Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair.

Mutational processes constantly shape the somatic genome, leading to immunity, aging, cancer, and other diseases. When cancer is the outcome, we are afforded a glimpse into these processes by the clonal expansion of the malignant cell. Here, we characterize a less explored layer of the mutational landscape of cancer: mutational asymmetries between the two DNA strands. Analyzing whole-genome sequences of 590 tumors from 14 different cancer types, we reveal widespread asymmetries across mutagenic processes, with transcriptional ("T-class") asymmetry dominating UV-, smoking-, and liver-cancer-associated mutations and replicative ("R-class") asymmetry dominating POLE-, APOBEC-, and MSI-associated mutations. We report a striking phenomenon of transcription-coupled damage (TCD) on the non-transcribed DNA strand and provide evidence that APOBEC mutagenesis occurs on the lagging-strand template during DNA replication. As more genomes are sequenced, studying and classifying their asymmetries will illuminate the underlying biological mechanisms of DNA damage and repair.

Early effectiveness and toxicity outcomes of reirradiation after breast conserving surgery for recurrent or new primary breast cancer.

PURPOSE: Breast reirradiation (reRT) after breast conserving surgery (BCS) has emerged as a viable alternative to mastectomy for women presenting with recurrent or new primary breast cancer. There are limited data on safety of different fractionation regimens. This study reports safety and efficacy among women treated with repeat BCS and reRT. METHODS AND MATERIALS: Patients who underwent repeat BCS followed by RT from 2015 to 2021 at 2 institutions were analyzed. Univariate logistic regression models were used to identify predictors of acute and late toxicities. Kaplan-Meier estimates were used to evaluate overall survival (OS), distant metastasis-free survival (DMFS) and locoregional recurrence-free survival (LR-RFS). RESULTS: Sixty-six patients were reviewed with median follow-up of 16 months (range: 3-60 months). At time of first recurrence, 41% had invasive carcinoma with a ductal carcinoma in situ (DCIS) component, 41% had invasive carcinoma alone and 18% had DCIS alone. All were clinically node negative. For the reirradiation course, 95% received partial breast irradiation (PBI) (57.5% with 1.5 Gy BID; 27% with 1.8 Gy daily; 10.5% with hypofractionation), and 5% received whole breast irradiation (1.8-2 Gy/fx), all of whom had received PBI for initial course. One patient experienced grade 3 fibrosis, and one patient experienced grade 3 telangiectasia. None had grade 4 or higher late adverse events. We found no association between the fractionation of the second course of RT or the cumulative dose (measured as EQD2) with acute or late toxicity. At 2 years, OS was 100%, DMFS was 91.6%, and LR-RFS was 100%. CONCLUSION: In this series of patients with recurrent or new primary breast cancer, a second breast conservation surgery followed by reirradiation was effective with no local recurrences and an acceptable toxicity profile across a range of available fractionation regimens at a median follow up of 16 months. Longer follow up is required.

Metaplastic carcinoma of the breast: matched cohort analysis of recurrence and survival.

PURPOSE: Metaplastic breast carcinoma (MBC) is a rare subtype of breast cancer, defined as mammary carcinoma with squamous or mesenchymal differentiation, that may include spindle cell, chondroid, osseous, or rhabdomyoid differentiation patterns. The implications of MBC recurrence and survival outcomes remains unclear. METHODS: Cases were ascertained from a prospectively maintained institutional database of patients treated from 1998 to 2015. Patients with MBC were matched 1:1 to non-MBC cases. Cox proportional-hazards models and Kaplan-Meier estimates were used to evaluate outcome differences between cohorts. RESULTS: 111 patients with MBC were matched 1:1 with non-MBC patients from an initial set of 2400 patients. Median follow-up time was 8 years. Most patients with MBC received chemotherapy (88%) and radiotherapy (71%). On univariate competing risk regression, MBC was not associated with locoregional recurrence (HR = 1.08; p = 0.8), distant recurrence (HR = 1.65; p = 0.092); disease-free survival (HR = 1.52; p = 0.065), or overall survival (HR = 1.56; p = 0.1). Absolute differences were noted in 8-year disease-free survival (49.6% MBC vs 66.4% non-MBC) and overall survival (61.3% MBC vs 74.4% non-MBC), though neither of these reached statistical significance (p = 0.07 and 0.11, respectively). CONCLUSION: Appropriately-treated MBC may exhibit recurrence and survival outcomes that are difficult to distinguish from those of non-MBC. While prior studies suggest that MBC has a worse natural history than non-MBC triple-negative breast cancer, prudent use of chemotherapy and radiotherapy may narrow these differences, although studies with more power will be required to inform clinical management. Longer follow-up among larger populations may further elucidate the clinical and therapeutic implications of MBC.

How Often Do Sentinel Lymph Node Biopsy Results Affect Adjuvant Therapy Decisions Among Postmenopausal Women with Early-Stage HR+/HER2- Breast Cancer in the Post-RxPONDER Era?

BACKGROUND: The RxPONDER trial reported no benefit to chemotherapy among postmenopausal patients with HR+/HER2- tumors, one to three positive nodes, and low recurrence scores, questioning the role of axillary staging in this population. Here, we evaluate the impact of sentinel lymph node biopsy (SLNB) results on adjuvant therapy decisions in postmenopausal women with HR+/HER2- breast cancer. PATIENTS AND METHODS: Postmenopausal women with cT1-2N0, HR+/HER2- breast cancer treated with lumpectomy and SLNB from 2012 to 2018 were identified. Receipt of nodal irradiation, indication for axillary lymph node dissection (ALND) and chemotherapy, and partial breast irradiation (PBI) eligibility were reviewed with pre- and post-SLNB results. RESULTS: A total of 1786 women were identified: median age 62 years, 84% with pT1 tumors, and 16% with pT2-3 tumors. Of those, 85% (n = 1525) remained pN0, 14% (n = 244) were pN1, and 1% (n = 17) were pN2-3. A total of 20 (1%) patients had > 2 positive SLNs, necessitating ALND. Pre-SLNB, 1478 women were considered PBI eligible; post-SLNB, 227 (13%) converted to PBI ineligible. In total, 58 patients with positive nodes received nodal irradiation, representing 3% of the entire cohort and 22% of pN+ patients. Overall, 1401 patients had an Oncotype DX recurrence score available, including 1273 patients with pN0 stage and 128 with pN1, with 173 (14%) and 16 (13%), respectively, having a recurrence score > 25, warranting chemotherapy. CONCLUSIONS: While few cN0 postmenopausal women with HR+/HER2- tumors had nodal pathology that warranted ALND, receipt of nodal irradiation, or indicated need for chemotherapy, in 13%, SLNB would have an impact on consideration for PBI. Among patients eligible for PBI, findings from SLNB may help refine selection among postmenopausal women with this tumor profile.

Breast conservation among older patients with early-stage breast cancer: Locoregional recurrence following adjuvant radiation or hormonal therapy.

BACKGROUND: For patients with breast cancer undergoing breast-conserving surgery (BCS), adjuvant radiation (RT) and hormonal therapy (HT) reduce the risk of locoregional recurrence (LRR). Although several studies have evaluated adjuvant HT ± RT, the outcomes of HT versus RT monotherapy remain less clear. In this study, the risk of LRR is characterized among older patients with early-stage breast cancer following adjuvant RT alone, HT alone, neither, or both. METHODS: This study included female patients from the Memorial Sloan Kettering Cancer Center (New York, New York) who were aged ≥65 years with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) T1N0 breast cancer treated with BCS. The primary endpoint was time to LRR evaluated by Cox regression analysis. RESULTS: There were 888 women evaluated with a median age of 71 years (range, 65-100 years) and median follow-up of 4.9 years (range, 0.0-9.5 years). There were 27 LRR events (3.0%). Five-year LRR was 11% for those receiving no adjuvant treatment, 3% for HT alone, 4% for RT alone, and 1% for HT and RT. LRR rates were significantly different between the groups (P < .001). Compared with neither HT nor RT, HT or RT monotherapy each yielded similar LRR reductions: HT alone (HR, 0.27; 95% CI, 0.10-0.68; P = .006) and RT alone (HR, 0.32; 95% CI, 0.11-0.92; P = .034). Distant recurrence and breast cancer-specific survival rates did not significantly differ between groups. CONCLUSIONS: LRR risk following BCS is low among women aged ≥65 years with T1N0, ER+/HER2- breast cancer. Adjuvant RT and HT monotherapy each similarly reduce this risk; the combination yields a marginal improvement. Further study is needed to elucidate whether appropriate patients may feasibly receive adjuvant RT monotherapy versus the current standards of HT monotherapy or combined RT/HT.

Management of ipsilateral breast tumor recurrence following breast conservation surgery: a comparative study of re-conservation vs mastectomy.

BACKGROUND: Breast conservation therapy (BCT) is well established for the management of primary operable breast cancer, with oncologic outcomes comparable to those of mastectomy. It remains unclear whether re-conservation therapy (RCT) is suitable for those patients who develop ipsilateral breast tumor recurrence (IBTR), for whom mastectomy is generally recommended. METHODS: We identified women who underwent BCT for invasive or ductal carcinoma in situ and developed IBTR as a first event, comparing the pattern of subsequent events and survival for those treated by RCT versus mastectomy. RESULTS: Of 16,968 patents who had BCT, 322 (1.9%) developed an isolated IBTR as a first event between 1999 and 2019. 130 (40%) had RCT and 192 (60%) mastectomy. Compared to mastectomy, the RCT patients were older (66 vs 53, < 0.001), had a longer disease-free interval (DFI: 5.8 vs 2.7 years (p < 0.001)), were less likely to have received RT (p < 0.001), endocrine therapy (ET) (p < 0.005) or combined RT/ET (< 0.001) as initial treatment, but the characteristics of their initial primary cancers and of their IBTR were comparable. At a median follow-up of 10.7 years following initial BCT and 6.5 years following IBTR, there were no differences in BCSS or OS between RCT and mastectomy. CONCLUSION: For BCT patients who developed IBTR as a first event, we observed comparable BCSS and OS from time of initial treatment and from time of IBTR, whether treated by RCT or mastectomy. These results support wider consideration of RCT in the management of IBTR, especially in the setting of older age and longer DFI.

Salvage of locally recurrent breast cancer with repeat breast conservation using 45 Gy hyperfractionated partial breast re-irradiation.

PURPOSE: Mastectomy has long been the preferred approach for local salvage of recurrent breast cancer following breast-conservation therapy (BCT). Growing interest in avoiding mastectomy prompted RTOG 1014, a landmark phase two study demonstrating the feasibility of repeat BCT using a novel radiotherapy (RT) regimen (i.e., 45 Gy administered in 30 fractions of 1.5 Gy twice-daily to the partial breast, "rePBI"). We adopted this regimen as our institutional standard and report our observations regarding the safety and efficacy of rePBI as salvage therapy. METHODS: All patients at our institution who underwent repeat BCT and subsequently received rePBI from 2011 to 2019 were identified. Clinicopathologic features and treatment characteristics for both primary breast cancers and recurrences were collected, as were rates of subsequent recurrence and treatment-associated toxicities. RESULTS: The cohort included 34 patients with a median age of 65.8 (46.2-78.2) at the time of rePBI. At a median follow-up of 23.5 months, there were two subsequent locoregional recurrences (2-year local control rate 97%). There was no grade ≥ 3 toxicity. The most common acute toxicity (< 3 months) was radiation dermatitis (100%), and common grade 1-2 late toxicities (> 3 months) included fibrosis in 14 (41%), breast asymmetry in 12 (35%), and chest wall pain in 11 (32%). CONCLUSIONS: Repeat breast conservation using the hyperfractionated partial breast RT regimen defined by RTOG 1014 (45 Gy administered in 30 1.5 Gy twice-daily fractions) appears effective and well tolerated. No grade 3 or higher toxicities were observed and local control was excellent. Longer term follow-up among larger cohorts will define whether salvage mastectomy should remain the preferred standard.

Evaluation of radiation-induced cardiac toxicity in breast cancer patients treated with Trastuzumab-based chemotherapy.

PURPOSE: Patients with Her2-positive breast cancer treated with trastuzumab have higher rates of cardiotoxicity (CT). Left-breast radiation might increase the risk for CT from cardiac exposure to radiation. The goal of our study is to evaluate the contribution of radiotherapy (RT) in the development of CT in breast cancer patients receiving trastuzumab. METHODS: Two hundred and two patients were treated with RT and trastuzumab from 2000 to 2014. The RT plans for left-side disease were recalled from archives. The heart, each chamber, and left anterior descending artery (LAD) were independently contoured. New dose-volume histograms (DVH) were generated. Their serial left-ventricular ejection fractions (LVEF) were studied. CT for left and right side were compared using Fisher's exact test. The DVH data were correlated with the predefined cardiac events using actuarial Cox regression analysis. RESULTS: Compared to the right sided, the left-side cases showed statistically significant development of arrhythmia (14.2%) versus (< 1%) (p < 0.001). Cardiac ischemia was found in 10 patients in left and one patient in right side (p = 0.011). The equivalent uniform dose (EUD) to the left ventricle (LV), right ventricle (RV), and LAD was significantly associated with decrease in LVEF by > 10% (p = 0.037, p = 0.023 and p = 0.049, respectively). CONCLUSIONS: Among patients treated for left-sided lesions, there were no significant differences in EF decline. However, there was a higher rate of ischemia and arrhythmia compared to those with right-sided disease. The EUD index of LV, RV, and LAD could be considered as a parameter to describe the risk of radiation-induced CT.

Predictors of surveillance mammography outcomes in women with a personal history of breast cancer.

PURPOSE: To identify predictors of poor mammography surveillance outcomes based on clinico-pathologic features. METHODS: This study was HIPAA compliant and IRB approved. We performed an electronic medical record review for a cohort of women with American Joint Committee on Cancer (AJCC) Stage I or II invasive breast cancer treated with breast conservation therapy who developed subsequent in-breast treatment recurrence (IBTR) or contralateral breast cancer (CBC). Poor surveillance outcome was defined as second breast cancer not detected by surveillance mammography, including interval cancers (diagnosed within 365 days of surveillance mammogram with negative results) and clinically detected cancers (diagnosed without a surveillance mammogram in the preceding 365 days). Univariate and multivariate logistic regression were performed to identify predictors of poor mammography surveillance outcome, including patient and primary tumor characteristics, breast density, mode of primary tumor detection, and time to second cancer diagnosis. RESULTS: 164 women met inclusion criteria (65 with IBTR, 99 with CBC); 124 had screen-detected second cancers. On univariate analysis, poor surveillance outcome (n = 40) was associated with age at primary cancer diagnosis < 50 years (p < 0.0001), AJCC stage II primary cancers (p = 0.007), and heterogeneously or extremely dense breasts (p = 0.04). On multivariate analysis, age < 50 years at primary breast cancer diagnosis remained a significant predictor of poor surveillance outcome (p = 0.001). CONCLUSION: Women younger than age 50 at primary breast cancer diagnosis are at risk of poor surveillance mammography outcomes, and may be appropriate candidates for more intensive clinical and imaging surveillance.

Impact of an In Situ Component on Outcome After In-Breast Tumor Recurrence in Patients Treated with Breast-Conserving Therapy.

BACKGROUND: Among all in-breast tumor recurrences (IBTR) following breast-conserving therapy (BCT), some comprise metachronous new primaries (NPs) while others are true recurrences (TRs). Establishing this distinction remains a challenge. METHODS: We studied 3932 women who underwent BCT for stage I-III breast cancer from 1998 to 2008. Of these, 115 (2.9%) had an IBTR. Excluding patients with inoperable/unresectable recurrences or simultaneous distant metastases, 81 patients with isolated IBTR comprised the study population. An IBTR was categorized as an NP rather than a TR if it included an in situ component. The log-rank test and Kaplan-Meier method were used to evaluate disease-free survival (DFS) and overall survival (OS), and univariate and multivariate analyses were performed using Cox proportional hazards regression models. RESULTS: At a median of 64.5 months from IBTR diagnosis, 28 of 81 patients had DFS events. Five-year DFS was 43.1% in the TR group (p = 0.0001) versus 80.3% in the NP group, while 5-year OS was 59.7% in the TR group versus 91.7% among those with NPs (p = 0.0011). On univariate analysis, increasing tumor size, high grade, positive margins, lymphovascular invasion, node involvement, lack of axillary surgery, chemotherapy, radiation therapy, and IBTR type (TR vs. NP) were significantly associated with worse DFS. Controlling for tumor size and margin status, TRs remained significantly associated with lower DFS (hazard ratio 3.717, 95% confidence interval 1.607-8.595, p = 0.002). CONCLUSION: The presence of an in situ component is associated with prognosis among patients with IBTR following BCT and may be useful in differentiating TRs and NPs.

Breast-cancer subtype, age, and lymph node status as predictors of local recurrence following breast-conserving therapy.

PURPOSE/OBJECTIVES: Advances in breast-conserving therapy (BCT) have yielded local control rates comparable or superior to those of mastectomy. In this study, we sought to identify contemporary risk factors associated with local recurrence (LR) following BCT. METHODS: We analyzed a multi-institutional cohort of 2233 consecutive breast-cancer patients who underwent BCT between 1998 and 2007. Patients were stratified by age, biologic subtype (as approximated by receptor status and tumor grade), and nodal status. Patients who received HER2/neu-directed therapy were excluded due to variations in practice over the study period. The association of clinicopathologic features with LR was evaluated using Cox proportional hazards regression models. RESULTS: With a median follow-up of 106 months, 69 LRs (3 %) were observed. On univariate analysis, LR was associated with non-luminal-A subtype (hazard ratio [HR] for luminal-B = 3.01, HER2 = 6.29, triple-negative [TNBC] = 4.72; p < 0.001 each), younger age (HR of oldest vs. youngest quartile = 0.43; p = 0.005), regional nodal involvement (HR for 4-9 involved nodes = 3.04; >9 nodes = 5.82; p < 0.01 for each), positive margins (HR 2.43; p = 0.005), and high grade (HR 5.37; p < 0.001). Multivariate Cox regression demonstrated that non-luminal-A subtypes (HR for luminal-B = 2.64, HER2 = 5.42, TNBC = 4.32; p < 0.001 for each), younger age (HR for age >50 = 0.56; p = 0.01), and nodal disease (HR 1.06 per involved node; p < 0.004) were associated with LR. The 8-year risk of LR was 2.8 % for node-negative patients and 5.2 % for node-positive patients. CONCLUSION: BCT yields favorable outcomes for the large majority of patients, although increased LR was observed among those with non-luminal-A subtypes, younger age, and increasing lymph node involvement. Risk factors for LR after BCT appear to be converging with those after mastectomy in the current era.

The Impact of Reexcision and Residual Disease on Local Recurrence Following Breast-Conserving Therapy.

PURPOSE: Risk factors for local recurrence (LR) following breast-conserving therapy (BCT) inform the need for local therapy. A Danish population-based cohort study identified residual disease on reexcision as an independent risk factor for LR but was limited by incomplete data on biologic subtype (Bodilsen et al. 2015 in Ann Surg Oncol 22: S476-S485). We sought to elaborate this risk in an independent cohort with clearly defined biologic subtypes. METHODS: The study population included patients with localized invasive breast cancer with complete biologic subtype data treated with BCT with one or zero reexcisions at one institution from 1998 to 2008. Cumulative incidence of LR was calculated using competing risk analysis, and associated risk factors were evaluated using Cox proportional hazards regression. RESULTS: A total 1073 consecutive patients were included with a median follow-up of 10 years. The 10-year LR rates were 2.4% [95% confidence interval (CI) 1.4-3.9%] without reexcision, 6.0% (95% CI 3.8-8.9%) with reexcision, and 8.2% (95% CI 4.1-14.0%) with any reexcised residual disease. On univariate regression, residual disease [hazard ratio (HR) = 1.50, p = 0.31] was not significantly associated with LR. Subtype other than luminal A/luminal-HER2 (luminal B HR = 2.29, p = 0.033; HER2/triple-negative HR = 2.85, p = 0.004), age (HR = 0.95 per year, p < 0.001), and nodal involvement (HR = 1.12 per involved node, p = 0.001) remained significant on multivariate regression. The impact of residual disease was confounded by its association (p < 0.001) with nodal involvement. CONCLUSIONS: Our findings suggest that LR is associated with younger age, nodal involvement, and biologic subtype but not with residual disease at reexcision. The study's power is limited by the low incidence of LR despite detailed clinical data and long-term follow-up. Further study is required.

Invasive lobular carcinoma of the breast: local recurrence after breast-conserving therapy by subtype approximation and surgical margin.

Invasive lobular carcinoma (ILC) typically presents at a later stage than invasive ductal carcinoma (IDC) and poses unique radiographic and surgical challenges. However, current principles of breast-conserving therapy (BCT) do not distinguish between histologic subtypes, raising uncertainty about the optimal approach for patients with ILC. We studied 998 BCT patients from 1998-2007, comprised 74 % IDC, 8 % ILC, and 18 % with mixed ILC/IDC. In light of recent guidelines addressing surgical margins, specimens were assessed for margin width and biologic subtype. The Kaplan-Meier method and Cox proportional hazards models were used to analyze effects of patient and disease characteristics on local recurrence (LR). At a median of 119 months, 45 patients had an isolated LR. 10-year LR was 5.5 % for patients with IDC, 4.4 % for ILC, and 1.2 % for mixed histology (p = 0.08). The majority of ILC cases had luminal A biologic subtype (91.1 %), and analysis among all luminal A cases revealed 10-year LR of 2.6 % for IDC, 3.4 % for ILC, and 0 % for mixed tumors (p = 0.12). Patients with ILC were more likely to have initially positive surgical margins (45.0 vs 17.5 %; p < 0.001) resulting in more frequent re-excision (57.1 % vs 40.4 %; p = 0.02), though final margins were similar between ILC and IDC (p = 0.88). No LR was observed among ILC or mixed histology patients with margins <2 mm (n = 28). On multivariate analysis, histologic subtype was not associated with LR (p = 0.52). Modern approaches confer similarly favorable LR rates for ILC, IDC, and mixed histology breast cancers despite inherent histologic differences. Patients with ILC did not require more extensive surgical margins than those with IDC.

Long-term outcomes among breast cancer patients with extensive regional lymph node involvement: implications for locoregional management.

Extensive lymph node (LN) involvement portends significant risk for distant metastasis (DM) among breast cancer patients. As a result, local management may be of secondary import to systemic control in this population. We analyzed patients with ≥10 involved LNs (N3) to evaluate the feasibility of breast conserving therapy (BCT) vs modified radical mastectomy (MRM) in this high-risk cohort. Among 98 women with N3 disease 46 (46.9%) underwent BCT and 52 (53.1%) received MRM. Nearly all patients (92%) received comprehensive radiotherapy (RT) including axillary and supraclavicular fields. The Kaplan-Meier method and Cox regression analyses were used to analyze time-to-event outcomes. Median follow-up was 76 months, with a 5-year DFS of 64.9% and OS of 71.9% among the cohort. Poorly differentiated (p = 0.007), ER-negative tumors (p = 0.015) had adverse DFS outcomes. Treatment groups did not differ with regard to 10-year DFS (45.4% for MRM vs. 57.6% for BCT; p = 0.31), or OS (61.4 vs. 63.7%; p = 0.79). DM-free survival was 48.9% following MRM and 60.6% following BCT (p = 0.19). Patients with ≥10 involved LNs have similar outcomes following BCT or MRM, suggesting that RT may obviate the need for more-extensive surgery. While local control is comparably favorable regardless of surgical approach, systemic control remains a challenge in this population.

Outcome following local-regional recurrence in women with early-stage breast cancer: impact of biologic subtype.

Local-regional recurrence (LRR) after breast-conserving therapy (BCT) can result in distant metastasis and decreased disease-free survival (DFS). This study examines factors associated with DFS following LRR. The initial population included 2,233 consecutive women who underwent BCT from 1998 to 2007. Biologic subtype was approximated using a combination of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and tumor grade. Cumulative incidence of DFS after LRR was calculated. The association of clinical, pathologic, and treatment parameters with DFS was evaluated using a Cox regression model. At a median follow-up of 105 months, 82 patients (3.7%) had a LRR. Of these, 66 (80%) were in-breast and 16 (20%) involved the ipsilateral lymph nodes. Twenty patients subsequently developed distant metastases. Five-year DFS after initial recurrence was 69.6% for the overall cohort. On univariate analysis, triple-negative disease (ER/PR/HER2 negative, TNBC) was associated with reduced DFS (HR = 3.8; 95% CI: 1.8-8.1; p < 0.001). Other factors associated with reduced DFS were larger tumor size (HR = 1.3; 95% CI: 1.03-1.6; p = 0.02), shorter interval from initial diagnosis to LRR (HR = 0.98 per month; 95% CI: 0.97-0.99; p = 0.02), and no salvage surgery (HR = 0.2; 95% CI: 0.09-0.5; p = 0.001). On multivariate analysis, TNBC remained the most significant factor associated with reduced DFS (HR = 4.8; 95% CI: 2.25-10.4; p < 0.001). Compared to women with luminal A disease, those with TNBC had significantly worse DFS (37.5% versus 88.3% at 5 years; p < 0.001). Women with TNBC who developed LRR were at high risk of subsequent recurrence. Efforts should be targeted toward both preventing initial recurrence and decreasing subsequent metastasis.