Evaluating locoregional recurrence in breast cancer

Low local recurrence rate without postmastectomy radiation in node-negative breast cancer patients with tumors 5 cm and larger

Background: Isolated local or regional recurrence (ILRR) of breast cancer (BC) after mastectomy or lumpectomy indicates a poor prognosis and patients with ILRR hold a substantial risk of developing subsequent distant metastasis. Limited randomized evidence supports the recommendation of systemic treatment for hormone receptor-positive (HR+) lLRR. Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors, such as palbociclib, have shown activity and safety in the first-line treatment of metastatic HR+/HER2-negative BC. The POLAR hypothesis is based on the results of the CALOR trial (IBCSG Trial 27-02), which showed effectiveness of adjuvant chemotherapy among patients with resected HR-negative ILRR, but not for HR+ ILRR. Considering these findings and compelling evidence supporting the activity of the combination of CDK4/6 inhibitors and endocrine therapy (ET), we hypothesize that palbociclib in combination with ET may be effective as adjuvant therapy in patients with HR+/HER2-negative resected ILRR of BC. Trial design: POLAR is a phase III open-label, multicenter, randomized trial of adjuvant palbociclib in combination with standard ET versus standard ET alone for women and men with histologically confirmed HR+/HER2-negative resected ILRR of BC. Protocol treatment consists of palbociclib (125 mg/d orally for 21 days, followed by 7 days rest) for 3 years plus standard ET for at least 3 years (Arm A) or standard ET for at least 3 years (Arm B). Patients must be enrolled within 6 months of complete gross excision of the ILRR. Patients may have started standard ET prior to entry. Randomization (1:1) is stratified according to (1) gender and menopausal status; (2) planned ET (oral aromatase inhibitor or tamoxifen vs. fulvestrant). The primary endpoint, invasive disease-free survival (iDFS), will be compared between treatment groups using a stratified log-rank test. The sample size provides 80% power to detect a 50% reduction in hazard (HR=0.50) for palbociclib plus ET versus ET-alone, using a log-rank test with two-sided α=0.05 test with 66 iDFS events. The 3-year iDFS is assumed to be 76% on the basis of patients in the CALOR trial who had ER+ ILRRs. Accrual: The trial will recruit 400 patients from approximately 50 Centers in Austria, France, Hungary, Italy, Spain and Switzerland. The first patient was randomized in August 2019. Accrual as of mid-June 2020 was 25 patients. The POLAR trial (IBCSG 59-19 / BIG 18-02) is sponsored and coordinated by IBCSG with financial support from Pfizer. The trial is conducted under the BIG umbrella in collaboration with ABCSG, GEICAM, SOLTI, SAKK and Unicancer. NCT03820830 Citation Format: Elisabetta Munzone, Stefan Aebi, Noelia Martínez Jañez, Uwe Güth, Meritxell Bellet, Barbara Pistilli, Marija Balic, Heidi Roschitzki-Voser, Meredith M Regan. Phase III open-label, multicenter, randomized trial of adjuvant palbociclib in combination with endocrine therapy versus endocrine therapy alone for patients with hormone receptor-positive / HER2-negative resected isolated locoregional recurrence of breast cancer - The POLAR Trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-26-02.

BackgroundTo analyze the patterns of locoregional recurrence in breast cancer patients after mastectomy.MethodsThe retrospective study included 7073 women with breast cancer without post-mastectomy radiotherapy: 4604 (65.1%) had pT1–2 N0 disease (low risk); 2042 (28.9%), pT1–2 N1 (intermediate risk); and 427 (6.0%), pT3–4 and/or pN2–3, or pT1–2 N1 after neoadjuvant chemotherapy (high risk). The distribution of cumulative locoregional recurrence was analyzed. The local recurrence and regional recurrence rates were estimated by the Kaplan-Meier method, and differences were compared with the log-rank test. Multivariate analysis was performed using Cox logistic regression analysis.ResultsIn the median follow-up of 63.0 months, 469 patients had locoregional recurrence: chest wall recurrence in 238 (50.7%) cases, supraclavicular/infraclavicular nodes in 236 (50.3%) cases, axilla in 92 (19.6%), and internal mammary nodes in 50 (10.7%) cases. The 5-year local recurrence and regional recurrence rates were 2.5 and 4.4%, respectively. Subgroup analysis of the three risk groups and five molecular subtypes (luminal A, luminal B-Her2 negative, luminal B-Her2 positive, Her2-enriched, and triple negative) also showed that the chest wall and supraclavicular/infraclavicular nodes were the most common recurrence sites. Age, tumor location, T stage, N stage, and hormone receptor status were independent prognostic factors for both local recurrence and regional recurrence (p < 0.05).ConclusionsThe chest wall and supraclavicular/infraclavicular nodes are common sites of locoregional recurrence in breast cancer, irrespective of disease stage or molecular subtype, and the prognostic factors for local recurrence and regional recurrence are similar. Therefore, chest wall and supraclavicular/infraclavicular nodes irradiation should always be considered in post-mastectomy radiotherapy.

Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials

The locoregional recurrence of breast cancer is not a sign of distant metastases, and a substantial proportion of cases are cured by salvage therapy. Patients with locoregional recurrence should not be treated with palliative intent as if they have visceral metastases. The recommended treatment for ipsilateral breast recurrence after breast conservative therapy is a mastectomy. For patients who suffer from isolated chest wall recurrence after mastectomy, a surgical approach is recommended. Neoadjuvant chemotherapy is considered for patients with unresectable disease in order to render the disease resectable. For patients with isolated chest wall recurrence who have received no prior radiotherapy, postoperative radiotherapy involving the chest wall and regional lymph nodes is recommended. Patients with isolated axillary lymph node recurrence should be treated with axillary dissection or resection. Although the effectiveness of systemic therapy for patients with locoregional recurrence is unclear, there is a trend toward treating patients with supraclavicular lymph node recurrence with radiotherapy plus systemic therapy. Pain relief and the eradication of other distressing symptoms resulting from inoperable disease are achieved in two-thirds to three-quarters of patients by radiotherapy with or without systemic therapy. New anti-cancer agents and molecular target therapies should be evaluated with the objective of improving the treatment outcome of patients with locoregional recurrence. A combination of approaches is required for treatment of patients with locoregional recurrence, and a multidisciplinary tumor board should be organized at each institute.

e12549 Background: Triple-negative breast cancer (TNBC) presents a poorer prognosis compared to other breast cancer subtypes, characterized by a higher likelihood of early recurrence and increased incidence of visceral metastases. Evidence from numerous randomized clinical trials indicates that postmastectomy radiotherapy (PMRT) reduces locoregional recurrence (LRR) and improves breast cancer survival in TNBC. Previous reports creatively divided TNBC into four molecular subtypes for personalized treatment. The present study aims to elucidate patterns of LRR in different subtypes of TNBC after PMRT. Methods: From 2019 to 2022, data from 349 AJCC 7th edition stage II-III breast cancer patients treated with mastectomy and PMRT were retrospectively analyzed. These patients were classified into the basal-like immune-suppressed (BLIS) and non-BLIS groups based on the immunohistochemistry biomarkers. The cumulative incidence function was applied to estimated LRR rates, with death as a competing risk, using Gray's test for comparisons. Results: According to the IHC results, a total of 255 patients belonged to the non-BLIS group and 94 to the BLIS group. The 3-year LRR for the entire cohort was 5.16%. There were 9 cases each in the non-BLIS subtype (3.5%) and BLIS subtype (9.6%). The cumulative incidence of LRR between the two groups was significantly different, with a rate of 4.0% in the non-BLIS group and 9.0% in the BLIS group ( P = 0.02). Among the 18 patients with LRR in the whole population, 11 had isolated LRR and 7 were diagnosed with LRR with concurrent distant metastases. The most common area of recurrence in both subtypes was the supraclavicular region. The majority of recurrences occurred within the RT field (in-field), and no isolated out-of-field relapse was observed. In multivariate analysis, independent factors predicting higher LRR were the BLIS subtype (HR = 3.06, P = 0.02). Conclusions: Study results suggest that TNBC of the BLIS subtype is at higher risk for LRR. Immunohistochemistry-based molecular typing may serve as a prognostic biomarker to guide postmastectomy radiotherapy in patients with TNBC. New strategies are needed to improve local control rates in patients with BLIS subtype.

BackgroundTranscriptomic features of breast cancer locoregional recurrence (LRR) remain poorly understood. We therefore sought to investigate transcriptomic features associated with LRR in newly diagnosed invasive breast tumors from our institutional dataset.MethodsTranscriptomic profiling was performed on 632 tumors from consecutive patients treated within our health system for newly diagnosed non-metastatic breast cancer. Univariable Cox models identified genes whose expression was associated with LRR (q-value < 0.05). Up-regulated (UR) genes were defined as hazard ratio (HR) > 1 and down-regulated (DR) genes were defined as HR < 1. Gene set enrichment analyses were performed for UR and DR gene sets and validated within two external cohorts of ER- tumors.ResultsWith a median follow-up of 7.6 years, we observed 38 LRRs: 28/481 (5.8%) in ER + and 10/151 (6.6%) in ER-. There were 43 UR and 7 DR genes associated with LRR in ER + tumors, while 417 UR and 1150 DR genes were associated with LRR in ER- tumors. UR genes in ER + tumors were enriched for roles in cell proliferation (q < 0.05). In contrast, LRR in ER- tumors was most strongly associated with DR genes enriched for MHC-II-mediated antigen presentation and T cell activation (q < 0.05). In external cohorts of ER- tumors, 97 significant DR genes (p < 0.05) were enriched for 18 pathways, including 5 pathways involved in MHC-II signaling, antigen presentation and T-cell activation.ConclusionsTranscriptomic patterns associated with LRR appear distinct between ER + and ER- tumors. In ER + tumors, LRR appears predominantly associated with proliferation, whereas ER- LRR suggests a robust pattern of suppressed antigen presentation via MHC-II.

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.

Surgical margins and risk of locoregional recurrence in invasive breast cancer: An analysis of 10-year data from the Breast Cancer Treatment Quality Assurance Project

PurposeImmunohistochemistry (IHC)-based molecular subtyping provides a comprehensive profile of triple-negative breast cancer (TNBC). We aimed to elucidate patterns of locoregional recurrence (LRR) in different subtypes of TNBC.Methods and MaterialsIn this study, 352 patients with breast cancer treated with mastectomy and postmastectomy radiation therapy from November 2019 to March 2022 were retrospectively analyzed. Based on IHC, these patients were classified into the basal-like immune-suppressed (BLIS) and non-BLIS groups. We compared LRR as the first event, disease-free survival, and overall survival (OS) between the 2 groups. Univariate and multivariate analysis was performed.ResultsThe median follow-up time was 44.6 months. Twenty-six LRR (including 9 isolated LRR) and 70 distant metastases (DMs) were observed. The cumulative incidence of LRR was significantly different between the 2 groups, with an LRR rate of 5.8% in the non-BLIS group and 14.9% in the BLIS group (P = .005). The difference in OS was also significant (91.9% vs 83.0%, P = .01). However, there was no significant difference in disease-free survival between the non-BLIS and BLIS groups (80.2% vs 74.5%, P = .35). Multivariate analysis demonstrated that IHC-based molecular subtyping was an independently prognostic factor for LRR and OS (P = .03; P = .03).ConclusionsThis study demonstrated that the BLIS subtype appears to be at a higher risk of developing LRR, and IHC-based molecular subtyping might be used as prognostic biomarkers to guide postmastectomy radiation therapy in patients with TNBC. New strategies that improve locoregional control rates in patients with BLIS are warranted.

Locoregional recurrences from breast cancer represent a heterogeneous group of disease that poses a therapeutic challenge and needs a multidisciplinary team management. The incidence of local recurrence after breast conservation surgery ranges from 10 to 22% and 5-15% after mastectomy at 10-year follow-up. Management of locoregional recurrence depends on tumor biology, stage at presentation, and prior local and systemic therapy. With improvements in diagnostic, pathological, and surgical techniques, radiation and systemic therapy approach, outcomes in these patients have improved. In this review, we discuss the risk factors, prognostic factors, surgical and reconstruction options, re-irradiation, and role of systemic therapy to define a reasonable treatment approach without compromising oncologic safety and achieve good cosmetic and survival outcomes.

The impact of surgical techniques on locoregional recurrence in breast cancer

CT staging of loco-regional breast cancer recurrence. A worthwhile practice?

Relevance. Breast cancer remains one of the most common and socially significant malignancies among women. Given the high frequency of mastectomies, the risk of locoregional recurrences remains substantial, necessitating the development of effective diagnostic, surveillance, and therapeutic algorithms. Objective. To identify clinical, morphological, and molecular risk factors for breast cancer recurrence and to propose a stratification system and personalized approach to treatment and follow-up. Materials and methods of the study. The study included 206 patients with verified breast cancer who underwent mastectomy. Imaging, immunohistochemical (IHC) typing, and tumor marker monitoring were used. Molecular subtypes, Ki-67 index, and completeness of therapy were assessed. Statistical analysis was performed using the StatTech environment. Research results. A high recurrence risk was found in patients with HER2-positive and triple-negative tumors, stage IIB–IIIA, and high Ki-67 levels. Incomplete adjuvant therapy significantly increased recurrence probability. A follow-up algorithm and risk stratification system were developed. Conclusion. Locoregional breast cancer recurrences are associated with tumor biology and insufficient treatment. Therapy individualization based on IHC profiles improves survival and reduces oncological burden.

BackgroundThe Nottingham prognostic index (NPI) has been shown to negatively impact survival in breast cancer (BC). However, its ability to predict the locoregional recurrence (LRR) of BC remains still unclear. This study aims to determine whether a higher NPI serves as a significant predictor of LRR in BC.MethodsIn total, 238 patients with BC were included in this analysis, and relevant clinicopathological features were collected. Correlation analysis was performed between NPI scores and clinicopathological characteristics. The optimal nomogram model was determined by Akaike information criterion. The accuracy of the model’s predictions was evaluated using receiver operating characteristic curves (ROC curves), calibration curves and goodness of fit tests. The clinical application value was assessed through decision curve analysis.ResultsSix significant variables were identified, including age, body mass index (BMI), TNM stage, NPI, vascular invasion, perineural invasion (P<0.05). Two prediction models, namely a TNM-stage-based model and an NPI-based model, were constructed. The area under the curve (AUC) for the TNM-stage- and NPI-based models were 0.843 (0.785,0.901) and 0.830 (0.766,0.893) in training set and 0.649 (0.520,0.778) and 0.728 (0.610,0.846) in validation set, respectively. Both models exhibited good calibration and goodness of fit. The F-measures were 0.761vs 0.756 and 0.556 vs 0.696, respectively. Clinical decision curve analysis showed that both models provided clinical benefits in evaluating risk judgments based on the nomogram model.Conclusionsa higher NPI is an independent risk factor for predicting LRR in BC. The nomogram model based on NPI demonstrates good discrimination and calibration, offering potential clinical benefits. Therefore, it merits widespread adoption and application.