60.6years. After a median follow-up of 63months DFS reached 76% with and 73% without chemotherapy, and after 74months overall survivalamounted to 94% and 70%, respectively. Almost all patients with ILRR were operated. Especially patients with hormone receptor-negative recurrent breast cancer seemed to show a benefit having been treated with chemotherapy. Most patients were without recurrence after their particular therapies.

Efficacy and safety of CT-guided high-dose-rate interstitial brachytherapy in primary and secondary malignancies of the pancreas

PurposeTo evaluate efficacy and safety of CT-guided iBT in patients with primary and secondary malignancies of the pancreas. Material and methods13 patients with 13 lesions of the pancreatic corpus and tail were included: 8 secondary malignancies (metastatic lesions = ML) and 5 primary malignancies, including 3 primary tumors (PT) and 2 isolated locoregional recurrences (ILR) after surgical resection were treated with image-guided iBT using a 192iridium source (single fraction irradiation). Every 3 months after treatment clinical and imaging follow-up were conducted to evaluate efficacy. Peri- and postinterventional complications were assessed descriptively. ResultsThe median diameter of the gross tumor volume (GTV) was 3 cm (range 1–6.5 cm), treated with a median D100 (minimal enclosing tumor dose) of 15.3 Gy (range 9.2–25.4 Gy). Local tumor control (LTC) was 92.3% within a median follow-up period of 6.7 months (range 3.2–55.7 months). Cumulative median progression free survival (PFS) was 6.2 months (range 2.8–25.7 months; PFS of primary and secondary malignancies was 5.8 and 6.2 months, respectively). Cumulative median over all survival (OS) after iBT was 16.2 months (range 3.3–55.7 months; OS of primary and secondary malignancies was 7.4 months and 45.6 months, respectively). 1 patient developed mild acute pancreatits post iBT, spontanously resolved within 1 week. No severe adverse events (grade 3+) were recorded. ConclusionImage-guided iBT is a safe and particularly effective treatment in patients with primary and secondary malignancies of the pancreas and might provide a well-tolerated additional therapeutic option in the multidisciplinary management of selected patients.

Outcomes Following Salvage Radiation and Systemic Therapy for Isolated Locoregional Recurrence of Breast Cancer after Mastectomy: Impact of Constructed Biologic Subtype.

Purpose This study examines factors associated with outcomes following salvage radiation and systemic therapy for breast cancer patients who developed isolated locoregional recurrence (ILRR) after mastectomy alone, while focusing on the prognostic significance of constructed biologic subtype in this setting. Methods and Materials 269 postmastectomy patients in total treated for ILRR were included. Cumulative incidence of locoregional control (LRC), distant metastasis (DM)-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) were calculated using Kaplan-Meier method. For statistical analysis, biologic subtypes were constructed from hormonal receptors (Rec) and HER2, consisting of Rec+/HER2-, Rec+/HER2+, Rec-/HER2+, and Rec-/HER2-. The association of clinic-pathological and treatment-related parameters with outcomes was evaluated using a Cox regression model. Results At a median follow-up of 65 months, 56 (20.8%) patients failed to secure LRC after radiotherapy, and 165 patients (61.3%) developed DM. Overall, the actuarial 5-year LRC, DMFS, DFS, and OS rate was 77.3%, 45.6%, 43.9%, and 66.8%, respectively. Multivariate analysis revealed that constructed biologic subtype represented the most significant prognostic factor for any outcome. Compared to patients with Rec+/HER2- disease, those with Rec-/HER2- had significantly poorer 5-year LRC (84.2% versus 58.3%, HR = 4.36, P < 0.001) and worse survivals including 5-year DMFS (63.0% versus 15.8%, HR = 4.28, P < 0.001), DFS (59.7% versus 13.6%, HR=3.92, P < 0.001), and OS (87.8% versus 22.3%, HR = 8.55, P < 0.001). Other factors associated with reduced LRC were no radical surgery and involved field irradiation alone, whereas factors associated with poor survivals included positive nodes at primary diagnosis and regional recurrence. Conclusions Constructed biologic subtypes remained to be predictive of both disease control and survivals after salvage radiation for postmastectomy ILRR. Notably, Rec-/HER2- patients were demonstrated to be at high risk of locoregional failure and subsequent DM and tended to have worse survivals despite salvage therapies.

Efficacy of Chemotherapy for ER-Negative and ER-Positive Isolated Locoregional Recurrence of Breast Cancer: Final Analysis of the CALOR Trial.

Purpose Isolated locoregional recurrence (ILRR) predicts a high risk of developing breast cancer distant metastases and death. The Chemotherapy as Adjuvant for LOcally Recurrent breast cancer (CALOR) trial investigated the effectiveness of chemotherapy (CT) after local therapy for ILRR. A report at 5 years of median follow-up showed significant benefit of CT for estrogen receptor (ER)-negative ILRR, but additional follow-up was required in ER-positive ILRR. Patients and Methods CALOR was an open-label, randomized trial for patients with completely excised ILRR after unilateral breast cancer. Eligible patients were randomly assigned to receive CT or no CT and stratified by prior CT, hormone receptor status, and location of ILRR. Patients with hormone receptor-positive ILRR received adjuvant endocrine therapy. Radiation therapy was mandated for patients with microscopically involved margins, and anti-human epidermal growth factor receptor 2 therapy was optional. End points were disease-free survival (DFS), overall survival, and breast cancer-free interval. Results From August 2003 to January 2010, 162 patients were enrolled: 58 with ER-negative and 104 with ER-positive ILRR. At 9 years of median follow-up, 27 DFS events were observed in the ER-negative group and 40 in the ER-positive group. The hazard ratios (HR) of a DFS event were 0.29 (95% CI, 0.13 to 0.67; 10-year DFS, 70% v 34%, CT v no CT, respectively) in patients with ER-negative ILRR and 1.07 (95% CI, 0.57 to 2.00; 10-year DFS, 50% v 59%, respectively) in patients with ER-positive ILRR ( Pinteraction = .013). HRs were 0.29 (95% CI, 0.13 to 0.67) and 0.94 (95% CI, 0.47 to 1.85), respectively, for breast cancer-free interval ( Pinteraction = .034) and 0.48 (95% CI, 0.19 to 1.20) and 0.70 (95% CI, 0.32 to 1.55), respectively, for overall survival ( Pinteraction = .53). Results for the three end points were consistent in multivariable analyses adjusting for location of ILRR, prior CT, and interval from primary surgery. Conclusion The final analysis of CALOR confirms that CT benefits patients with resected ER-negative ILRR and does not support the use of CT for ER-positive ILRR.

Chemotherapy (CT) for isolated locoregional recurrence (ILRR) of breast cancer in ER-positive (ER+) and ER-negative (ER-) cohorts: Final analysis of the CALOR trial.

513 Background: ILRR is associated with a high risk of developing breast cancer distant metastases and death. The CALOR trial (NCT00074152) investigated the effectiveness of CT following local therapy for ILRR. Previously reported results at 5-yrs median follow-up (MFU) showed significant benefit of CT for ER- ILRR, but further follow-up was required in ER+ ILRR. This report presents results at 8.8 yrs MFU within ER status cohorts. Methods: CALOR is an open-label, randomized trial for patients with completely excised ILRR after unilateral breast cancer. Eligible patients were randomized to CT (selected by the investigator; multidrug for at least 3 months recommended) or No-CT, and stratified by prior CT, hormone-receptor (ER, PR) status, and location of ILRR. Patients with ER and/or PR positive ILRR received adjuvant endocrine therapy. Radiation therapy was mandated for patients with microscopically involved margins, and anti-HER2 therapy was optional. Endpoints are disease-free survival (DFS), overall survival (OS) and breast cancer-free interval (BCFI). Results: From August 2003 to January 2010, 162 patients were enrolled: 104 ER+ and 58 ER-. The results at 8.8 years MFU in ER status cohorts are summarized in the Table (40 and 27 DFS events, respectively). The reduction in the hazard of an event associated with CT for the ER- ILRR cohort was sustained, but no benefit was observed for the ER+ cohort; interactions were significant for DFS and BCFI. The reduction in the hazard of an event seen in the ER- cohort was not apparent in ER+, with significant interactions for DFS and BCFI. Results for the 3 endpoints were consistent in multi-variable analyses adjusting for location of ILRR, prior chemotherapy, and interval from primary surgery. Conclusions: The final analysis of CALOR confirms that CT benefits patients with resected ER- ILRR. Long-term CALOR trial results do not support the use of CT for ER+ ILRR. Clinical trial information: NCT00074152. [Table: see text]

Poor Prognosis After Second Locoregional Recurrences in the CALOR Trial.

Isolated locoregional recurrences (ILRRs) of breast cancer confer a significant risk for the development of distant metastasis. Management practices and second ILRR events in the Chemotherapy as Adjuvant for LOcally Recurrent breast cancer (CALOR) trial were investigated. In this study, 162 patients with ILRR were randomly assigned to receive postoperative chemotherapy or no chemotherapy. Descriptive statistics characterize outcomes according to local therapy and the influence of hormone receptor status on subsequent recurrences. Competing risk regression models, Kaplan-Meier estimates, and Cox proportional hazards models were used to evaluate associations between treatment, site of second recurrence, and outcome. The median follow-up period was 4.9 years. Of the 98 patients who received breast-conserving primary surgery 89 had an ipsilateral-breast tumor recurrence. Salvage mastectomy was performed for 73 patients and repeat lumpectomy for 16 patients. Another eight patients had nodal ILRR, and one patient had chest wall ILRR. Among 64 patients whose primary surgery was mastectomy, 52 had chest wall/skin ILRR, and 12 had nodal ILRR. For 15 patients, a second ILRR developed a median of 1.6 years (range 0.08-4.8 years) after ILRR. All second ILRRs occurred for patients with progesterone receptor-negative ILRR. Death occurred for 7 (47 %) of 15 patients with a second ILRR and 19 (51 %) of 37 patients with a distant recurrence. As shown in the multivariable analysis, the significant predictors of survival after either a second ILRR or distant recurrence were chemotherapy for the primary cancer (hazard ratio [HR], 3.55; 95 % confidence interval [CI], 1.15-10.9; p = 0.03) and the interval (continuous) from the primary surgery (HR, 0.87; 95 % CI, 0.75-1.00; p = 0.05). Second ILRRs represented about one third of all recurrence events after ILRR, and all were PR-negative. These second ILRRs and distant metastases portend an unfavorable outcome.

Isolated locoregional recurrence patterns of breast cancer after mastectomy and adjuvant systemic therapies in the contemporary era.

To evaluate the recurrence patterns in a series of patients who presented with isolated locoregional recurrences (ILRRs) after mastectomy and adjuvant systemic therapies in the contemporary era. A total of 235 patients who developed ILRRs between 2005 and 2013 were classified into subgroups based on nodal status, hormone receptor status, and biologic subtype. The annual frequency of recurrences, association between biologic subtype and interval to recurrence (ITR), and anatomical distribution were evaluated. For the entire group, recurrence peaked within the first 3 years after mastectomy, and then decreased significantly with time. Node-positive patients were observed to recur early, and a greater proportion recurred within 5 years (86.7% vs. 72.8%, χ2 = 6.83, P = 0.008) than did node-negative subgroup. Overall, the median ITR was 33.2 (range, 4.5 - 236) months. Biologic subtype specific median ITR were 43.3 (7.9 - 236.0) months for luminal A, 42.2 (6.1 - 143.3) months for luminal B, 23.8 (6.9 - 47.3) months for luminal HER2, 18.2 (6.6 - 117.5) months for HER2, and 21.8 (4.5 - 138.2) months for TNBC, and their difference was statistically significant (χ2 = 7.4, P = 0.001). Among all ILRRs, 51.5% (n = 121) were isolated to regional nodes. We demonstrates that the time course is consistent with previous description, biologic subtype is associated with ITR, and regional nodes is the most common place for recurrences in this series of patients who developed ILRRs following mastectomy and contemporary adjuvant systemic therapies but without PMRT.

Abstract P2-18-05: Isolated loco-regional recurrence in the breast: Re-quadrantectomy and systemic treatment

Abstract Background: Local or regional recurrence in breast cancer is associated with poor prognosis. Mastectomy is the classic indication in these situations. However, second attempts of breast conservation in previously radiated patients with small, histologically favorable local relapse have been reported. Also, prospective data (The CALOR Trial) suggest that adjuvant chemotherapy should be recommended in patients with isolated loco-regional recurrence, especially if the recurrence is HR negative. The purpose of our study was to determine the frequency of use of re-quadrantectomy and systemic treatment in isolated loco-regional recurrence (ILR) in breast cancer. Methods: Retrospective review of the database of our institution. Inclusion criteria: ILR in surgical bed, breast or lymph nodes with complete resection (mastectomy, re-quadrantectomy or axillary resection) with or without systemic treatment and radiotherapy. Findings: 4695 patients were analyzed from april 2000 to april 2014. 78 patients had a ILR, 66 were analyzed. Median age 49,5 years (27-86). 54,5% of the patients were postmenopausal and 16,6% had bilateral involvement at diagnosis. Characteristics of the primary tumor: Mean tumor size 2 cm, 66,6% were HR positive, 6% HER2 positive, 13,6% TN and 14% unknown. Initial treatment: breast conserving surgery 62 p (sentinel node 25, axillary node disection 36); mastectomy 4 patients. 42 patients underwent adjuvant chemotherapy, 57 patients radiotherapy and 62 patients hormonotherapy. Time to recurrence: 94,3 months. Characteristics of the ILR: Mean tumor size 1.8 cm. 65% were HR positive, 12% triple negative, 6% HER positive and 17% unknown. Treatment at relapse was as follows: 27 re-quadrantectomy, 34 mastectomy, 1 lymph node dissection; all these patients had previous quadrantectomy. The other patients underwent to mastectomy (1) and complete resection of the lesion (3). 29 patients received chemotherapy (43.9%), : 70% anthracyclines and taxanes, 6% trastuzumab, 30% other and 65% received hormonotherapy. Local progression free survival 30,7 months; distance progression free survival 100 months. Local relapse was evidenced in 30% of patients who had a re-quadrantectomy procedure. Conclusions: Second attemp of breast conservation in previously radiated patients with small, histologically favorable ILR and long recurrence free interval disease is feasible as described. The target population is of good prognosis as evidenced the long free disease interval at recurrence (94,3 m), the mean size of tumor at recurrence (1.8 cm) and the high proportion of HR positive disease. The percentage of local recurrence after re quadrantectomy is as described in some reports, 30% (20-35%). The indication of chemotherapy was mostly in HR negative or HER 2 positive tumors, but the low number of patients does not permit a valid comparaison. Citation Format: Victoria Costanzo, Veronica Fabiano, Mercedes Maino, Federico Colo, Reinaldo Chacon, Adrian Nervo, Jorge Nadal, Martin Loza, Jose Loza, Daniel Mysler, Mora Amat. Isolated loco-regional recurrence in the breast: Re-quadrantectomy and systemic treatment [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-18-05.

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

Recurrence patterns among T1-2N0 triple-negative breast cancer patients following mastectomy.

93 Background: Women with early-stage TN breast cancers are at increased risk for recurrence (RR) compared to other molecular subtypes, and are often treated with mastectomy without local adjuvant therapy. We wish to evaluate the RR for these women. Methods: In this single institution retrospective study, women with T1-2N0 TN breast cancer who underwent mastectomy between 2008-12 were identified from tumor registry. Adjuvant chemotherapy was allowed, but adjuvant radiotherapy (RT) was excluded. Of 3,000 cases reviewed, 52 women were identified. Median age was 58.5 (30–90). Lesions were high-grade (83%), and T1-2 (47%, 53%). 21 women (42%) had at least 1 risk factor. 5 women were BRCA+. Women underwent total mastectomy or modified radical mastectomy, and the majority (84%) had adjuvant chemotherapy. Results: At a median follow-up of 3.5 years (6-71 months), there were 8 recurrences (15.4%). 3 (5.8% of cohort) were locoregional (LR) only (2 chest wall (CW) and 1 ipsilateral axilla), 6 (11.5%) involved a concurrent LR and distant recurrence, and 2 (3.8%) were distant only. Median time to recurrence was 17.3 months. The isolated LR recurrences (LRR) were at 14, 15.6 and 15.1 months. Most women (41, 78.8%) were alive with NED. 3 were alive with disease, underdoing treatment, and 1 woman was disease free after treatment for CW recurrence. 8 patients (15.4%) are deceased, half from their cancer. On univariate analysis, there was no significant correlation (p&gt;0.05) between age or high-risk features and RR (STATA v 11). Conclusions: T1-2N0 breast cancer patients are believed to have a low RR following mastectomy. TN disease, however, is more aggressive, and the question of irradiating early stage disease after mastectomy has arisen. A single institution, retrospective study found women with T1-2N0 TN disease fare better with BCT that includes RT, compared to mastectomy alone. Other studies have shown no statistical difference in RR between these 2 groups. We found an isolated LRR rate at 3.5 years of 5.8%. Follow-up and ultimately prospective data is needed to determine whether the isolated LRR warrants a change in treatment recommendations for this pt subset.

Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): a randomised trial

Patients with isolated locoregional recurrences (ILRR) of breast cancer have a high risk of distant metastasis and death from breast cancer. We aimed to establish whether adjuvant chemotherapy improves the outcome of such patients. The CALOR trial was a pragmatic, open-label, randomised trial that accrued patients with histologically proven and completely excised ILRR after unilateral breast cancer who had undergone a mastectomy or lumpectomy with clear surgical margins. Eligible patients were enrolled from hospitals worldwide and were centrally randomised (1:1) to chemotherapy (type selected by the investigator; multidrug for at least four courses recommended) or no chemotherapy, using permuted blocks, and stratified by previous chemotherapy, oestrogen-receptor and progesterone-receptor status, and location of ILRR. Patients with oestrogen-receptor-positive ILRR received adjuvant endocrine therapy, radiation therapy was mandated for patients with microscopically involved surgical margins, and anti-HER2 therapy was optional. The primary endpoint was disease-free survival. All analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00074152. From Aug 22, 2003, to Jan 31, 2010, 85 patients were randomly assigned to receive chemotherapy and 77 were assigned to no chemotherapy. At a median follow-up of 4·9 years (IQR 3·6-6 ·0), 24 (28%) patients had disease-free survival events in the chemotherapy group compared with 34 (44%) in the no chemotherapy group. 5-year disease-free survival was 69% (95% CI 56-79) with chemotherapy versus 57% (44-67) without chemotherapy (hazard ratio 0·59 [95% CI 0·35-0·99]; p=0·046). Adjuvant chemotherapy was significantly more effective for women with oestrogen-receptor-negative ILRR (pinteraction=0·046), but analyses of disease-free survival according to the oestrogen-receptor status of the primary tumour were not statistically significant (pinteraction=0·43). Of the 81 patients who received chemotherapy, 12 (15%) had serious adverse events. The most common adverse events were neutropenia, febrile neutropenia, and intestinal infection. Adjuvant chemotherapy should be recommended for patients with completely resected ILRR of breast cancer, especially if the recurrence is oestrogen-receptor negative. US Department of Health and Human Services, Swiss Group for Clinical Cancer Research (SAKK), Frontier Science and Technology Research Foundation, Australian and New Zealand Breast Cancer Trials Group, Swedish Cancer Society, Oncosuisse, Cancer Association of South Africa, Foundation for Clinical Research of Eastern Switzerland (OSKK), Grupo Español de Investigación en Cáncer de Mama (GEICAM), and the Dutch Breast Cancer Trialists' Group (BOOG).

Clinical Outcome of Isolated Locoregional Recurrence in Patients With Breast Cancer According to Their Primary Local Treatment

IntroductionThis study assessed the clinical outcome and prognostic factors in patients with breast cancer who presented with isolated locoregional recurrence (ILRR) as a first event. Materials and MethodsBetween 1970 and 2008, 2960 patients with pT1-2, N0-3, M0 primary invasive breast cancer had either breast-conserving therapy (BCT) using lumpectomy and radiation therapy (RT) (group A = 1849 patients) or mastectomy without RT (group B = 1111 patients). Out of groups A and B, 117 and 103 patients, respectively, developed ILRR as a first event. Those 220 patients served as the basis for this study. A multivariate analysis was performed to estimate the clinical outcome of both groups, taking into account clinically relevant variables for the primary tumor and ILRR. ResultsThe median follow-up after ILRR was 83 months. The median disease-free interval (DFI) was 79 and 38 months for groups A and B, respectively. The overall survival (OS) for group A was 81% and 69% at 5 and 8 years, respectively. For group B, it was 61% and 46%, respectively. The distant metastasis–free survival (DMFS) for group A was 84% at 5 years and remained 84% at 8 years. The DMFS for group B was 60% at 5 years and 52% at 8 years. In multivariate analysis, initial local treatment (BCT vs. mastectomy without RT), pathologic T stage, locoregional recurrence site (local vs. regional), and DFI (≤ 4 years vs. > 4 years) were significant prognostic variables for both OS and DMFS. ConclusionPatients with breast cancer who developed ILRR after BCT as their initial local treatment have better clinical outcome compared with those who had mastectomy without RT.

Multi-state model for studying an intermediate event using time-dependent covariates: application to breast cancer

BackgroundThe aim of this article is to propose several methods that allow to investigate how and whether the shape of the hazard ratio after an intermediate event depends on the waiting time to occurrence of this event and/or the sojourn time in this state.MethodsA simple multi-state model, the illness-death model, is used as a framework to investigate the occurrence of this intermediate event. Several approaches are shown and their advantages and disadvantages are discussed. All these approaches are based on Cox regression. As different time-scales are used, these models go beyond Markov models. Different estimation methods for the transition hazards are presented. Additionally, time-varying covariates are included into the model using an approach based on fractional polynomials. The different methods of this article are then applied to a dataset consisting of four studies conducted by the German Breast Cancer Study Group (GBSG). The occurrence of the first isolated locoregional recurrence (ILRR) is studied. The results contribute to the debate on the role of the ILRR with respect to the course of the breast cancer disease and the resulting prognosis.ResultsWe have investigated different modelling strategies for the transition hazard after ILRR or in general after an intermediate event. Including time-dependent structures altered the resulting hazard functions considerably and it was shown that this time-dependent structure has to be taken into account in the case of our breast cancer dataset. The results indicate that an early recurrence increases the risk of death. A late ILRR increases the hazard function much less and after the successful removal of the second tumour the risk of death is almost the same as before the recurrence. With respect to distant disease, the appearance of the ILRR only slightly increases the risk of death if the recurrence was treated successfully.ConclusionsIt is important to realize that there are several modelling strategies for the intermediate event and that each of these strategies has restrictions and may lead to different results. Especially in the medical literature considering breast cancer development, the time-dependency is often neglected in the statistical analyses. We show that the time-varying variables cannot be neglected in the case of ILRR and that fractional polynomials are a useful tool for finding the functional form of these time-varying variables.

Abstract P6-07-06: Patterns of locoregional failure in the CALOR (Chemotheraphy as Adjuvant for Locally Recurrent Breast Cancer) Trial

Abstract Introduction: The risk of developing distant metastasis is elevated in patients (pts) who experience isolated locoregional recurrences (ILRR) after initial breast cancer treatment. Surgical resection of ILRR, radiation therapy (RT), and adjuvant hormonal therapy are common practice strategies. However, the role of chemotherapy (C) is unknown. Pts with complete excision of an ILRR were randomly assigned to C or no C. We report treatments, estrogen (ER) and progesterone receptor (PR) status in primary tumors and ILRR, incidence of second-ILRR failure events, and deaths. Methods: 162 pts were enrolled in IBCSG 27-02, BIG 1-02, NSABP B-37. RT was recommended but not required if a completion/salvage mastectomy was performed after an ipsilateral breast tumor recurrence. Hormonal therapy was required for ER+ and/or PR+ tumors and anti-HER2 therapy was given at investigator discretion. Stratification criteria were hormone receptor status of recurrence, site of recurrence (breast, mastectomy scar/chest, regional lymph nodes), and use of prior C. Results: Primary surgery was breast conserving: 98 (60%) and mastectomy: 64 (40%). Types of nodal surgery for primary cancer included sentinel node resection: 20 (12%), axillary node (AN) sampling: 37 (23%), AN dissection: 88 (54%), more extensive nodal surgery: 6 (4%), and no nodal surgery: 8 (5%). The sites of first ILRR were breast: 88 (54%), mastectomy scar/chest wall: 53 (33%), and regional lymph nodes: 21 (13%), and were similarly distributed by treatment arms. Of the 98 pts who originally had a lumpectomy, 92 (94%) received RT. Among these 92, ILRR were in-breast: 83 (90%), chest wall: 1 (1%), and regional node: 8 (9%). Salvage mastectomy was performed in 76/98 (78%) with prior lumpectomy. Of the other 22 pts, 17 had repeat lumpectomies and 5 had AN resection. Of the 64 who originally had mastectomy, 52 (81%) recurred in the scar/chest wall, 12 (19%) in the regional nodes and 15 pts (23%) received post-mastectomy RT, 4 of whom had regional nodal recurrences. Of the 143 pts who had ER status reported for the primary tumor, 21 (15%) had a different ER status reported for the ILRR (table). PR expression was discordant in 35 (26%) of the patients with known values. Average time from surgery for ILRR to surgery for second ILRR was 1.6 yrs (range: 0.08 -4.8). The average pt age for second LRR was 58.9 yrs versus 54.6 yrs for those who developed distant failures. At median follow up of 4.9 yrs, 15 pts developed a second ILRR (10 local, 5 regional), 7 (47%) of whom have died. Of the 37 (23%) pts who developed a distant failure 19 (51%) have died. Conclusions Similar to the effect observed in distant failure rates, a second ILRR following multimodality therapy for an ILRR is a strong prognostic indicator of subsequent death in this population. Funding: NCI PHS grants U10-CA-37377, -69974, -12027, -69651, 44066, and CA-75362. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-06.

Comprehensive Locoregional Treatment and Systemic Therapy for Postmastectomy Isolated Locoregional Recurrence

To assess the impact of comprehensive locoregional therapy and systemic therapy on disease control and survival for postmastectomy patients with isolated locoregional recurrence (ILRR). A total of 115 postmastectomy breast cancer patients treated for ILRR were included. Of the patients, 98 underwent comprehensive locoregional treatment (local tumor excision plus postoperative radiotherapy), and 17 received definitive radiotherapy alone. Involved-field radiotherapy was given to 69 patients, whereas entire-field radiotherapy (both involved-field and elective-field, involving the chest wall and regional lymphatics) was given to 46 patients. Systemic therapy consisting of hormone therapy, chemotherapy, or both was given to 69% of patients. Patients treated with comprehensive locoregional treatment had a significantly better 5-year invasive disease-free survival (IDFS) and overall survival (OS) after ILRR than patients treated with definitive radiotherapy alone (IDFS rate, 51% vs. 16%, p = 0.006; OS rate, 62% vs. 37%, p = 0.017). Patients with the most comprehensive locoregional treatment (recurrent tumor excision and entire-field radiotherapy) and systemic therapy had a significantly better 5-year IDFS and OS than patients given either treatment or neither treatment (IDFS rate, 52% vs. 39%, p = 0.011; OS rate, 63% vs. 50%, p = 0.026). Multivariate analysis revealed that positive axillary lymph nodes, Grade III tumor, negative estrogen and progesterone receptor status at primary diagnosis, disease-free interval of less than 2 years, and less comprehensive locoregional treatment were significantly associated with worse IDFS and OS. Use of comprehensive locoregional therapy and systemic therapy can achieve good survival outcome in a substantial proportion of postmastectomy patients with ILRR.

Adjuvant therapy after excision and radiation of isolated postmastectomy locoregional breast cancer recurrence: definitive results of a phase III randomized trial (SAKK 23/82) comparing tamoxifen with observation

BackgroundAdjuvant systemic treatment for patients with isolated locoregional recurrence (ILRR) ofbreast cancer is based on a single reported randomized trial. The trial, conducted by the Swiss Group for Clinical Cancer Research, compared tamoxifen (TAM) with observation after complete excision of the ILRR and proper radiotherapy. We performed a definitive analysis of treatment outcome at >11 years of follow-up, after the majority of the patients had a subsequent event of interest. Patient and methodsOne hundred and sixty-seven patients with ‘good-risk’ characteristics of disease were randomized. ‘Good-risk’ was defined as estrogen receptor expression in the ILRR, or having a disease-free interval of >12 months and a recurrence consisting of three or less tumor nodules, each ≤3 cm in diameter. Seventy-nine percent of the patients were postmenopausal at randomization. ResultsThe median follow-up time of the surviving patients was 11.6 years. The median post ILRR disease-free survival (DFS) was 6.5 years with TAM and 2.7 years with observation (P = 0.053). The difference was mainly due to reduction of further local relapses (P = 0.011). In postmenopausal patients, TAM led to an increase of DFS from 33% to 61% (P = 0.006). In premenopausal women, 5-year DFS was 60%, independent of TAM medication. For the whole study population, the median post-recurrence overall survival (OS) was 11.2 and 11.5 years in the observation and the TAM group, respectively; premenopausal patients experienced a 5-year OS of 90% for observation compared with 67% for TAM (P = 0.175), while the respective figures for postmenopausal patients were both 75%. ConclusionsThese definitive results confirmed that TAM significantly improves the post-recurrence DFS of patients after local treatment for ILRR. This beneficial effect does not translate into a detectable OS advantage.