Intermediate-risk Breast Cancer Research Articles

Are education and cohabitation associated with health-related quality of life and self-management during breast cancer follow-up? A longitudinal study

Background Oncologist-led follow-up after breast cancer (BC) is increasingly replaced with less intensive follow-up based on higher self-management, which may overburden the less resourceful patients. We examined whether socioeconomic factors measured recently after the implementation of a new follow-up program for BC patients were associated with health-related quality of life (HRQoL) and self-management 12 months later. Methodology Between January and August 2017, we invited 1773 patients in Region Zealand, Denmark, to participate in baseline and 12 months follow-up questionnaires. The patients had surgery for low- and intermediate risk BC 1–10 years prior to the survey, and they had recently been allocated to the new follow-up program of either patient-initiated follow-up, or in-person or telephone follow-up with a nurse, based on patients’ preferences. We examined associations between socioeconomic factors (education and cohabitation) at baseline and two outcomes: HRQoL (EORTC QLQ-C30 and QLQ-BR23) and self-management factors (health care provider, confidence in follow-up, contact at symptoms of concern, and self-efficacy) at 12 months follow-up. Sensitivity analyses were performed according to time since diagnosis (≤ 5 > 5 years). Furthermore, we investigated whether treatment and self-management factors modified the associations. Results A total of 987 patients were included in the analyses. We found no statistically significant associations between socioeconomic factors and HRQoL, except in patients ≤ 5 years from diagnosis. For self-management patients with short education were more likely to report that they had not experience relevant symptoms of concern compared to those with medium/long education (OR 1.75 95% CI: 1.04; 2.95). We found no clear patterns indicating that treatment or self-management factors modified the associations between socioeconomics’ and HRQoL. Conclusion Overall socioeconomic factors did not influence HRQoL and self-management factors except for experiencing and reporting relevant symptoms of concern. Socioeconomic factors may, however, influence HRQoL in patients within five years of diagnosis.

Prognostic impact of 18F-FDG PET/CT in pathologic stage II invasive ductal carcinoma of the breast: re-illuminating the value of PET/CT in intermediate-risk breast cancer

BackgroundThe aim of this study is to investigate the impact of 18F-FDG PET/CT on prognosis of stage II invasive ductal carcinoma (IDC) of the breast primarily treated with surgery.MethodsThe clinical records of 297 consecutive IDC with preoperative PET/CT and pathologically staged II in surgery from 2013 to 2017 were retrospectively reviewed. The maximum standardized uptake value (SUVmax), peak standardized uptake value (SUVpeak), tumor-to-liver ratio (TLR), and metabolic tumor volume (MTV) were measured. Association of clinicopathologic factors (age, T stage, N stage, AJCC pathologic stage of IIA or IIB, pathologic prognostic stage, grade, hormonal receptor status, HER2 status, Ki-67, and adjuvant therapy) and PET parameters with DFS was assessed using the Cox proportional hazards model.ResultsThere were 35 recurrences and 10 deaths at a median follow-up of 49 months (range 0.8 ~ 87.3). All PET parameters were significantly associated with DFS in univariate analysis but in multivariate analysis, SUVpeak was the only factor significantly associated with DFS (hazard ratio 2.58, 95% confidence interval 1.29–5.15, P = 0.007). In cohorts with higher values of SUVpeak or TLR, patients who received adjuvant chemotherapy had significantly superior DFS.ConclusionMetabolic parameters derived from preoperative PET/CT was significantly associated with recurrence in stage II IDC primarily treated with surgery. PET/CT can be a powerful prognostic tool in conjunction with novel staging systems and current biomarkers for patients undergoing contemporary therapy. Our results urge to reconsider the currently underestimated value of PET/CT confined to diagnostic aspect and to newly recognize its prognostic impact in these intermediate-risk breast cancer.

Outcome analysis of primary breast cancer patients who declined adjuvant chemotherapy\u2014results from the prospective multi-center BRENDA II study

BackgroundThis study examined 5-year overall, recurrence and distant metastasis-free survival (OS, RFS, MFS) of high- and intermediate-risk breast cancer (BC) patients who declined guideline-recommended adjuvant chemotherapy (CHT).MethodsIn the prospective multicenter cohort study BRENDA II, patients with primary BC were sampled over a period of four years (2009–2012). A multi-professional team (tumorboard) discussed recommendation for adjuvant CHT according to the German guideline. Potential differences in 5 year survival were analyzed using Kaplan–Meier curves and Cox regression. The hazard ratios (HR) were adjusted for age, Charlson Comorbidity Score, American Society of Anesthesiologist (ASA) physical status classification, and endocrine therapy.ResultsA total of 759 patients were enrolled of which 688 could receive CHT according to the guidelines (n = 219 had a clear indication, in n = 304 it was possible). For 360 patients, the tumorboard advised to perform CHT, for 304 it advised against and in 24 cases, no decision was documented. Of those with a positive suggestion, 83% received CHT. Until 5 years after diagnosis, 57 patients were deceased, 41 had at least one distant metastasis and 29 a recurrence. There was no evidence for differences in OS and MFS in patients who declined CHT despite tumorboard recommendation (HR 3.5, 95% CI 0.8–15.1 for OS, HR 1.9, 95% 0.6–6.6 for MFS). Patients who received CHT had significantly better 5-year RFS compared to those who declined (HR 0.3, 95% CI 0.1–0.9, p = 0.03). There was no evidence for different survival in those who had no CHT because of comorbidity and those who declined actively, neither for OS, MFS nor RFS.ConclusionThe prospective BRENDA II study demonstrates benefit in RFS by guideline adherence in adjuvant breast cancer treatment, indicating prospectively the value of internationally validated guidelines in breast cancer care.

Trends in pegfilgrastim average sales price and cost-effectiveness of primary prophylaxis for patients at intermediate risk for febrile neutropenia.

58 Background: The introduction of biosimilar colony-stimulating factors has led to the reduction in prices for these historically expensive therapies. To understand the impact of recent pricing trends on delivering efficient care, the cost-effectiveness of primary prophylaxis (PP) versus secondary prophylaxis (SP) using pegfilgrastim was assessed in patients with breast cancer, non–small-cell lung cancer (NSCLC), and non-Hodgkin lymphoma (NHL) receiving potentially curative chemotherapy at intermediate risk for febrile neutropenia per NCCN guidelines. Methods: A Markov decision analytic model was constructed from the US payer perspective over a lifetime horizon to evaluate pegfilgrastim PP versus SP in patients with breast cancer, NSCLC, and NHL receiving curative chemotherapy at intermediate risk of FN. Modeled chemotherapy regimens were adjuvant docetaxel (breast cancer), adjuvant carboplatin/paclitaxel (NSCLC), and R-CHOP (NHL) representing baseline FN risk of 16%, 18%, and 18%, respectively. Historical average sales prices (ASP) according to the Centers for Medicare and Medicaid Services of all pegfilgrastim products were obtained from January 2017 to April 2021. When more than one pegfilgrastim product was available, the average ASP was used as the cost input for the model. Cost-effectiveness for the base case scenario of each cancer type was evaluated over the range of years for cost per quality-adjusted life year (QALY) gained. Results: Pegfilgrastim as PP vs. SP provided an additional 0.069, 0.112, and 0.166 QALYs for breast cancer, NSCLC, and NHL, respectively. The peak ASP for pegfilgrastim was $4,554 per 6 mg during July 2018. Afterwards, a linear regression observed a declining ASP of approximately $134 dollars every 3 months to $3,024 per 6 mg during April 2021. At peak ASP, the incremental cost-effectiveness ratios (ICERs) for pegfilgrastim PP in patients with breast cancer, NSCLC, and NHL were $200,320, $113,942, and $103,495 per QALY, respectively. For April 2021, the ICERs were $124,845, $67,294, and $57,269 per QALY, respectively (Table). Conclusions: The trend of decreasing pegfilgrastim ASP improved the cost-effectiveness of PP vs. SP across intermediate risk breast cancer, NHL, and NSCLC indications between July 2018 to April 2021. For the most recent ASP, PP was cost-effective at a willingness-to-pay threshold of $100,000/QALY for NSCLC and NHL, and $150,000/QALY for breast cancer. This analysis provides support to expand the use of growth factor PP to intermediate risk patients. [Table: see text]

Toxicity and cosmetic outcome after hypofractionated whole breast irradiation and boost-IOERT in early stage breast cancer (HIOB): First results of a prospective multicenter trial (NCT01343459)

Background and purposeTo assess the role of intraoperative radiation with electrons (IOERT) as tumor bed boost followed by hypofractionated whole breast irradiation (HWBI) after breast conserving surgery (BCS) of patients with low to intermediate risk breast cancer focusing on acute/late toxicity and cosmetic outcome. Material and methodsIn 2011, a prospective multicenter trial (NCT01343459) was started. Treatment consisted of BCS, IOERT (11.1 Gy) and HWBI (40.5 Gy in 15 fractions). In a single-arm design, 5-year IBR-rates are benchmarked by a sequential ratio test (SQRT) against best published evidences in 3 age groups (35–40 y, 41–50 y, >50 y). Acute/late toxicity and cosmesis were evaluated by validated scorings systems. ResultsOf 627 eligible patients, 44 were excluded, leaving 583 to analyze. After a median follow-up (FUP) of 45 months (range 0–74), for acute effects CTCAE-score 0/1 was noted in 91% (end of HWBI) and 92% (4 weeks later), respectively. Late toxicity Grading 0/1 (mean values, ranges) by LENT-SOMA criteria were observed in 92.7% (89–97.3) at 4/5 months, rising to 96.5% (91–100) at 6 years post HWBI. Baseline cosmesis after wound healing prior to HWBI was scored as excellent/good in 86% of cases by subjective (patient) and in 74% by objective (doctor) assessment with no impairment thereafter. ConclusionsAcute and late treatment tolerance of a combined Boost-IOERT/HWBI regimen is excellent in short/mid-term assessment. Postoperative cosmetic appearance is not impaired after 3 years FUP.

Post mastectomy radiotherapy for elderly patients with intermediate risk (T1-2N1 OR T3N0) breast cancer: a systematic review and meta-analysis.

BackgroundTo determine if PMRT for elderly patients (>65 years old) with intermediate risk breast cancer (T1-2N1, T3N0) improves outcomes.MethodsWe performed a systematic review and meta-analysis to compare the effects of PMRT to no PMRT for elderly patients with intermediate-risk breast cancer. We searched PubMed for eligible studies from Jan 2008 to Dec 2018. We assessed the methodological quality of the included studies using the ROBINS-I tool and performed the meta-analysis with random effects model. The primary outcome of interest was overall survival (OS); secondary outcomes were breast cancer specific survival (BCSS), loco-regional (LRR) and distant disease recurrence (DDR).ResultsWe found 2 retrospective cohort studies with 743 patients directly comparing PMRT to no PMRT. Both studies were judged to have serious risk of bias in their methodological quality. The pooled results suggest that PMRT was associated with a 20% relative reduction in the hazard in death, ranging from 41% relative reduction, a substantial negative association to 10% relative increase, a small positive association (HR 0.80, 95% CI: 0.59–1.1, P=0.62, I2=0%). PMRT was also associated with a 17% relative reduction in the hazard for breast cancer related death, ranging from 52% relative reduction, a substantial negative association to 41% relative increase, a substantial positive association (HR 0.83, 95% CI: 0.48–1.41, P=0.48, I2=0%). One study did not observe any significant differences in LRR and DDR between the two groups.ConclusionsThe survival benefits from PMRT in unselected elderly patients with intermediate risk breast cancer is unclear. Further research to better select elderly patients who may benefit from PMRT is warranted. Patients with a multiple pathological risk factors suggestive of high risk of loco-regional recurrence post-mastectomy should consider PMRT.

The Impact of Post-Mastectomy Chest-Wall Radiation on Overall Survival for Intermediate-Risk Breast Cancer Patients: A National Cancer Data Base Analysis

The recommendation of post-mastectomy radiation therapy (PMRT) to breast cancer women with intermediate risk disease still requires a great deal of clinical judgment without a single, validated formula. We aimed to assess the impact of PMRT on overall survival (OS) among patients with breast cancer considered intermediate risk for local recurrence by querying the National Cancer Data Base (NCDB) 2004-2014 for breast cancer. We replicated the SUPREMO phase III clinical trial by including patients (age >=18) with pT1-2N1 (or pT2N0 with either histologic Grade = 3 or presence of LVI) who underwent total mastectomy and did not receive neoadjuvant therapy. PMRT had a total radiation dose 40-70 Gy and was given within 6 months after surgery. OS was defined as months from the date of surgery. Logistic regression was applied to assess the pattern of PMRT utilization. Cox proportional hazard model was used for the association with OS. Propensity score (PS) overlap weighting was implemented to balance all observed baseline characteristics and to eliminate the selection bias. The effect of PMRT in the subgroups was estimated through the multivariable model (MVA) with interactions. We obtained 35,244 eligible subjects with a median follow up of 65.5 months. The median age was 57, 82.6% were white, 55.6% had 1 positive lymph node (PLN), 43.7% of tumors were pT1, the median tumor size was 2.2 cm, 38.4% had Grade III-IV, 96.2% had a negative surgical margin, and 68.3% received adjuvant chemotherapy. 4841 (13.7%) received PMRT while 30,403 (86.3%) received no radiation (NR). There was a clearly increasing trend of PMRT utilization over the years. In MVA by logistic regression, the factors associated with a higher probability of PMRT usage include PLN =2-3, present of LVI, pT2, and younger age. The 10-year survival rate was 72.1% (PMRT) vs. 68.7% (NR) by KM method. In MVA with OS by controlling for baseline demographic and disease characteristics, the hazard ratio (HR) for PMRT vs. NR was 0.81 (95%CI: 0.74-0.89), and it was 0.84 (95%CI: 0.74-0.95) by the PS weighting approach. In the subgroups, the HR was 0.75 (95%CI: 0.64-0.88) among patients with PLN = 3, 0.69 (95%CI: 0.59-0.81) among women not receiving adjuvant chemotherapy, 0.68 (95%CI: 0.60-0.77) among women with age > 60, and 0.72 (95%CI: 0.58-0.90) among patients whose tumors exhibited LVI. In this large retrospective study based on NCDB, on average, PMRT provided significant long-term survival benefit among intermediate risk breast cancer patients, with a larger survival benefits noted amongst patients with 3 PLN, age > 60, or the presence of LVI. More informative guidance for the utilization of PMRT may require additional information such as disease specific survival or recurrence (which is unavailable in NCDB), and we are looking forward to the results from the SUPREMO trial.

Radiotherapy after skin-sparing mastectomy with immediate breast reconstruction in intermediate-risk breast cancer : Indication and technical considerations.

Skin-sparing (SSME) and nipple-sparing mastectomy (NSME) were developed to improve the cosmetic results for breast cancer (BC) patients, both allowing for immediate breast reconstruction. Recommendations for post-mastectomy radiotherapy (PMRT) are primarily derived from trials where patients were treated by standard mastectomies. Due to their more conservative character, SSME and especially NSME potentially leave more glandular tissue at risk for subclinical disease. Rates and sites of locoregional failures following SSME and NSME plus/minus reconstruction were analyzed regarding tumor stage and biological risk factors. In particular, the role of PMRT in "intermediate"-risk and early stage high-risk breast cancer patients was revisited. Implications on targeting and dose delivery of PMRT were critically reviewed. The value of PMRT in stageIII BC remains undisputed. For node-negative BC patients, the majority of reports classify clinical and biological features such as tumor size, close surgical margins, premenopausal status, multicentricity, lymphangiosis, triple-negativity, HER2-overexpression, and poor tumor grading as associated with higher rates of locoregional relapse, thus, building an "intermediate" risk group. Surveys revealed that the majority of radiation oncologists use risk-adaptive models also considering the number of coinciding factors for the estimation of recurrence probability following SSME and NSME. Constellations with a10-year locoregional recurrence risk of >10% are usually triggering the indication for PMRT. There was no common belief that the amount of residual tissue, e.g., tissue thickness over flaps, serves as additional decision aid. Modern treatment planning can ensure optimal dose distribution for PMRT in almost all patients with SSME. There are no reliable data supporting areduction of the treatment volume from the CTV chest wall, e.g., to the nipple-areola complex, to the dorsal aspect behind the implant volume, the pectoralis muscle, nor the regional interpectoral, axillary, or complete regional lymph nodes only. The omission of askin bolus in intermediate-risk BC does not compromise oncological safety. For intermediate-risk as well as early stage high-risk BC patients, the DEGRO Breast Cancer Expert Panel recommends the use of PMRT following SSME and NSME when a10-year locoregional recurrence risk is likely to be greater than 10%, as estimated by clinical and biological risk factors. Subvolume-only radiation is discouraged outside of trials. The impact of adequate systemic treatment and the value of radiotherapy on optimal locoregional tumor control, with the goal of less than 5% LRR at 10-years follow-up, has to be verified in prospective trials.

Quality of life after postmastectomy radiotherapy in patients with intermediate-risk breast cancer (SUPREMO): 2-year follow-up results of a randomised controlled trial.

Postmastectomy radiotherapy in patients with four or more positive axillary nodes reduces breast cancer mortality, but its role in patients with one to three involved nodes is controversial. We assessed the effects of postmastectomy radiotherapy on quality of life (QOL) in women with intermediate-risk breast cancer. SUPREMO is an open-label, international, parallel-group, randomised, controlled trial. Women aged 18 years or older with intermediate-risk breast cancer (defined as pT1-2N1; pT3N0; or pT2N0 if also grade III or with lymphovascular invasion) who had undergone mastectomy and, if node positive, axillary surgery, were randomly assigned (1:1) to receive chest wall radiotherapy (50 Gy in 25 fractions or a radiobiologically equivalent dose of 45 Gy in 20 fractions or 40 Gy in 15 fractions) or no radiotherapy. Randomisation was done with permuted blocks of varying block length, and stratified by centre, without masking of patients or investigators. The primary endpoint is 10-year overall survival. Here, we present 2-year results of QOL (a prespecified secondary endpoint). The QOL substudy, open to all UK patients, consists of questionnaires (European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR23, Body Image Scale, Hospital Anxiety and Depression Scale [HADS], and EQ-5D-3L) completed before randomisation, and at 1, 2, 5, and 10 years. The prespecified primary outcomes within this QOL substudy were global QOL, fatigue, physical function, chest wall symptoms, shoulder and arm symptoms, body image, and anxiety and depression. Data were analysed by intention to treat, using repeated mixed-effects methods. This trial is registered with the ISRCTN registry, number ISRCTN61145589. Between Aug 4, 2006, and April 29, 2013, 1688 patients were enrolled internationally and randomly assigned to receive chest wall radiotherapy (n=853) or not (n=835). 989 (79%) of 1258 patients from 111 UK centres consented to participate in the QOL substudy (487 in the radiotherapy group and 502 in the no radiotherapy group), of whom 947 (96%) returned the baseline questionnaires and were included in the analysis (radiotherapy, n=471; no radiotherapy, n=476). At up to 2 years, chest wall symptoms were worse in the radiotherapy group than in the no radiotherapy group (mean score 14·1 [SD 15·8] in the radiotherapy group vs 11·6 [14·6] in the no radiotherapy group; effect estimate 2·17, 95% CI 0·40-3·94; p=0·016); however, there was an improvement in both groups between years 1 and 2 (visit effect -1·34, 95% CI -2·36 to -0·31; p=0·010). No differences were seen between treatment groups in arm and shoulder symptoms, body image, fatigue, overall QOL, physical function, or anxiety or depression scores. Postmastectomy radiotherapy led to more local (chest wall) symptoms up to 2 years postrandomisation compared with no radiotherapy, but the difference between groups was small. These data will inform shared decision making while we await survival (trial primary endpoint) results. Medical Research Council, European Organisation for Research and Treatment of Cancer, Cancer Australia, Dutch Cancer Society, Trustees of Hong Kong and Shanghai Banking Corporation.

The holistic impact of oncotype DX for patients with an intermediate risk breast cancer: A single centre experience

The holistic impact of oncotype DX for patients with an intermediate risk breast cancer: A single centre experience

Risk-adapted postmastectomy radiotherapy based on local-regional recurrence for T1-2N1M0 breast Cancer

Objective: To establish a risk-adapted postmastectomy radiotherapy strategy based on local-regional recurrence for intermediate-risk breast cancer (T1~2N1M0 stage). Methods: A total of 2413 patients with T1-2N1M0 breast cancer were retrospectively reviewed. Of them, 588 patients (24.4%) received postmastectomy radiotherapy (PMRT), while 1 825 (75.6%) patients did not. A comprehensive comparative study was performed by using multivariable and propensity score-matched (PSM) analyses. Results: The median follow-up time was 67.0 months, the 5-year local region recurrence free-survival (LRRFS), disease-free survival (DFS) and overall survival (OS) were 93.8%, 85.7% and 93.3%, respectively. The 5-year local region recurrence (LRR) was 6.1%. For patients without PMRT, multivariable analysis indicated that age, tumor localization, molecular subtype, pathologic T stage and number of positive lymph node were independent factors for LRRFS (all of P<0.05). Patients with T1-2N1 breast cancer were classified into low-risk group (0-1 risk factor, 768 patients), intermediate-risk group (2 risk factors, 690 patients) and high-risk groups (≥3 risk factors, 544 patients) based on the five independent factors mentioned above. The 5-year LRRFS, DFS and OS were significantly different among the three groups (P<0.001). In low- and intermediate-risk groups, there were no significant differences in LRRFS, DFS and OS of patients who received PMRT or not (P>0.05). In high-risk group, the DFS of patients received PMRT or not were 79.8% and 74.4%, respectively (P=0.127), the OS of them were 86.8% and 87.1%, respectively (P=0.174), and the LRRFS were 93.3% and 84.3%, respectively (P=0.002). After PSM adjustment, no significant differences in LRRFS, DFS and OS were observed between PMRT-received subgroup and no PMRT subgroup of low-risk group (P>0.05). In intermediate-risk group, the LRRFS of patients received PMRT or not were 95.2% and 91.0%, respectively (P=0.037). However, in the high-risk group, the LRRFS, DFS and OS of patients received PMRT were 93.3%, 79.7% and 86.6%, respectively, while those of patients did not receive PMRT were 78.5% (P<0.001), 69.5% (P=0.038) and 85.7% (P=0.080), respectively. Conclusions: The local-regional recurrence risks of patients with pT1-2N1 breast cancer are viable and risk-adapted PMRT is available for them. Better prognoses can be achieved by the patients of intermediate and high-risk group. More samples on this subject are needed to validate the results.

Risk-Adapted Postmastectomy Radiation Therapy for pT1-2N1M0 Breast Cancer: A Single Institution Study

The definite role of postmastectomy radiotherapy (PMRT) following chemotherapy (CT) for intermediate-risk(T1-2N1M0) breast cancer are not well-defined. The aim of this study was to create a risk-adapted therapeutic strategy for intermediate-risk breast cancer. A total of 2413 patients with T1-2N1M0 breast cancer were retrospectively reviewed between 1986 and 2014. Of them, 588 patients received PMRT, and 1825 patients did not receive PMRT. A comprehensive comparative study was performed using multivariable and propensity score-matched (PSM) analyses. There was no significant difference between PMRT and no PMRT groups for entire patients. The 5-year overall survival (OS, 93.4% vs 93.2%, P = .077), progression-free survival (PFS, 84.7% vs 86.0%, P = .778) and local recurrence free survival (LRFS, 95.3% vs 93.3%, P = .097) were comparable between two groups. In patients who did not receive PMRT, multivariable analysis indicated that age (≤45 years vs >45 years), tumor site (inner+central region vs lateral region), molecular subtype (Her2 enriched + Triple negative vs Luminal A + Luminal B), pathologic T stage (T2 vs T1) and positive lymph node numbers (2+3 vs 1) were independent factors for LRFS. Patients with T1-2N1 breast cancer were classified as low-risk (0-1 risk factor, 38.4%), moderate-risk (2 risk factors, 34.5% ) and high-risk groups (≥3 risk factors, 27.2%) based on these independent factors. Low-risk patients had significantly better outcome than moderate-risk and high-risk patients, with 5-year OS, PFS and LRFS rates of 96.5%, 91.9% and 97.3% for the low-risk group, 96.0%, 88.2% and 94.8% for the moderate-risk group and 87.0% (P<.001), 76.3% (P<.001) and 87.5% (P<.001) for the high-risk group. In low-risk group, patients who received PMRT or did not receive PMRT achieved a favorable OS (95.9% vs 96.6%,P=.808), PFS (87.7% vs 92.5%, P =.337) and LRFS (97.1% vs 97.3%, P=.740). Similarly, in moderate-risk group, no difference in OS (96.4% vs 95.9%, P=.253), PFS (88.9% vs 87.9%, P=.387) and LRFS (96.2% vs 94.4%, P=.090) was observed between PMRT or no PMRT in these patients. In high-risk group, compared with no PMRT, PMRT resulted in similar OS (86.8% vs. 87.1%, P=.174) and PFS (79.8% vs 74.4%, P=.127), but superior LRFS (93.3% vs 84.3%, P=.002). After PSM adjustment, no significant difference in OS, PFS and LRFS were observed between low-risk and moderate-risk groups. However, in the high-risk group, PMRT resulted significantly better survival in OS, PFS and LRFS than no PMRT. The 5-year OS, PFS and LRFS rates were 86.3%, 80.3% and 95.5% for PMRT, compared with 84.7% (P=.046), 68.2% (P=.022) and 79.2% (P<.001) for no PMRT. Risk-adapted PMRT for high-risk patients is a viable effective strategy for T1-2N1 breast cancer.

Prognostic impact of the inclusion of uPA/PAI-1 for adjuvant treatment decision-making in ER+/Her2- pN0 early breast cancers.

Intermediate-risk early breast cancer (EBC) is a heterogeneous group in which adjuvant chemotherapy decision proves to be difficult. Clinical and pathological criteria are sometimes insufficient to determine the best therapeutic options, and validated biomarkers such as uPA/PAI-1, are needed to contribute to the decision-making. The objective of this study was to evaluate the clinical outcome of an unselected ER+/HER2- pN0 EBC cohort of patients in whom the routine clinical decision process included a prospective uPA/PAI-1 determination. This monocentric retrospective study included 520 patients who underwent curative surgery in our institute between 2006 and 2011. Adjuvant therapeutic strategy was decided based on clinical-pathological data, altogether with a routine prospective determination of uPA/PAI-1 tumor levels using fresh, extemporaneously sampled tissue. We evaluated the correlation between uPA/PAI-1 levels, clinical-pathological variables, and the patient's outcome (relapse-free survival, RFS, and overall survival, OS). Median follow-up was 5.4years. The 5- and 10-year RFS rates were ,respectively, 95 and 89%, and the five-year OS rate was 96.3%. Forty percent of tumors had low uPA/PAI-1 levels. Seventy-five percent of patients with low uPA/PAI-1 levels did not receive chemotherapy, when 25% did. Sixty percent of patients with high uPA and/or PAI-1 levels received chemotherapy, while 40% did not. No statistical significant correlation was found between the uPA/PAI-1 levels and RFS or OS. The personalization of the patients' treatment using uPA/PAI-1 tumor levels allows the reversion of the well-known poor prognostic impact of high uPA/PAI-1 levels and strongly supports the use of this biomarker in clinical practice.

Abstract P6-09-28: Prognostic impact of the inclusion of uPA/PAI-1 in ER+/Her2- pN0 early breast cancer adjuvant treatments decision-making

Abstract Purpose: Intermediate-risk early breast cancer (EBC) is a heterogeneous group in which adjuvant chemotherapy decision prove to be difficult. Clinical and pathological criteria might be insufficient to determine the best therapeutic options for patients, and validated biomarkers are urgently needed to help decision making, such as the LOE-I uPA/PAI-1 biomarker. The aim of this study is to evaluate the clinical outcome of a large, unselected, ER+/HER2- pN0 EBC cohort of patients in whom the routine clinical decision process included a prospective uPA/PAI-1 determination. Methods: This monocentric retrospective study included 520 ER+/HER2- pN0/M0 EBC patients who had curative surgery in our center between 2006 and 2011. Adjuvant therapeutic strategy was decided based on clinico-pathological data, altogether with a routine prospective determination of uPA/PAI-1 tumor levels. We evaluated the correlation between uPA/PAI-1 levels, classical clinico-pathological variables and the patient's outcome (relapse free survival, RFS; overall survival, OS). Results: Median age was 54 years (range 27-85). 75% of tumors were classified T1, 25% T2 and above. We found 80.8% of ductal carcinomas, 12.3% of lobular carcinomas and 6.9% of other histological types. SBR grade 1-2 represented 82.5% of our cohort versus 17.5% of grade 3. Mitotic count was &amp;lt;10 in 63.5% of cases, and ≥10 in 36.5%. Peri-tumoral invasion (PVI) was seen in 17% of tumors. Progesterone receptors (PR) were positive in 79.6% of cases. Median follow-up was 5.4 years. 5 and 10 years RFS were respectively 95% and 89% (n=33 local or metastatic relapse). 5 year OS was 96.3%. We found 40% of low uPA/PAI-1 levels, and 60% of high uPA and/or PAI-1 levels. By using uPA/PAI-1 levels in our adjuvant treatment decision-making, 75% of patients with low uPA/PAI-1 levels did not received chemotherapy and 60% of patients with high uPA and/or PAI-1 levels received chemotherapy. 98.3% of our patients received endocrine therapy as adjuvant treatment for at least 5 years. No statistical significant correlation was found between uPA/PAI-1 levels and RFS (p=0.3) or OS (p=0.28). In univariate analysis, tumor size (p=0.048; p=0.0694), histological grade (p=0.007; p=0.0142), PR status (p=0.001; p=0.0002) and mitotic count (p=0.0001; p=0.0001) were statistically correlated with RFS and OS, respectively. Using cox regression model, PR status (p&amp;lt;0.003) and mitotic count (p&amp;lt;0.001) appeared to be strongly correlated with RFS. No changes in significant variables were seen when the analyses were restricted to the grade 2 subgroup (n=339). Conclusion: The individualization of patients' treatment using uPA/PAI-1 tumor levels allows the reversion of the well-known poor prognostic impact of high uPA/PAI-1 levels and strongly support the use of this LOE-I biomarker in clinical practice. PR status and mitotic activity remains independent major prognostic factors in optimally treated patients. The evaluation of the additional impact of multigene signature in this setting needs to be performed. Longer 10-years follow-up needs to be done in this ER+/HER2- subgroup, particularly to evaluate the risk of late relapse after endocrine therapy. Citation Format: Viala M, Alexandre M, Thézenas S, Lamy P-J, Bibeau F, Gutowski M, Colombo P-E, Romieu G, Jacot W, Guiu S. Prognostic impact of the inclusion of uPA/PAI-1 in ER+/Her2- pN0 early breast cancer adjuvant treatments decision-making [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-28.

Abstract P2-05-12: The ASCO-recommended prognostic factors uPA/PAI-1 in a multicenter cohort study (PiA)

Abstract Introduction The PiA-study (Prognostic assessment in routine Application, NCT 01592825) was designed as a representative cohort of breast cancer patients to estimate the proportions of traditional and modern prognostic factors. The ASCO-recommended biomarkers uPA (urokinase-type plasminogen activator) and its inhibitor PAI-1 were used for biological risk assessment particularly for intermediate risk breast cancer patients and disease-free survival of the patients after 5 yrs of follow-up (F/U) was calculated. Material &amp; Methods Between 2009 and 2011, 1,074 non-metastasized, primarily operated breast cancer patients from six centers in Germany were included. From 815 patients, fresh frozen tissue was obtained and processed for central testing uPA/PAI-1 by ELISA (FEMTELLE®, Sekisui Diagnostics GmbH). Low uPA/PAI-1 status is defined by uPA and PAI-1 concentrations below the published cut-offs, high status means one or both were higher than the corresponding cut-offs. Tumor characteristics were based on local pathology. The centers had to follow the national guidelines. In low-risk patients, adjuvant chemotherapy was spared. The median F/U is 56 months (range 0-78). Results In the total cohort of 1,074 patients, 166 had G1- and 237 had G3-tumors. Of the 671 patients with a G2-tumor, the following were allocated to the high-risk group: node-positive (n=371), younger than 35 yrs (n=17), and triple-negative (TN) or HER2-positive (n=118). For 253 tumors of the remaining 355 patients with an intermediate risk of recurrence (pN0, G2, HR positive, HER2-negative, ≥35 yrs), uPA/PAI-1 status was available. 126 (49.8%) were allocated to the low-risk group, one patient had a recurrence. At 5 yrs, in the total cohort 90.6% (95% CI, 89.5-91.7) of the patients were free of invasive disease. Of 114 HER2-positive tumors, 94 (82.4 %) had a high uPA/PAI-1 status, only one of the 38 HR negative/HER2 positive tumors had a low uPA/PAI-1 status. In the TN group, the majority of tumors had a high uPA/PAI-1 status (66 of 81; 81.5 %). In 30 patients lymph nodes were involved, 18.5% (n=15) had a low uPA/PAI-1 status, one event was detected. In N pos. patients with an high uPA/PAI-1 6 events were observed. Conclusion Testing for uPA/PAI-1 in the daily routine is feasible, fresh frozen tissue has been prepared from 76% of the tumors of the recruited patients, 37% of them had a low risk status. Using uPA/PAI-1, about half of the node-negative patients with an intermediate risk of recurrence were allocated to a group with an extremely low risk of recurrence and thus chemotherapy could be spared. Also in node-positive disease, uPA/PAI-1 has a prognostic impact. Tab 1: Proportion of the subgroups according to IHC, grading and uPA/PAI-1-statusTumor typetotallow uPA/PAI-1 statushigh uPA/PAI-1 statusn=815 (100%)n=304 (37%)n=511 (63%)Luminal A-like tumors:HRpos., HER2neg., G1, G2515 (63.2%)240 (78.9%)275 (53.9%)Luminal B/HER2-negative-like tumors:HRpos., HER2neg., G3104 (12.8%)29 (9.5%)75 (14.7%)Luminal B/HER2-positive-like tumors:HR pos., HER2 pos., all grades77 (9.4%)19 (6.2%)58 (11.4%)HER2-positive (nonluminal) - like tumors:HRneg., HER2pos., all grades38 (4.7%)1 (0.3%)37 (7.3%)TN tumors:HRneg., HER2neg., all grades81 (9.9%)15 (4.9%)66 (12.9%) Citation Format: Vetter M, Hartung C, Hanf V, Lantzsch T, Uleer C, Peschel S, John J, Buchmann J, Bürrig K-F, Weigert E, Thomssen C, Kantelhardt EJ. The ASCO-recommended prognostic factors uPA/PAI-1 in a multicenter cohort study (PiA) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-12.

The BIG 2.04 MRC/EORTC SUPREMO Trial: pathology quality assurance of a large phase 3 randomised international clinical trial of postmastectomy radiotherapy in intermediate-risk breast cancer

IntroductionSUPREMO is a phase 3 randomised trial evaluating radiotherapy post-mastectomy for intermediate-risk breast cancer. 1688 patients were enrolled from 16 countries between 2006 and 2013. We report the results of central pathology review carried out for quality assurance.Patients and methodsA single recut haematoxylin and eosin (H&E) tumour section was assessed by one of two reviewing pathologists, blinded to the originally reported pathology and patient data. Tumour type, grade and lymphovascular invasion were reviewed to assess if they met the inclusion criteria. Slides from potentially ineligible patients on central review were scanned and reviewed online together by the two pathologists and a consensus reached. A subset of 25 of these cases was double-reported independently by the pathologists prior to the online assessment.ResultsThe major contributors to the trial were the UK (75%) and the Netherlands (10%). There is a striking difference in lymphovascular invasion (LVi) rates (41.6 vs. 15.1% (UK); p = <0.0001) and proportions of grade 3 carcinomas (54.0 vs. 42.0% (UK); p = <0.0001) on comparing local reporting with central review. There was no difference in the locally reported frequency of LVi rates in node-positive (N+) and node-negative (N−) subgroups (40.3 vs. 38.0%; p = 0.40) but a significant difference in the reviewed frequency (16.9 vs. 9.9%; p = 0.004). Of the N− cases, 104 (25.1%) would have been ineligible by initial central review by virtue of grade and/or lymphovascular invasion status. Following online consensus review, this fell to 70 cases (16.3% of N− cases, 4.1% of all cases).ConclusionsThese data have important implications for the design, powering and interpretation of outcomes from this and future clinical trials. If critical pathology criteria are determinants for trial entry, serious consideration should be given to up-front central pathology review.

Quality of life results of BIG 02-04 MRC EORTC SUPREMO trial of chest wall radiotherapy in patients with intermediate risk stage II breast cancer after mastectomy

Background: BIG2-04 MRC/EORTC SUPREMO is an international randomised phase III trial assessing chest-wall irradiation in women with intermediate risk breast cancer following mastectomy (ISRCTN61145589). Patients were prospectively randomized to receive chest-wall radiotherapy or not. The primary endpoint is overall survival (OS at 10 years) with secondary endpoints of chest-wall/regional recurrence, disease-free survival, quality of life (QOL) and cost-effectiveness. The first OS analysis will be at 300 events (deaths). Here we report QOL results at 2 years. Method: Between April 2007 and May 2013 the trial recruited 1688 patients internationally; 990 were eligible for the QOL study (UK centres only). Patients completed the EORTC QLQ-C30 and BR23 questionnaires, Hospital Anxiety and Depression Scale (HADS) and EQ5D at baseline (pre-randomisation), 1 and 2 years. 947 patients (96%) returned the baseline questionnaires, 85% year 1 and 81% year 2 questionnaires. Repeated mixed effects methods were used to analyse the data, with baseline score and age included as covariates in the model. SAS's PROC MIXED was utilised due to its ability to deal with data missing at random. Results: Patients randomised to radiotherapy reported worse chest-wall symptoms (pain, swelling, oversensitivity and skin problems in the “area of the affected breast”) (p = 0.013), although an improvement in symptoms was seen between year 1 and 2 post-randomisation (p = 0.009). No significant between-group differences were observed for arm symptoms, body image, fatigue, pain, overall QOL, physical functioning or HADS scores. An age effect was found: younger patients reported significantly worse chest-wall (p = 0.0004) and arm symptoms (p = 0.005), body image problems (p = 0.0007) and anxiety (p = 0.0015). Conclusion: Chest wall radiotherapy led to more chest wall symptoms up to 2 years post-randomisation, but reassuringly there was no impact on arm symptoms, body image, overall QOL and patient functioning for this group. However, worse QOL seen in younger women will need further investigation.

Comparison of prognostic and predictive impact of genomic or central grade and immunohistochemical subtypes or IHC4 in HR+/HER2- early breast cancer: WSG-AGO EC-Doc Trial

Potential prognostic and predictive markers in early, intermediate-risk breast cancer (BC) include histological grade, Ki-67, genomic signatures, e.g. genomic grade index (GGI), and intrinsic subtypes. Their prognostic/predictive impact in hormone receptor (HR: ER and/or PR) positive/HER2- BC is controversial. WSG-AGO EC-Doc demonstrated superior event-free survival (EFS) in patients with 1-3 positive lymph node receiving epirubicin/cyclophosphamide-docetaxel (EC-Doc) versus 5-fluoruracil/epirubicin/cyclophosphamide (FEC). In a representative trial subset, we quantify concordance among factors used for clinical chemotherapy indication. We investigate the impact of central histology (n = 772), immunohistochemistry for intrinsic subtyping and IHC4, and dichotomous (GG) or continuous (GGI) genomic grade (n = 472) on patient outcome and benefit from taxane chemotherapy, focusing on HR+/HER2- patients (n = 459). Concordance of local grade (LG) with central (CG) or genomic grade was modest. In HR+/HER2- patients, low (GG-1: 16%), equivocal (GG-EQ: 17%), and high (GG-3: 67%) GG were associated with respective 5-year EFS of 100%, 93%, and 85%. GGI was prognostic for EFS within all LG subgroups and within CG3, whereas IHC4 was prognostic only in CG3 tumors.In unselected and HR+/HER2- patients, CG3 and luminal-A-like subtype entered the multivariate EFS model, but not IHC4 or GG. In the whole population, continuous GGI entered the model [hazard ratio (H.R.) of 75th versus 25th = 2.79; P = 0.01], displacing luminal-A-like subtype; within HR+/HER2- (H.R. = 5.36; P < 0.001), GGI was the only remaining prognostic factor.In multivariate interaction analysis (including central and genomic grade), luminal-B-like subtype [HR+ and (Ki-67 ≥20% or HER2+)] was predictive for benefit of EC-Doc versus FEC in unselected but not in HR+/HER2- patients. In the WSG-AGO EC-Doc trial for intermediate-risk BC, CG, intrinsic subtype (by IHC), and GG provide prognostic information. Continuous GGI (but not IHC4) adds prognostic information even when IHC subtype and CG are available. Finally, the high interobserver variability for histological grade and the still missing validation of Ki-67 preclude indicating or omitting adjuvant chemotherapy based on these single factors alone. The WSG-AGO/EC-Doc is registered at ClinicalTrials.gov, NCT02115204.

Penetrance of ATM Gene Mutations in Breast Cancer: A Meta-Analysis of Different Measures of Risk.

The gene responsible for ataxia-telangiectasia syndrome, ATM, is also an intermediate-risk breast cancer (BC) susceptibility gene. Numerous studies have been carried out to determine the contribution of ATM gene mutations to BC risk. Epidemiological cohorts, segregation analyses, and case-control studies reported BC risk in different forms, including penetrance, relative risk, standardized incidence ratio, and odds ratio. Because the reported estimates vary both qualitatively and quantitatively, we developed a general model allowing the integration of the different types of cancer risk available in the literature. We performed a comprehensive meta-analysis identifying 19 studies, and used our model to obtain a consensus estimate of BC penetrance. We estimated the cumulative risk of BC in heterozygous ATM mutation carriers to be 6.02% by 50 years of age (95% credible interval: 4.58-7.42%) and 32.83% by 80 years of age (95% credible interval: 24.55-40.43%). An accurate assessment of cancer penetrance is crucial to help mutation carriers make medical and lifestyle decisions that can reduce their chances of developing the disease.

Impact of guideline-based use of uPA/PAI-1 on patient outcome in intermediate-risk early breast cancer.

The purpose of this study was to evaluate the influence of guideline-based prospective use of uPA/PAI-1 on clinical outcome in an intermediate-risk cohort of breast cancer patients. We analyzed 381 consecutive primary breast cancer patients (2003-2011) at the breast center Ostbayern meeting the following criteria: M0/N0/estrogen receptor (ER)+/G2. Clinical-pathological data, uPA/PAI-1, and follow-up data were collected. Decisions for adjuvant chemotherapy were made upon consideration of prospectively measured uPA/PAI-1. Observed disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier estimates. Using guideline-based analysis of uPA/PAI-1, treatment with adjuvant chemotherapy was avoided in 86.5% of patients with low uPA/PAI-1, i.e., 38.8% of the total patient collective. Median follow-up was 52.5months. Five-year relapse-free survival in intermediate-risk patients (N0, G2) without chemotherapy was 99%. Five-year overall survival including all causes of death was 95%. By using uPA/PAI-1, adjuvant chemotherapy can be avoided in a major part of patients with intermediate-risk breast cancer. Nevertheless, DFS and OS of these patients at 5years remain excellent. The potential, but hardly measurable, benefit of adjuvant chemotherapy has to be set in contrast with its associated side effects and increased morbidity. Patients with high uPA/PAI-1 show benefit from chemotherapy. In this subgroup, a very good OS was observed as well. These findings strongly support the use of uPA/PAI-1 together with clinic-pathological parameters as an evidence-based, clinically relevant and inexpensive decision tool in the routine of a breast center.