Distant Metastasis-free Interval Research Articles

Prognosis of isolated locoregional recurrence after early breast cancer with immediate breast reconstruction surgery: a retrospective multi‑institutional study.

The prognosis in patients with breast cancer with isolated locoregional recurrence (ILRR) without simultaneous distant metastases after immediate breast reconstruction (IBR) remains unknown. We aimed to investigate the prognosis in this patient population. This multi-institutional retrospective observational study evaluated 3295 patients with primary breast cancer who underwent IBR at 12 Japanese medical facilities between January 1, 2008 and December 31, 2016. The outcome measures were the prognostic factors for ILRR after IBR, 5-year distant metastasis-free interval (DMFI), and 5-year overall survival (OS). Mastectomy or skin-sparing mastectomy was performed in 3295 patients. ILRR occurred in 70 patients, and the median observation period from ILRR diagnosis was 39.3months. Of the 70 patients, 9 (12.9%) had axillary lymph node recurrence (ALNR) at the time of ILRR diagnosis. The 5-year DMFI and OS rates after ILRR were 92.4% and 91.2%, respectively. Pathological lymph node metastasis at primary surgery (P = 0.041) and ALNR (P = 0.022) at ILRR were significantly associated with DMFI in the univariate analysis. ALNR was the only independent prognostic factor in the multivariate analysis (P = 0.041). Post-mastectomy radiation therapy (PMRT; P = 0.022) and ALNR (P = 0.043) were significantly associated with OS in the univariate analysis, and both PMRT (P = 0.010) and ALNR (P = 0.028) were independent prognostic factors in the multivariate analysis for OS. Although patients with breast cancer who had ILRR after IBR have favorable prognosis, ALNR may lead to poor prognosis. To the best of our knowledge, this study is the first to report the prognosis of these patients.

Clinicopathological and Genomic Identification of Breast Cancers with No Impact on Mortality.

Implementing mammogram screening means that clinicians are seeing many breast cancers that will never develop metastases. The purpose of this study was to identify subgroups of breast cancer patients who did not present events related to long-term breast cancer mortality, taking into account diagnosis at breast screening, absence of palpability and axillary involvement, and genomic analysis with PAM50. To identify them, a retrospective observational study was carried out selecting patients without any palpable tumor and without axillary involvement, and a genomic analysis was performed with PAM50. The probability of distant metastasis-free interval (DMFI) of 337 patients was 0.92 (95% CI, 0.90-0.93) at 20 years and 0.96 (95% CI, 0.92-1.00) in 95 patients (28%) with available PAM50 tests. In 22 (23.15%) luminal A tumors and in 9 (9.47%) luminal B tumors smaller than 1 cm, and in HER2 and basal type tumors, there were no metastatic events (20-year DMFI of 1.00). Patients with nonpalpable breast cancer found at screening with negative nodes are at very low risk. It is possible to identify subgroups without metastatic events by determining the intrinsic subtype and tumor size less than 1 cm. Therefore, de-escalation of treatment should be considered.

Molecular and Clinical Portrait of HER2-low Invasive Lobular Carcinomas

Invasive lobular carcinomas (ILCs) have a low frequency of ERBB2 amplification, therefore restricting the use of conventional anti-HER2 therapies for this histologic special type. Conversely, ILCs with low HER2 overexpression may represent a broader target for the use of emerging antibody drug conjugate therapies targeting HER2, since these treatments have proven effective in HER2-low breast cancers. Very scarce data about HER2-low ILCs have been so far published, although these tumors could have different prevalence and histomolecular specificities compared with invasive breast carcinoma of no special type (IBC-NST). Our aims in that context were to decipher the clinicopathological and molecular features of a large series of HER2-low ILCs. Comparative evaluation of HER2-low prevalence was done based on a retrospective series of 7970 patients from Institut Curie, with either primary invasive lobular (N = 1103) or no special type (N = 6867) invasive carcinoma. Clinicopathological and molecular analyses of HER2-zero, HER2-low, and HER2-positive ILCs were performed on a subgroup of 251 patients who underwent surgery for a primary ILC between 2005 and 2008. The mutational profile of these 251 cases was determined from RNAseq data. Compared with HER2-negative IBC-NSTs, the HER2-negative ILCs were found to display a higher frequency of HER2-zero cases (59.4% vs 53.7%) and a lower frequency of HER2-low (40.6% vs 46.3%) (P < .001). Clinicopathological features associated with HER2-low status (vs HER2-zero) in ILC were older age, postmenopausal status, nonclassic ILC histological types, higher grade, proliferation, and estrogen receptor expression levels. Survival curve analysis showed a significantly lower risk of local recurrence for HER2-low (vs HER2-zero) ILCs, but no association was found between HER2 status and either breast cancer–specific survival or distant metastasis-free interval. ERBB3 was the unique mutated gene exclusively associated with HER2-low ILCs yet being mutated at a low frequency (7.1%) (false discovery rate < 0.05). In conclusion, HER2-low ILCs exhibit their own particularities, both on clinical–pathological and molecular levels. Our findings call for larger multicenter validation studies.

Preoperative treatment with mFOLFIRINOX or Gemcitabine/Nab-paclitaxel +/- isotoxic high-dose stereotactic body Radiation Therapy (iHD-SBRT) for borderline resectable pancreatic adenocarcinoma (the STEREOPAC trial): study protocol for a randomised comparative multicenter phase II trial

BackgroundFor patients with pancreatic ductal adenocarcinoma (PDAC), surgical resection remains the only potentially curative treatment. Surgery is generally followed by postoperative chemotherapy associated with improved survival, yet neoadjuvant therapy is a rapidly emerging concept requiring to be explored and validated in terms of treatment options and oncological outcomes. In this context, stereotactic body radiation (SBRT) appears feasible and can be safely integrated into a neoadjuvant chemotherapy regimen of modified FOLFIRINOX (mFFX) with promising benefits in terms of R0 resection, local control and survival. However, the optimal therapeutic sequence is still not known, especially for borderline resectable PDAC, and the role of adding SBRT to chemotherapy in the neoadjuvant setting needs to be evaluated in randomised controlled trials. The aim of the STEREOPAC trial is to assess the impact and efficacy of adding isotoxic high-dose SBRT (iHD-SBRT) to neoadjuvant mFFX or Gemcitabine/Nab-Paclitaxel (Gem/Nab-P) in patients with borderline resectable PDAC.MethodsThis is a randomised comparative multicentre phase II trial, planning to enrol patients (n = 256) diagnosed with a borderline resectable biopsy-confirmed PDAC. Patients will receive 4 cycles of mFFX (or 6 doses of Gem/Nab-P). After full disease restaging, non-progressive patients will be randomised for receiving either 4 additional mFFX cycles (or 6 doses of Gem/Nab-P) (Arm A), or 2 mFFX cycles (or 3 doses of Gem/Nab-P) + iHD-SBRT (35 to 55 Gy in 5 fractions) + 2 mFFX cycles (or 3 doses of Gem/Nab-P) (Arm B). Then curative surgery will be performed followed by adjuvant chemotherapy according to patient’s condition. The co-primary endpoints are R0 resection and disease-free survival after the complete sequence strategy. The secondary endpoints include resection rate, overall survival, locoregional failure / distant metastasis free interval, pathologic complete response, toxicity, postoperative complications and quality of life assessment.DiscussionThis trial will help define the best neoadjuvant treatment sequence for borderline resectable PDAC and aims to evaluate if a total neoadjuvant treatment integrating iHD-SBRT improves the patients’ oncological outcomes.Trial registrationThe study was registered at ClinicalTrails.gov (NCT05083247) on October 19th, 2021, and in the Clinical Trials Information System (CTIS) EU CT database (2022-501181-22-01) on July 2022.

Whole Breast Irradiation in Comparison to Endocrine Therapy in Early Stage Breast Cancer-A Direct and Network Meta-Analysis of Published Randomized Trials.

Multiple randomized trials have established adjuvant endocrine therapy (ET) and whole breast irradiation (WBI) as the standard approach after breast-conserving surgery (BCS) in early-stage breast cancer. The omission of WBI has been studied in multiple trials and resulted in reduced local control with maintained survival rates and has therefore been adapted as a treatment option in selected patients in several guidelines. Omitting ET instead of WBI might also be a valuable option as both treatments have distinctly different side effect profiles. However, the clinical outcomes of BCS + ET vs. BCS + WBI have not been formally analyzed. We performed a systematic literature review searching for randomized trials comparing BCS + ET vs. BCS + WBI in low-risk breast cancer patients with publication dates after 2000. We excluded trials using any form of chemotherapy, regional nodal radiation and mastectomy. The meta-analysis was performed using a two-step process. First, we extracted all available published event rates and the effect sizes for overall and breast-cancer-specific survival (OS, BCSS), local (LR) and regional recurrence, disease-free survival, distant metastases-free interval, contralateral breast cancer, second cancer other than breast cancer and mastectomy-free interval as investigated endpoints and compared them in a network meta-analysis. Second, the published individual patient data from the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) publications were used to allow a comparison of OS and BCSS. We identified three studies, including a direct comparison of BCS + ET vs. BCS + WBI (n = 1059) and nine studies randomizing overall 7207 patients additionally to BCS only and BCS + WBI + ET resulting in a four-arm comparison. In the network analysis, LR was significantly lower in the BCS + WBI group in comparison with the BCS + ET group (HR = 0.62; CI-95%: 0.42-0.92; p = 0.019). We did not find any differences in OS (HR = 0.93; CI-95%: 0.53-1.62; p = 0.785) and BCSS (OR = 1.04; CI-95%: 0.45-2.41; p = 0.928). Further, we found a lower distant metastasis-free interval, a higher rate of contralateral breast cancer and a reduced mastectomy-free interval in the BCS + WBI-arm. Using the EBCTCG data, OS and BCSS were not significantly different between BCS + ET and BCS + WBI after 10 years (OS: OR = 0.85; CI-95%: 0.59-1.22; p = 0.369) (BCSS: OR = 0.72; CI-95%: 0.38-1.36; p = 0.305). Evidence from direct and indirect comparison suggests that BCS + WBI might be an equivalent de-escalation strategy to BCS + ET in low-risk breast cancer. Adverse events and quality of life measures have to be further compared between these approaches.

Abstract P4-02-20: Utility of the 70-gene signature and 10 year follow up in patients with early-stage breast cancer in a single institution study

Abstract Introduction: Genomic tests are routinely used by clinicians to guide treatment decisions in early-stage breast cancer (EBC). The 70-gene MammaPrint assay (MP) assesses the risk of distant recurrence in untreated patients with EBC and categorizes the tumors as High Risk (HR, MP index: -1 to ≤0) or Low Risk (LR, &amp;gt;0 to +1). The LR category is further divided into Low but non-UltraLow (LNUL; &amp;gt;0 to ≤0.355) and UltraLow Risk (UL; &amp;gt;0.355 to 1). Here, we report the risk of distant recurrence by MP and 10-year outcomes in patients with EBC diagnosed at Magee Women’s Hospital of the University of Pittsburgh Medical Center. Methods: In this retrospective analysis, 259 women diagnosed with EBC between 2005 and 2008, who received a MP result, were included. Patient clinical and tumor characteristics were collected. The median FU was 13.1 year among patients with clinical data. Treatment received, 10-year Distant Metastasis Free Interval (DMFI) and 10-year Breast Cancer Specific Survival (BCSS) are reported according to the MP groups. Differences in DMFI and BCSS between MP risk groups were assessed by log-rank. Patients were treated at the physician’s discretion. Treatment was started prior to obtaining MammaPrint results. Results: Among the 259 patients, 69% were post-menopausal women (mean [range] age: 58 [31-81] years) and diagnosed with hormone receptor-positive HER2-negative tumors (90%), grade 1 or 2 (64%), and without lymph node invasion (93%). In this cohort, 69% (n = 159) had a MP LR result and 31% (n = 100) had a MP HR result. Overall, 14% (n = 35) of patients had a MP UL risk of recurrence of whom 74% (n = 26/35) were post-menopausal women. Substantially more patients received chemotherapy in the HR group (57%, n = 57) compared with the LR group (15%, n = 24) (table). Considering that treatment was initiated before MammaPrint results were known, MP results might have allowed chemotherapy de-escalation in in 15% (n = 24) of patients with a MP LR. Similarly, in the 39% (n = 39) of women with a MP HR treated with endocrine therapy only, knowledge of MP results could have provided important information to add chemotherapy to the treatment plan.. In the MP UL group, 74 % (n = 26) of patients were treated with endocrine therapy only compared with those who received chemotherapy (9%, n = 3) and no adjuvant treatment (9%, n = 3). The 10-year DMFI and 10-year BCSS were higher in the LR compared with the HR group (table). When further stratifying the MP LR group in LNUL and UL, the 10y DMFI was 0.97 (95% CI; 0.94 – 1.00) and 1.00 for the MP LNUL and UL groups, respectively. Within the first 10 years, 8 of the 10 distant recurrences observed were in the MP HR group, and 2 were in the MP LNUL group. Among the 18 recorded deaths, 5 were breast cancer-related, 4 in the MP HR and 1 in the MP LR (LNUL) groups. Discussion: In this single-institution retrospective analysis, all patients showed excellent BCSS and DMFI outcomes confirming the ability of MP to correctly predict the good prognosis (LR) and poor prognosis (HR) in patients with EBC. In this analysis, as observed in other cohorts, women with a MP UL risk result had an excellent prognosis at 10 years while being treated mostly with endocrine therapy only. Taken together, with the low endocrine therapy adherence reported in the literature, these data suggest that patients with a MP UL result may be candidates for further treatment de-escalation to optimize the risk/benefit ratio of endocrine therapy in future studies. Table 1. Clinical outcomes and treatment received in patients stratified by MammaPrint results * Patients were treated at the physician’s discretion a p = 0.011, MP LR vs MP HR. b p = 0.032, MP UL vs LNUL vs HR. c p = 0.061 MP LR vs MP HR. d p = 0.170, MP UL vs LNUL vs HR. Citation Format: Azadeh Nasrazadani, Juan L. Gomez Marti, Margaret Q. Rosenzweig, Meghan McGuire, Katie Quinn, Josien Haan, Alexandre Houzelle, Rohit Bhargava, William Audeh, Adam M. Brufsky. Utility of the 70-gene signature and 10 year follow up in patients with early-stage breast cancer in a single institution study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-20.

Determinants of Long-Term Survival in Metastatic Choroidal and Ciliary Body Melanoma

To build and validate a prognostic model that predicts long-term overall survival (OS) in metastatic choroidal and ciliary body melanoma (CCBM) to facilitate patient counseling and planning, reporting, and interpreting clinical trials. Retrospective cohort study with validation. We analyzed predictors of intermediate (IMT; 25-<42 months) and long-term (LT; ≥42 months) OS in a Finnish nationwide cohort of 330 patients with metastatic CCBM. Short-term (<25 months), IMT, and LT survival were compared with pairwise and ordinal logistic regression. A single-center cohort of 259 patients from Italy was used for validation. Models were compared with a deviance test. Median OS was 12 and 17 months in the building and validation datasets, respectively; 40 (12%) and 31 (9%) compared with 44 (17%) and 32 (12%) patients were IMT and LT survivors, respectively. Alkaline phosphatase or lactate dehydrogenase level never exceeded 2 times the upper normal limit (UNL) in either LT cohort. Conditional to both being ≤2 times the UNL, distant metastasis-free interval (DMFI) >42 months (odds ratio [OR] 4.09-4.64; P < .001) paired with age <60 years (OR 3.23; P=.002), having no symptoms (OR 4.19; P=.005), and the largest diameter of the largest metastasis <30 mm (Tumor, Node, Metastasis stage M1a; OR 3.05; P=.001) independently predicted higher odds of surviving longer (IMT or LT) without model preference. These results were confirmed in the validation dataset. Alkaline phosphatase or lactate dehydrogenase >2 times the UNL essentially precluded LT survival. The most robust predictor otherwise was DMFI >42 months, followed by age <60 years, absence of symptoms, and Tumor, Node, Metastasis stage M1a.

Associations of a breast cancer polygenic risk score with tumor characteristics and survival.

563 Background: A polygenic risk score (PRS) consisting of 313 single nucleotide polymorphisms (PRS313) is associated with risk of breast cancer and contralateral breast cancer. One of the most promising clinical applications for the use of PRS is to provide a personalized risk assessment to individualize breast cancer screening programs. This study aimed to evaluate the association of the PRS313 with clinical-pathological characteristics and survival of breast cancer. Methods: Women of European ancestry with invasive breast cancer were included, 98,397 women from the Breast Cancer Association Consortium (BCAC) and 683 women from the MINDACT trial. Associations between PRS313 (continuous, per SD) and clinical-pathological characteristics, including the 70-gene signature for patients included in MINDACT, were evaluated with logistic regression analyses. Associations of PRS313 with overall survival (OS), breast cancer-specific survival (BCSS) and distant metastasis-free interval (DMFI) were evaluated with Cox regression analyses, adjusted for clinical-pathological characteristics and treatment. Results: The PRS313 was associated with favorable tumor characteristics. In BCAC, increasing PRS313 was mostly associated with lower grade, hormone receptor-positive tumors, and with smaller tumor size. In MINDACT, PRS313 was associated with a low risk 70-gene signature, but the association was attenuated after adjustment for clinical-pathological characteristics. In BCAC, univariable analyses showed an association of PRS313 with better survival, hazard ratio (HR) per unit SD increase of PRS313 for OS: 0.96 (95% confidence interval (CI): 0.94-0.97), for BCSS HR: 0.96 (95% CI: 0.94-0.98) and for DMFI HR: 0.98 (95% CI: 0.96-1.00). The association in the unadjusted analysis was explained by differences in clinical-pathological characteristics (and treatment) and disappeared after adjustment: OS HR: 1.01 (95% CI: 0.98-1.05), BCSS HR: 1.02 (95% CI: 0.98-1.07) and DMFI HR: 1.03 (95% CI: 0.99-1.07). Conclusions: An increased PRS313 is associated with favorable tumor characteristics but was not independently associated with prognosis. This information is crucial input for modelling effective stratified screening programs, especially in the current era of optimized (systemic) treatments. Given the significant increase in breast cancer risk associated with increasing PRS313, absolute breast cancer mortality will still be higher for women with higher PRS313.

Outcome of Patients With an Ultralow-Risk 70-Gene Signature in the MINDACT Trial.

Patients with 70-gene signature ultralow-risk breast cancers have shown excellent survival in historic cohorts, including randomized trials. The ultralow-risk subgroup was characterized to help avoid overtreatment. We evaluated outcomes of ultralow-risk patients in the largest cohort to date. Of the 6,693 patients enrolled in the EORTC-10041/BIG-3-04 randomized phase III MINDACT trial, profiling revealed an ultralow-risk 70-gene signature in 1,000 patients (15%). Distant metastasis-free interval (DMFI) and breast cancer-specific survival (BCSS) were assessed in patients stratified by 70-gene signature result (high, low, and ultralow) by Kaplan-Meier analysis and hazard ratios with 95% CI from Cox regression. Median follow-up was 8.7 years. Of the ultralow-risk patients (n = 1,000), 67% were > 50 years, 81% had tumors ≤ 2 cm, 80% were lymph node-negative, 96% had grade 1 or 2 tumors, and 99% were estrogen receptor (ER)-positive. Systemic therapy was received by 84% of patients (69% endocrine therapy, 14% endocrine therapy plus chemotherapy, 1% other) and 16% received no adjuvant systemic treatment. The 8-year DMFI for ultralow-risk patients was 97.0% (95% CI, 95.8 to 98.1), which was 2.5% higher than for patients with low-risk tumors (n = 3,295, 94.5% [95% CI, 93.6 to 95.3]). The hazard ratio for DMFI was 0.65 (95% CI, 0.45 to 0.94) for ultralow versus low risk, after adjusting for clinical-pathologic and treatment characteristics. The 8-year BCSS for ultralow-risk patients was 99.6% (95% CI, 99.1 to 100). Patients with an ultralow-risk 70-gene signature have the best prognosis, distinctive from low risk, with 8-year BCSS above 99%, and very few patients developed distant metastases with an 8-year DMFI rate of 97%. These patients could be candidates for further de-escalation of treatment, to avoid overtreatment and the risk of side effects.

Outcome without any adjuvant systemic treatment in stage I ER+/HER2− breast cancer patients included in the MINDACT trial

Adjuvant systemic treatments (AST) reduce mortality, but have associated short- and long-term toxicities. Careful selection of patients likely to benefit from AST is needed. We evaluated outcome of low-risk breast cancer patients of the EORTC 10041/BIG 3-04 MINDACT trial who received no AST.Patients with estrogen receptor-positive, HER2-negative, lymph node-negative tumors ≤2 cm who received no AST were matched 1 : 1 to patients with similar tumor characteristics treated with adjuvant endocrine therapy (ET), using propensity score matching and exact matching on age, genomic risk (70-gene signature) and grade. In a post hoc analysis, distant metastasis-free interval (DMFI) and overall survival (OS) were assessed by Kaplan-Meier analysis and hazard ratios (HR) by Cox regression. Cumulative incidences of locoregional recurrence (LRR) and contralateral breast cancer (CBC) were assessed with competing risk analyses.At 8 years, DMFI rates were 94.8% [95% confidence interval (CI) 92.7% to 96.9%] in 509 patients receiving no AST, and 97.3% (95% CI 95.8% to 98.8%) in 509 matched patients who received only ET [absolute difference: 2.5%, HR 0.56 (95% CI 0.30-1.03)]. No statistically significant difference was seen in 8-year OS rates, 95.4% (95% CI 93.5% to 97.4%) in patients receiving no AST and 95.6% (95% CI 93.8% to 97.5%) in patients receiving only ET [absolute difference: 0.2%, HR 0.86 (95% CI 0.53-1.41)]. Cumulative incidence rates of LRR and CBC were 4.7% (95% CI 3.0% to 7.0%) and 4.6% (95% CI 2.9% to 6.9%) in patients receiving no AST versus 1.4% (95% CI 0.6% to 2.9%) and 1.5% (95% CI 0.6% to 3.1%) in patients receiving only ET.In patients with stage I low-risk breast cancer, the effect of ET on DMFI was limited, but overall significantly fewer breast cancer events were observed in patients who received ET, after the relatively short follow-up of 8 years. These benefits and side-effects of ET should be discussed with all patients, even those at a very low risk of distant metastasis.

Combining method of detection and 70-gene signature for enhanced prognostication of breast cancer.

Studies have shown that screen detection by national screening programs is independently associated with better prognosis of breast cancer. The aim of this study is to evaluate the association between tumor biology according to the 70-gene signature (70-GS) and survival of patients with screen-detected and interval breast cancers. All Dutch breast cancer patients enrolled in the MINDACT trial (EORTC-10041/BIG3-04) accrued 2007-2011, who participated in the national screening program (biennial screening, ages 50-75) were included (n = 1102). Distant Metastasis-Free Interval (DMFI) was evaluated according to the 70-GS for patients with screen-detected (n = 754) and interval cancers (n = 348). Patients with screen-detected cancers had 8-year DMFI rates of 98.2% for 70-GS ultralow-, 94.6% for low-, and 93.8% for high-risk tumors (p = 0.4). For interval cancers, there was a significantly lower 8-year DMFI rate for patients with 70-GS high-risk tumors (85.2%) compared to low- (92.2%) and ultralow-risk tumors (97.4%, p = 0.0023). Among patients with 70-GS high-risk tumors, a significant difference in 8-year DMFI rate was observed between interval (85.2%, n = 166) versus screen-detected cancers (93.8%, n = 238; p = 0.002) with a HR of 2.3 (95%CI 1.2-4.4, p = 0.010) adjusted for clinical-pathological characteristics and adjuvant systemic treatment. Among patients with 70-GS high-risk tumors, a significant difference in DMFI was observed between screen-detected and interval cancers, suggesting that method of detection is an additional prognostic factor in this subgroup and should be taken into account when deciding on adjuvant treatment strategies.

Comparing Local and Systemic Control between Partial- and Whole-Breast Radiotherapy in Low-Risk Breast Cancer-A Meta-Analysis of Randomized Trials.

Simple SummaryThis meta-analysis compares the treatment results of partial-breast radiotherapy to those of whole-breast radiotherapy after breast conserving surgery in early-stage breast cancer. The results show that the tumor is slightly more likely to recur in the operated breast after partial radiotherapy compared to radiation therapy to the whole breast. These additional recurrences are located away from the original tumor bed. The technique by which partial-breast radiotherapy is applied also appears to affect the likeliness of tumor regrowth. Intraoperative radiation, given during the removal of the tumor, might lead to more relapses compared to other techniques. Partial-breast treatment also led to more lymph node recurrences in a very small number of patients. However, rates of distant relapses were not increased. We were unable to identify a specific subgroup that was most suitable for partial-breast irradiation. The differences between treatment of partial- and whole-breast radiotherapy are small when the patient groups and the radiation technique are appropriately selected.Purpose/Objective: The standard treatment for localized low-risk breast cancer is breast-conserving surgery, followed by adjuvant radiotherapy and appropriate systemic therapy. As the majority of local recurrences occur at the site of the primary tumor, numerous trials have investigated partial-breast irradiation (PBI) instead of whole-breast treatment (WBI) using a multitude of irradiation techniques and fractionation regimens. This meta-analysis addresses the impact on disease-specific endpoints, such as local and regional control, as well as disease-free survival of PBI compared to that of WBI in published randomized trials. Material and Methods: We conducted a systematic literature review and searched for randomized trials comparing WBI and PBI in early-stage breast cancer with publication dates after 2009. The meta-analysis was based on the published event rates and the effect sizes for available oncological endpoints of at least two trials reporting on them. We evaluated in-breast tumor recurrences (IBTR), local recurrences at the primary site and elsewhere in the ipsilateral breast, regional recurrences (RR), distant metastasis-free interval (DMFI), disease-free survival (DFS), contralateral breast cancer (CBC), and second primary cancer (SPC). Furthermore, we aimed to assess the impact of different PBI techniques and subgroups on IBTR. We performed all statistical analyses using the inverse variance heterogeneity model to pool effect sizes. Results: For the intended meta-analysis, we identified 13 trials (overall 15,561 patients) randomizing between PBI and WBI. IBTR was significantly higher after PBI (OR = 1.66; CI-95%: 1.07–2.58; p = 0.024) with an absolute difference of 1.35%. We detected significant heterogeneity in the analysis of the PBI technique with intraoperative radiotherapy resulting in higher local relapse rates (OR = 3.67; CI-95%: 2.28–5.90; p < 0.001). Other PBI techniques did not show differences to WBI in IBTR. Both strategies were equally effective at the primary tumor site, but PBI resulted in statistically more IBTRs elsewhere in the ipsilateral breast. IBTRs after WBI were more likely to be located at the primary tumor bed, whereas they appeared equally distributed within the breast after PBI. RR was also more frequent after PBI (OR = 1.75; CI-95%: 1.07–2.88; p < 0.001), yet we did not detect any differences in DMFI (OR = 1.08; CI-95%: 0.89–1.30; p = 0.475). DFS was significantly longer in patients treated with WBI (OR = 1.14; CI-95%: 1.02–1.27; p = 0.003). CBC and SPC were not different in the test groups (OR = 0.81; CI-95%: 0.65–1.01; p = 0.067 and OR = 1.09; CI-95%: 0.85–1.40; p = 0.481, respectively). Conclusion: Limiting the target volume to partial-breast radiotherapy appears to be appropriate when selecting patients with a low risk for local and regional recurrences and using a suitable technique.

Outcome of patients with an ultralow risk 70-gene signature in the MINDACT trial.

500 Background: Gene signatures have proven successful in identifying patients with a low risk of distant recurrence who could forego chemotherapy (CT) and are currently included in international treatment guidelines for breast cancer. For the 70-gene signature (MammaPrint) an additional threshold was established within the low risk category to identify patients with an ultralow risk of distant recurrence. In independent cohorts, these patients had excellent breast cancer specific survival at 15 years, suggesting that ultralow risk cancers represent indolent disease (Esserman, JAMA Oncol 2017, Delahaye, BC Res Treat 2017). Here we evaluate survival of patients with an ultralow risk 70-gene signature who participated in the randomized phase 3 MINDACT trial (Piccart, Lancet Oncol 2021). Methods: Of the 6,693 patients enrolled in the MINDACT trial (EORTC 10041/BIG 3-04) between 2007-2011, profiling revealed an ultralow risk 70-gene signature in 1,000 patients (15%). We assessed 5- and 8-year distant metastasis free interval (DMFI) and breast cancer specific survival (BCSS) in patients stratified by 70-gene signature result (high, low, ultralow), and within the ultralow risk group stratified by clinical risk. For these exploratory analyses, we used Kaplan-Meier estimates for time to event endpoints and Cox-regression models to calculate hazard ratio’s (HR). Results: Median follow-up was 8.7 years. Among the ultralow risk patients (n = 1,000), 67% were ≥50 years, 81% had tumors &lt; 2cm, 80% were lymph node negative, 96% had grade 1 or 2 tumors and 99% were ER-positive. Systemic therapy was received by 83% of patients (69% endocrine therapy (ET), 14% ET + CT) and 16% received no adjuvant systemic treatment (AST). Survival estimates for all endpoints are shown in the table; 8-year DMFI was 97.0% (95% CI 95.8-98.1) for ultralow risk. The 8-year DMFI in ultralow risk patients who received no AST or ET only was 97.8% (95% CI 95.3-100) and 97.4% (95% CI 96.1-98.7), respectively. The HR for DMFI was 0.66 (95% CI 0.46-0.95) for ultralow vs low risk, after adjusting for tumor and treatment characteristics (preliminary results). Conclusions: In this prospective study, patients with an ultralow risk 70-gene signature have an excellent prognosis with 8-year BCSS above 99% regardless of clinical risk status, and with an 8-year DMFI of 95-98%.[Table: see text]

Abstract GS4-11: How low is low risk: MINDACT updated outcome and treatment benefit in patients considered clinical low risk and stratified by genomic signature, age and nodal status

Abstract Background With 8.7 years follow-up, the prospective phase III randomized MINDACT trial (EORTC 10041/BIG3-04) continues to meet its primary objective, i.e. 95.1% (95%CI 93.1-96.6), 5-year distant metastasis-free survival (DMFS) in clinical high (C-High)/genomic low (G-Low) risk patients who did not receive adjuvant chemotherapy (ACT) (Cardoso et al., ASCO 2020). In addition, about half of the MINDACT patients had a low clinical risk (C-Low) defined by pre-specified clinical-pathological characteristics. Here, we evaluated the outcome of this C-Low population stratified by the 70-gene signature (MammaPrint®) (G-Low or G-High) for outcome considering age, and present data on the total G-low population (C-Low and C-High combined). Methods Of 6693 patients enrolled in the MINDACT trial between 2007 and 2011, 3337 were C-Low, characterized as mainly T1, grade 1 or 2, and node negative. We evaluated the pre-specified DMFS, distant metastasis free interval (DMFI), and overall survival (OS) rates at 5 and 8 years in the C-Low population: i) in patients with genomic low risk (C-Low/G-Low, n=2744) who were recommended to receive endocrine therapy only (for 99% HR+), and ii) in C-Low/G-High who received ACT or not following randomization (ITT, n=690, 81% HR+). Exploratory analyses by age, ≤50 and &amp;gt;50, were conducted for ACT vs no ACT received in C-Low/G-High. In parallel we estimated survival rates for all G-low patients if all would have followed the genomic low risk assignment and received no ACT (C-Low/G-Low, and C-High/G-Low randomized to no ACT double weighted, n=4130). We used Kaplan-Meier estimates for time to event endpoints and hazard ratios with 95%CI from Cox-regression models adjusted for stratification factors used for the randomization. Results C-low/G-low patients who were recommended endocrine therapy only (compliance &amp;gt; 79%, based on local guidelines) have excellent 5 and 8 year survival rates for all endpoints (Table 1). The estimated survival rates for all G-Low patients, if all would have followed the genomic low risk assignment and received no ACT, is excellent as well (Table 1), albeit this population includes both C-Low and C-High patients. The survival estimates for C-Low/G-High patients are for all endpoints a few percentage points lower than for the C-Low/G-Low group (Table 1). At 8 years of follow-up, in the relatively small subset of 690 patients with C-Low/G-High tumors assigned to ACT or not by randomization (ITT), a 1.5% (SE ±2.3%) higher DMFS is seen in the ACT group, and a 2.9% (SE ±2.0%) higher DMFI. This suggested benefit is mostly seen in patients under 50 years of age (absolute Δ in DMFS for ACT vs no ACT at 8 years: 5.4% for age ≤50 vs -0.3% for age &amp;gt;50). Conclusion Patients with a 70-gene G-Low risk tumor have an excellent 8 year outcome in the context of C-Low characteristics when recommended for endocrine therapy only, very close to the outcome in the larger group of all G-Low patients regardless of clinical risk. Stratification of C-Low patients in to G-Low and G-high provides meaningful information. The benefit of ACT in C-Low patients with a 70-gene G-High risk tumor needs further confirmation, especially relevant in younger women. Table 1All Patients PopulationPatientsObserved events% at 5 years (95% CI)% at 8 years (95% CI)DMFSC-Low / G-Low274417097.3 (96.6-97.9)94.7 (93.8-95.6)C-Low / G-High5936194.2 (92.0-95.9)91.1 (88.4-93.3)DMFIC-Low / G-Low274410398.5 (97.9-98.9)96.7 (95.9-97.3)C-Low / G-High5934695.8 (93.8-97.2)93.5 (91.0-95.3)OSC-Low / G-Low274412298.2 (97.6-98.7)96.5 (95.7-97.2)C-Low / G-High5934496.8 (94.9-98.0)93.1 (90.5-95.0)Patients G-low (C-Low &amp; C-High)PatientsEstimated events% at 5 years% at 8 yearsDMFSAll G-Low - no ACT413033996.492.8DMFIAll G-Low - no ACT413024497.494.6OSAll G-Low - no ACT413022397.995.7 Citation Format: Laura J van 't Veer, Fatima Cardoso, Coralie Poncet, Josephine Lopes Cardozo, Suzette Delaloge, Jean-Yves Pierga, Peter Vuylsteke, Etienne Brain, Giuseppe Viale, Sherko Kümmel, Isabel T Rubio, Gabriele Zoppoli, Alistair Thompson, Erika Matos, Khalil Zaman, Susan Knox, Florentine Hilbers, Aleksandra Peric, Bart Meulemans, Martine Picccart, Emiel J Th Rutgers. How low is low risk: MINDACT updated outcome and treatment benefit in patients considered clinical low risk and stratified by genomic signature, age and nodal status [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 GS4-11.

Abstract PS6-01: How low is low risk: MINDACT updated outcome and treatment benefit in patients considered clinical low risk and stratified by genomic signature, age and nodal status

Abstract Background With 8.7 years follow-up, the prospective phase III randomized MINDACT trial (EORTC 10041/BIG3-04) continues to meet its primary objective, i.e. 95.1% (95%CI 93.1-96.6), 5-year distant metastasis-free survival (DMFS) in clinical high (C-High)/genomic low (G-Low) risk patients who did not receive adjuvant chemotherapy (ACT) (Cardoso et al., ASCO 2020). In addition, about half of the MINDACT patients had a low clinical risk (C-Low) defined by pre-specified clinical-pathological characteristics. Here, we evaluated the outcome of this C-Low population stratified by the 70-gene signature (MammaPrint®) (G-Low or G-High) for outcome considering age, and present data on the total G-low population (C-Low and C-High combined). Methods Of 6693 patients enrolled in the MINDACT trial between 2007 and 2011, 3337 were C-Low, characterized as mainly T1, grade 1 or 2, and node negative. We evaluated the pre-specified DMFS, distant metastasis free interval (DMFI), and overall survival (OS) rates at 5 and 8 years in the C-Low population: i) in patients with genomic low risk (C-Low/G-Low, n=2744) who were recommended to receive endocrine therapy only (for 99% HR+), and ii) in C-Low/G-High who received ACT or not following randomization (ITT, n=690, 81% HR+). Exploratory analyses by age, ≤50 and &amp;gt;50, were conducted for ACT vs no ACT received in C-Low/G-High. In parallel we estimated survival rates for all G-low patients if all would have followed the genomic low risk assignment and received no ACT (C-Low/G-Low, and C-High/G-Low randomized to no ACT double weighted, n=4130). We used Kaplan-Meier estimates for time to event endpoints and hazard ratios with 95%CI from Cox-regression models adjusted for stratification factors used for the randomization. Results C-low/G-low patients who were recommended endocrine therapy only (compliance &amp;gt; 79%, based on local guidelines) have excellent 5 and 8 year survival rates for all endpoints (Table 1). The estimated survival rates for all G-Low patients, if all would have followed the genomic low risk assignment and received no ACT, is excellent as well (Table 1), albeit this population includes both C-Low and C-High patients. The survival estimates for C-Low/G-High patients are for all endpoints a few percentage points lower than for the C-Low/G-Low group (Table 1). At 8 years of follow-up, in the relatively small subset of 690 patients with C-Low/G-High tumors assigned to ACT or not by randomization (ITT), a 1.5% (SE ±2.3%) higher DMFS is seen in the ACT group, and a 2.9% (SE ±2.0%) higher DMFI. This suggested benefit is mostly seen in patients under 50 years of age (absolute Δ in DMFS for ACT vs no ACT at 8 years: 5.4% for age ≤50 vs -0.3% for age &amp;gt;50). Conclusion Patients with a 70-gene G-Low risk tumor have an excellent 8 year outcome in the context of C-Low characteristics when recommended for endocrine therapy only, very close to the outcome in the larger group of all G-Low patients regardless of clinical risk. Stratification of C-Low patients in to G-Low and G-high provides meaningful information. The benefit of ACT in C-Low patients with a 70-gene G-High risk tumor needs further confirmation, especially relevant in younger women. Table 1All Patients PopulationPatientsObserved events% at 5 years (95% CI)% at 8 years (95% CI)DMFSC-Low / G-Low274417097.3 (96.6-97.9)94.7 (93.8-95.6)C-Low / G-High5936194.2 (92.0-95.9)91.1 (88.4-93.3)DMFIC-Low / G-Low274410398.5 (97.9-98.9)96.7 (95.9-97.3)C-Low / G-High5934695.8 (93.8-97.2)93.5 (91.0-95.3)OSC-Low / G-Low274412298.2 (97.6-98.7)96.5 (95.7-97.2)C-Low / G-High5934496.8 (94.9-98.0)93.1 (90.5-95.0)Patients G-low (C-Low &amp; C-High)PatientsEstimated events% at 5 years% at 8 yearsDMFSAll G-Low - no ACT413033996.492.8DMFIAll G-Low - no ACT413024497.494.6OSAll G-Low - no ACT413022397.995.7 Citation Format: Laura J van 't Veer, Fatima Cardoso, Coralie Poncet, Josephine Lopes Cardozo, Suzette Delaloge, Jean-Yves Pierga, Peter Vuylsteke, Etienne Brain, Giuseppe Viale, Sherko Kümmel, Isabel T Rubio, Gabriele Zoppoli, Alistair Thompson, Erika Matos, Khalil Zaman, Susan Knox, Florentine Hilbers, Aleksandra Peric, Bart Meulemans, Martine Picccart, Emiel J Th Rutgers. How low is low risk: MINDACT updated outcome and treatment benefit in patients considered clinical low risk and stratified by genomic signature, age and nodal status [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 PS6-01.

Abstract PS11-01: Outcome without adjuvant systemic treatment in breast cancer patients included in the MINDACT trial

Abstract Background: Adjuvant systemic treatments have played an important role in the decline of breast cancer mortality over the years. Because of the extensive short- and long-term toxicities associated with these treatments, careful selection of patients likely to benefit from them is needed. Studies have shown excellent survival in subgroups of patients receiving no adjuvant systemic treatments. Some national guidelines advise no adjuvant systemic treatments in specific groups of patients with clinical low risk breast cancer. The aim of this study is to investigate the survival of breast cancer patients who received no adjuvant treatment (chemotherapy nor endocrine therapy) using data from the EORTC 10041/BIG 3-04 MINDACT trial. Material and methods: Of the 6693 patients enrolled in the MINDACT trial, accrued 2007-2011, 509 patients with hormone receptor positive, HER2 negative, lymph node negative tumors &amp;lt;2cm received no adjuvant systemic treatment, mostly following local recommendations. Median follow-up was 8.7 years. Using propensity score matching and exact matching, we will identify groups of patients treated with adjuvant endocrine therapy and/or chemotherapy with similar tumor characteristics to the untreated patients. We will use the Kaplan-Meier method to estimate distant metastasis free interval and overall survival at 5 and 8 years for each group. Differences between groups will be evaluated using the log-rank test, and hazard ratios with 95% CI derived from Cox proportional hazards models. Planned analyses: The long-term data of the MINDACT trial has recently become available. The date of planned analysis is August 10th 2020.For this study, the primary clinical endpoint will be distant metastasis free interval, which will be assessed in the matched groups of untreated patients, patients who received endocrine therapy only, and patients who received chemotherapy with or without endocrine therapy. Kaplan-Meier estimates will be provided at 5 years, and at 8 years to assess the long-term outcomes in this population. A statistical plan for this analysis was specifically developed and approved prior to performing any analysis. Citation Format: Josephine MN Lopes Cardozo, Danalyn Byng, Caroline A Drukker, Marjanka K Schmidt, Laura J van 't Veer, Fatima Cardoso, Martine Piccart, Coralie Poncet, Emiel JTh Rutgers. Outcome without adjuvant systemic treatment in breast cancer patients included in the MINDACT 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 PS11-01.

Prognostic Factors for Premenopausal Women with Distant Metastatic Breast Cancer

Purpose Several studies have reported that the survival after distant metastasis in younger patients with breast cancer was similar to that in elderly patients. Moreover, few studies have observed better survival outcome after distant metastasis in younger patients with breast cancer. Here, we have identified the factors that affect the prognosis after distant metastasis in these patients. Methods We reviewed 7,157 patients that underwent primary breast cancer surgery between January 2003 and December 2013 at the Samsung Medical Center. Three hundred and thirty two premenopausal patients aged <50 years showed distant metastasis and were included in the analysis. For further analysis, the patients older or younger than 40 years were divided into 2 groups. Results There were no demographic differences in the patient characteristics such as clinical stage, nuclear grade, lymphovascular invasion, distant metastasis site, distant metastasis free interval (DMFI), except the estrogen receptor (ER) and progesterone receptor (PR) statuses, histopathology, and molecular subtype in both the groups (p-value=0.023, 0.035, 0.016, 0.046, respectively). The median follow-up period was 79.4 months. Next, we did not observe significant difference in the overall survival (OS) between the two groups (Log rank p-value=0.975). However, patients in the luminal A and luminal B group showed better OS than those in human epidermal growth factor receptor-2 (HER-2) positive, and triple-negative breast cancer (TNBC) group (Log-rank p-value<0.001). Furthermore, patients showed worse OS when they developed distant metastases within 36 months post-surgery (Log-rank p-value<0.001). In overall, age did not affect the survival outcome (p-value=0.547); however, the molecular subtype, DMFI, and distant metastasis sites showed significant differences in the patient outcome (p-value<0.001, respectively). Conclusion Our analysis suggests that the molecular subtype, DMFI, and distant metastasis site serve as useful predictors for prognosis in younger breast cancer patients with distant metastasis. However, age in these patients did not correlate well with mortality. Keywords: Breast neoplasms; Neoplasm metastasis; Premenopause; Prognosis; Survival

Comparison of Carboplatin With 5-Fluorouracil vs. Cisplatin as Concomitant Chemoradiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma.

Background: Chemoradiotherapy (CRT) including three cycles of cisplatin is considered the standard of care for locally advanced head and neck squamous cell carcinoma (LA-HNSCC). However, around one-third of the patients cannot complete cisplatin because of toxicity. Carboplatin plus 5-fluorouracil (carbo-5FU) is another accepted treatment option with a different toxicity profile. We compared tolerability and efficacy of concomitant carbo-5FU and cisplatin.Patients and Methods: We conducted a retrospective analysis of LA-HNSCC patients treated with CRT in two Dutch cancer centers between 2007 and 2016. All patients received intensity-modulated radiotherapy. One center routinely administered carboplatin 300–350 mg/m2 at day 1, 22, and 43 followed by 5FU 600 mg/m2/day for 96 h. The other center used cisplatin 100 mg/m2 at day 1, 22, and 43. The primary endpoint of this study was chemotherapy completion rate. Secondary endpoints included overall survival (OS), disease-free survival (DFS), locoregional control (LRC) and distant metastasis–free interval (DMFS), toxicity, and unplanned admissions.Results: In the carbo-5FU cohort (n = 211), 60.2% of the patients completed chemotherapy vs. 76.7% (p < 0.001) of the patients in the cisplatin cohort (n = 223). Univariate analysis showed a higher risk of death in the carbo-5FU cohort [hazard ratio (HR) 1.53, 95% CI, 1.09–2.14, p = 0.01] with a 3-year OS of 65.4 vs. 76.5% for cisplatin. OS was independently associated with T and N stage and p16 status, but not with chemotherapy regimen (HR 1.08, 95% CI, 0.76–1.55, p = 0.65). Three-year DFS was 70.0% for carbo-5FU vs. 78.6% for cisplatin (HR 1.37, 95% CI, 0.93–2.01, p = 0.05). A similar outcome was observed for both LRC (HR 1.27, 95% CI, 0.74–2.09, p = 0.4) and DMFS (HR 1.08, 95% CI 0.62–1.90, p = 0.77). The risk of discontinuation for chemotherapy-associated toxicity was higher in the carbo-5FU cohort than in the cisplatin cohort (relative risk = 1.69).Conclusion: LA-HNSCC patients treated with concomitant carbo-5FU completed chemotherapy less frequently than patients treated with cisplatin. Treatment regimen was not an independent prognostic factor for OS.

Programmed death-ligand 1 gene expression is a prognostic marker in early breast cancer and provides additional prognostic value to 21-gene and 70-gene signatures in estrogen receptor-positive disease.

Gene and protein expression of programmed death‐ligand 1 (PD‐L1) are prognostic in early breast cancer (BC), but their prognostic information is inconsistent at least in some biological subgroups. The validated prognostic gene signatures (GS) in BC are mainly based on proliferation and estrogen receptor (ER)‐related genes. Here, we aimed to explore the prognostic capacity of PD‐L1 expression at the protein vs mRNA levels and to investigate the prognostic information that PD‐L1 can potentially add to routinely used GS. Gene expression data were derived from two early BC cohorts (cohort 1: 562 patients; cohort 2: 1081 patients). Tissue microarrays from cohort 1 were immunohistochemically (IHC) stained for PD‐L1 using the SP263 clone. GS scores (21‐gene, 70‐gene) were calculated, and likelihood‐ratio (LR) tests and concordance indices were used to evaluate the additional prognostic information for each signature. The immune cell composition was also evaluated using the CIBERSORT in silico tool. PD‐L1 gene and protein expressions were independently associated with better prognosis. In ER+/HER2− patients, PD‐L1 gene expression provided significant additional prognostic information beyond that of both 21‐GS [LR‐Δχ2 = 15.289 and LR‐Δχ2 = 8.812, P < 0.01 for distant metastasis‐free interval (DMFI) in cohorts 1 and 2, respectively] and 70‐GS score alone (LR‐Δχ2 = 18.198 and LR‐Δχ2 = 8.467, P < 0.01 for DMFI in cohorts 1 and 2, respectively). PD‐L1 expression was correlated with IHC‐determined CD3+ cells (r = 0.41, P < 0.001) and with CD8+ (r = 0.62, P < 0.001) and CD4+ memory activated (r = 0.66, P < 0.001) but not with memory resting (r = −0.063, P = 0.14) or regulatory (r = −0.12, P < 0.01) T cells in silico. PD‐L1 gene expression represents a promising favorable prognostic marker and can provide additional prognostic value to 21‐ and 70‐gene scores in ER+/HER2− BC.

282P - Identification of ultralow risk breast cancer patients (probable overdiagnosis)

BackgroundThe universalisation of mammographic screening has caused an increase in ultralow risk breast cancer diagnosis. Identifying subgroups with no events related to mortality due to breast cancer in the long term (overdiagnosis) may be useful so as not to subject them to unnecessary treatment (overtreatment). MethodsNew ultralow risk criteria are described by means of mammographic screening diagnosis, tumour palpability, tumour phenotype, and absence of axillary node involvement. We identified patients with no events related to breast cancer mortality through a descriptive, observational, and retrospective study. ResultsAmong the 746 patients with stage I and IIA breast cancer attended between 1/1/2001 and 31/12/2014, 110 (14.75%) came from mammographic screening with non-palpable tumours. The median age was 58 years old (38-71). 88 (80%) were hormone receptor positive (HR+), 10 (9.10%) were triple negatives, and 11 (10%) were HER-2. The median follow-up was 10 years (3.5-17). Only 3 patients developed metastasis, there were no loco-regional recurrence, 7 showed second primary tumours, and there were 4 deaths, 2 due to breast cancer and 2 due to other reasons. Overall survival (OS) was 92.80%, disease-free survival (DFS) was 85.20%, and the distant metastasis-free interval (DMFI) was 95.60%. In 88 patients with HR+ tumours, OS was 95.7%, DFS was 86.50%, and DMFI was 96.30%. In 34 (38.60%) histological grade 1HR+ tumours (probably Luminal A), and in 54 (61.40%) histological grade 2-3HR+ tumours (probably Luminal B), OS was 93.80% and 96.90% (p=0.669), DFS was 81.90% and 89.30% (p=0.400), and DMFI was 100% and 94.40% (p=0.307). In triple negatives, OS was 85.70%, DFS 77.10%, and DMFI was 100%. In subgroup HER-2, there were no events. In tumours smaller and larger than 1cm, OS was 100% and 90.20% (p=0.168), DFS was 93.20% and 84.10% (p=0.742), and DMFI was 100% and 95.50% (p=0.296). ConclusionsPatients with non-palpable tumours detected in mammographic screening have an ultralow risk. The absence of events related to breast cancer mortality makes them candidates for overdiagnosis. De-escalation of treatment should be considered. The authors will incorporate genomic risk to optimise the identification of overdiagnosis. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.