De-escalated neoadjuvant pertuzumab plus trastuzumab therapy with or without weekly paclitaxel in HER2-positive, hormone receptor-negative, early breast cancer (WSG-ADAPT-HER2+/HR-): survival outcomes from a multicentre, open-label, randomised, phase 2 trial.

BACKGROUND: Several de-escalation neoadjuvant strategies have been investigated to reduce the use of chemotherapy in HER2-positive early breast cancer using pathological complete response as a surrogate endpoint; there are few survival data from these trials. Here, we report 5-year survival data in the WSG-ADAPT-HER2+/HR- trial and address the effect of pathological complete response, early therapy response, and molecular subtype. METHODS: WSG-ASAPT-HER2+/HR-, a part of the ADAPT umbrella trial performed in patients with different subtypes of early breast cancer, was an investigator-initiated, multicentre, open-label, randomised, phase 2 trial done at 40 Breast Cancer Centres in Germany. Eligible patients were aged 18 years or older with histologically confirmed, unilateral, primary invasive, non-inflammatory early breast cancer, hormone receptor-negative and HER2-positive status, and an Eastern Cooperative Oncology Group performance status of 0 or 1 or a Karnofsky performance status of at least 80%. Patients were randomly assigned (5:2, block size 21, stratified by centre and clinical nodal status) to 12 weeks of either trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks) plus pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) or trastuzumab plus pertuzumab plus paclitaxel (80 mg/m2 weekly); all drugs were administered intravenously. The primary objective of the trial was to compare the number of patients with a pathological complete response at surgery (ie, no invasive tumour cells in breast and lymph nodes [ypT0/is ypN0], the primary endpoint) in early responders (ie, low cellularity or Ki67 decrease ≥30% after 3 weeks) in the trastuzumab plus pertuzumab group versus all patients (irrespective of an early response) in the trastuzumab plus pertuzumab plus paclitaxel group. Non-inferiority was defined as a pathological complete response no worse than 23% lower in the early-responder proportion of patients in the trastuzumab plus pertuzumab group than in the entire trastuzumab plus pertuzumab plus paclitaxel group. The primary endpoint has been reported previously. Additionally, the primary objective of the ADAPT umbrella trial was the evaluation of the effect of pathological complete response on invasive disease-free survival. At investigator's discretion, further chemotherapy could be omitted in patients with a pathological complete response. Secondary survival endpoints were 5-year invasive disease-free survival, relapse-free survival, locoregional relapse-free survival, distant disease-free survival, and overall survival. The effect of pathological complete response on survival was estimated by Cox regression analysis. All analyses are reported in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01817452, and is closed to recruitment. FINDINGS: Between March 3, 2014, and Oct 6, 2015, 134 patients were recruited and randomly assigned to treatment, 92 to trastuzumab plus pertuzumab and 42 to trastuzumab plus pertuzumab plus paclitaxel. Median follow-up in survivors was 59·9 months (IQR 53·4-61·4). There were no significant differences between the treatment groups in invasive disease-free survival, relapse-free survival, locoregional relapse-free survival, distant disease-free survival, and overall survival. In the trastuzumab plus pertuzumab plus paclitaxel group and in the trastuzumab plus pertuzumab group, the proportions of patients achieving 5-year survival respectively were 98% (95% CI 84-100) and 87% (78-93) for invasive disease-free survival (hazard ratio [HR] 0·32, 95% CI 0·07-1·49; p=0·15); 98% (95% CI 84-100) and 89% (79-94) for relapse-free survival (HR 0·41, 95% CI 0·09-1·91; p=0·25); 100% (95% CI not estimable) and 95% (88-98) for locoregional relapse-free survival (HR 0·41, 95% CI 0·05-3·75; p=0·43); 98% (95% CI 84-100) and 92% (83-96) for distant disease-free survival (HR 0·35, 95% CI 0·04-3·12; p=0·36), and 98% (95% CI 84-100) and 94% (86-97) for overall survival (HR 0·41, 95% CI 0·05-3·63; p=0·43). Pathological complete response was associated with improved invasive disease-free survival (HR 0·14, 95% CI 0·03-0·64; p=0·011). Two invasive disease-free survival events occurred after a pathological complete response (one in each treatment group). INTERPRETATION: The WSG-ADAPT-HER2+/HR- trial showed good survival rates in patients with a pathological complete response after de-escalated 12-week trastuzumab plus pertuzumab with or without weekly paclitaxel. Omission of further chemotherapy did not affect invasive disease-free survival in patients with a pathological complete response. 12 weeks of weekly paclitaxel plus dual HER2 blockade could be an efficacious de-escalated neoadjuvant regimen in patients with hormone receptor-negative, HER2-positive early breast cancer with high pathological complete response rates and good 5-year outcomes. Further trials of this approach are ongoing. FUNDING: Roche, Bayer. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.

Impact of stromal tumor-infiltrating lymphocytes (sTILs) on response to neoadjuvant chemotherapy in triple-negative early breast cancer in the WSG-ADAPT TN trial.

BACKGROUND: Higher density of stromal tumor-infiltrating lymphocytes (sTILs) at baseline has been associated with increased rates of pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) in triple-negative breast cancer (TNBC). While evidence supports favorable association of pCR with survival in TNBC, an independent impact of sTILs (after adjustment for pCR) on survival is not yet established. Moreover, the impact of sTIL dynamics during NACT on pCR and survival in TNBC is unknown. METHODS: The randomized WSG-ADAPT TN phase II trial compared efficacy of 12-week nab-paclitaxel with gemcitabine versus carboplatin. This preplanned translational analysis assessed impacts of sTIL measurements at baseline (sTIL-0) and after 3 weeks of chemotherapy (sTIL-3) on pCR and invasive disease-free survival (iDFS). Predictive performance of sTIL-0 and sTIL-3 for pCR was quantified by ROC analysis and logistic regression; Kaplan-Meier estimation and Cox regression (with mediation analysis) were used to determine their impact on iDFS. RESULTS: For prediction of pCR, the AUC statistics for sTIL-0 and sTIL-3 were 0.60 and 0.63, respectively, in all patients; AUC for sTIL-3 was higher in NP/G. The positive predictive value (PPV) of "lymphocyte-predominant" status (sTIL-0 ≥ 60%) at baseline was 59.3%, though only 13.0% of patients had this status. To predict non-pCR, the cut point sTIL-0 ≤ 10% yielded PPV = 69.5% while addressing 33.8% of patients. Higher sTIL levels (particularly at 3 weeks) were independently and favorably associated with better iDFS, even after adjusting for pCR. For example, the adjusted hazard ratio for 3-week sTILs ≥ 60% (vs. < 60%) was 0.48 [0.23-0.99]. Low cellularity in 3-week biopsies was the strongest individual predictor for pCR (in both therapy arms), but not for iDFS. CONCLUSION: The independent impact of sTILs on iDFS suggests that favorable immune response can influence key tumor biological processes for long-term survival. The results suggest that the reliability of pCR following neoadjuvant therapy as a surrogate for survival could vary among subgroups in TNBC defined by immune response or other factors. Dynamic measurements of sTILs under NACT could support immune response-guided patient selection for individualized therapy approaches for both very low levels (more effective therapies) and very high levels (de-escalation concepts). TRIAL REGISTRATION: Clinical trials No: NCT01815242, retrospectively registered January 25, 2013.

Early response by MR imaging and ultrasound as predictor of pathologic complete response to 12-week neoadjuvant therapy for different early breast cancer subtypes: Combined analysis from the WSG ADAPT subtrials.

We evaluated the role of early response after 3 weeks of neoadjuvant treatment (NAT) assessed by ultrasound (US), magnetic resonance imaging (MRI) and Ki-67 dynamics for prediction of pathologic complete response (pCR) in different early breast cancer subtypes. Patients with HR+/HER2+, HR-/HER2- and HR-/HER2+ tumors enrolled into three neoadjuvant WSG ADAPT subtrials underwent US, MRI and Ki-67 assessment at diagnosis and after 3 weeks of NAT. Early response was defined as complete or partial response (US, MRI) and ≥30% proliferation decrease or <500 invasive tumor cells (Ki-67). Predictive values and area under the receiver operating characteristic (AUC) curves for prediction of pCR (ypT0/is ypN0) after 12-week NAT were calculated. Two hundred twenty-six had MRI and 401 US; 107 underwent both MRI and US. All three methods yielded a similar AUC in HR+/HER2+ (0.66-0.67) and HR-/HER2- tumors (0.53-0.63), while MRI and Ki-67 performed better than US in HR-/HER2+ tumors (0.83 and 0.79 vs 0.56). Adding MRI+/-Ki-67 increased AUC of US in HR-/HER2+ tumors to 0.64 to 0.75. MRI and Ki-67 demonstrated highest sensitivity in HR-/HER2- (0.8-1) and HR-/HER2+ tumors (1, both). Negative predictive value was similar for all methods in HR+/HER2+ (0.71-0.74) and HR-/HER2- tumors (0.85-1), while it was higher for MRI and Ki-67 compared to US in HR-/HER2+ subtype (1 vs 0.5). Early response assessed by US, MRI and Ki-67 is a strong predictor for pCR after 12-week NAT. Strength of pCR prediction varies according to tumor subtype. Adding MRI+/-Ki-67 to US did not improve pCR prediction in majority of our patients.

Efficacy of deescalated chemotherapy according to PAM50 subtypes, immune and proliferation genes in triple-negative early breast cancer: Primary translational analysis of the WSG-ADAPT-TN trial.

In the neoadjuvant WSG-ADAPT-TN trial, 12-week nab-paclitaxel + carboplatin (nab-pac/carbo) was highly effective and superior to nab-paclitaxel + gemcitabine (nab-pac/gem) in triple-negative breast cancer regarding pathological complete response (pCR). Predictive markers for deescalated taxane/carbo use in TNBC need to be identified. Patients received 4 × nab-pac 125 mg/m2 (plus carbo AUC2 or gem 1,000 mg/m2 d1,8 q21). Expression of 119 genes and PAM50 scores by nCounter were available in 306/336 pretherapeutic samples. Interim survival analysis was planned after 36 months median follow-up. Basal-like (83.3%) compared to other subtypes was positively associated with pCR (38% vs. 20%, p = 0.015), as was lower HER2 score (p < 0.001). Proliferation biomarkers were positively associated with pCR, that is, PAM50 proliferation, ROR scores (all p < 0.004), higher Ki-67 (IHC; p < 0.001). For nab-pac/carbo, expression of immunological (CD8, PD1 and PFDL1) genes and proliferation markers (proliferation and ROR scores, MKI67, CDC20, NUF2, KIF2C, CENPF, EMP3 and TYMS) were positively associated with pCR (p < 0.05 for all). For nab-pac/gem, angiogenesis genes were negatively associated with pCR (ANGPTL4: p = 0.05; FGFR4: p = 0.02; VEGFA: p = 0.03). pCR after 12 weeks was strongly associated with favorable outcome (3y event-free survival: 92% vs. 71%, p < 0.001). In early TNBC, basal-like subtype, higher Ki-67 (IHC) and lower HER2 score were, associated with chemosensitivity. Chemoresistance pathways differed between the two taxane based combinations. Combination of proliferation/immune markers and PAM50 subtype could allow patient selection for further deescalated chemotherapy and/or immune treatment approaches.

A randomized phase II study to determine the efficacy and tolerability of two doses of eribulin plus lapatinib in trastuzumab-pretreated patients with HER-2-positive metastatic breast cancer (E-VITA).

The E-VITA study evaluated the efficacy and tolerability of two schedules of eribulin and lapatinib in patients with trastuzumab-pretreated HER-2-positive metastatic breast cancer. This multicenter, open-label phase II trial, randomly assigned patients with trastuzumab-pretreated HER-2-positive metastatic breast cancer to lapatinib 1000 mg daily with eribulin 1.23 mg/m (equivalent to 1.4 mg/m eribulin mesylate) days 1+8 every 21 days (split-dose arm) or eribulin 1.76 mg/m (equivalent to 2.0 mg/m eribulin mesylate) day 1 every 21 days (3-weekly arm). Time to progression and tolerability were defined as primary end points; no sample size calculation for formal comparison of efficacy data has been performed. Secondary end points included objective response rate, clinical benefit rate, and overall survival. Overall, 43 patients of a planned number of 80 patients were recruited. At a median follow-up of 28.7 months, the median time to progression was 8.1 months [95% confidence interval (CI): 4.8-9.4] in the split-dose arm and 6.5 months (95% CI: 4.6-13.4) in the 3-weekly arm. Objective response rate was 52.4% (95% CI: 31.0-73.7) in the split-dose arm and 45.0% (95% CI: 23.2-66.8) in the 3-weekly arm, and clinical benefit rate was 71.4% (95% CI: 52.1-90.8) and 75.0% (95% CI: 56.0-94.0), respectively. Overall survival was also similar in both arms. The most frequent grade 3-4 adverse events were neutropenia (58.5%) and leukopenia (39.0%). The combination of eribulin and lapatinib showed an acceptable safety profile with less toxicity observed in the eribulin 1.23 mg/m day 1+8 group. This might be an alternative regimen when other treatment options are exhausted. Therefore, further clinical studies are warranted.

Phase III study on efficacy of taxanes plus bevacizumab with or without capecitabine as first-line chemotherapy in metastatic breast cancer.

Taxanes (T) plus bevacizumab (B) and taxanes plus capecitabine (X) showed better progression-free survival (PFS) compared to taxanes alone. Since life-threatening or highly symptomatic situations require polychemotherapy in metastatic breast cancer (MBC), combination of taxanes, capecitabine plus bevacizumab appears reasonable. TABEA (NCT01200212), a prospectively randomized, open-label, phase III trial compares taxanes (paclitaxel 80 mg/m(2) i.v. d1,8,15 q22 or docetaxel 75 mg/m(2) i.v. d1 q22) plus bevacizumab (15 mg/kg i.v. d1 q22) with (TBX) or without capecitabine (TB, 1800 mg/m(2) daily d1-14 q22) as first-line therapy in MBC. Histologically confirmed HER2-negative, locally advanced or MBC patients with a chemotherapy indication and measurable or non-measurable target lesions (RECIST criteria) were included. Primary objective was PFS. Secondary objectives were response rate and duration, clinical benefit rate (complete response, partial response, stable disease ≥24 weeks), 3-year overall survival, PFS in patients ≥65 years, toxicity, and compliance. We assumed 10 and 13.3 months PFS for TB and TBX, respectively (HR = 0.75), requiring 432 patients and 386 events. Preplanned interim futility and safety analyses after 100 events in 202 patients showed no efficacy benefit and higher toxicity for TBX. Recruitment and therapy were stopped following advice from the IDMC. Final analysis revealed a HR 1.13 [95 %CI 0.806-1.59], P = 0.474, for PFS. Overall grade 3-4 adverse event (77.3 vs. 62.1 %, P = 0.014) and serious adverse event (40.0 vs. 30.2 %, P = 0.127) rates were higher for TBX after 26.1 months median follow-up, with six deaths for TBX versus 1 for TB. Adding capecitabine to TB cannot be recommended as first-line therapy in MBC.

Functional and Radiologic Outcomes of Degenerative Versus Traumatic Full-Thickness Rotator Cuff Tears Involving the Supraspinatus Tendon.

BACKGROUND: Arthroscopic rotator cuff repair (ARCR) is among the most commonly performed orthopaedic procedures. Several factors-including age, sex, and tear severity-have been identified as predictors for outcome after repair. The influence of the tear etiology on functional and structural outcome remains controversial. PURPOSE: To investigate the influence of tear etiology (degenerative vs traumatic) on functional and structural outcomes in patients with supraspinatus tendon tears. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Patients undergoing ARCR from 19 centers were prospectively enrolled between June 2020 and November 2021. Full-thickness, nonmassive tears involving the supraspinatus tendon were included. Tears were classified as degenerative (chronic shoulder pain, no history of trauma) or traumatic (acute, traumatic onset, no previous shoulder pain). Range of motion, strength, the Subjective Shoulder Value, the Oxford Shoulder Score (OSS), and the Constant-Murley Score (CMS) were assessed before (baseline) and 6 and 12 months after ARCR. The Subjective Shoulder Value and the OSS were also determined at the 24-month follow-up. Repair integrity after 12 months was documented, as well as additional surgeries up to the 24-month follow-up. Tear groups were compared using mixed models adjusted for potential confounding effects. RESULTS: From a cohort of 973 consecutive patients, 421 patients (degenerative tear, n = 230; traumatic tear, n = 191) met the inclusion criteria. The traumatic tear group had lower mean baseline OSS and CMS scores but significantly greater score changes 12 months after ARCR (OSS, 18 [SD, 8]; CMS, 34 [SD,18] vs degenerative: OSS, 15 [SD, 8]; CMS, 22 [SD, 15]) (P < .001) and significantly higher 12-month overall scores (OSS, 44 [SD, 5]; CMS, 79 [SD, 9] vs degenerative: OSS, 42 [SD, 7]; CMS, 76 [SD, 12]) (P≤ .006). At the 24-month follow-up, neither the OSS (degenerative, 44 [SD, 6]; traumatic, 45 [SD, 6]; P = .346) nor the rates of repair failure (degenerative, 14 [6.1%]; traumatic 12 [6.3%]; P = .934) and additional surgeries (7 [3%]; 7 [3.7%]; P = .723) differed between groups. CONCLUSION: Patients with degenerative and traumatic full-thickness supraspinatus tendon tears who had ARCR show satisfactory short-term functional results. Although patients with traumatic tears have lower baseline functional scores, they rehabilitate over time and show comparable clinical results 1 year after ARCR. Similarly, degenerative and traumatic rotator cuff tears show comparable structural outcomes, which suggests that degenerated tendons retain healing potential.

Staging for Breast Cancer: A Comparison Between Old and New Approaches.

Background/Aim: Staging for breast cancer in advanced stages or prior to neoadjuvant chemotherapy is recommended to be performed with CT scan of the chest and abdomen and a bone scan. This recommendation is valid since 2012, when conventional staging with chest x-ray and ultrasound of the abdomen was replaced by the more sensitive CT scan. However, it remains unclear if this approach improves patient outcome and prognosis. Patients and Methods: We identified patients who were treated for breast cancer at the breast center of the St. Elisabeth Hospital, Cologne, in 2012 and 2014. Clinical information such as age at diagnosis, stage, tumor biology, grading, and the applied method for staging was abstracted from the patient chart. We also looked for local or distant recurrence and data of survival. Results: A total of 1,122 patients were identified. Of those, 104 patients developed local or distant recurrence and 54 died. Conventional staging with chest x-ray, abdominal ultrasound and a bone scan was more often in 2012 (482 cases) than in 2014 (135), but CT-staging was more often in 2014 (180 vs. 29 cases). In general, less patients were staged in 2014 than in 2012. There were no significant survival differences between the two groups. Conclusion: Staging habits changed in 2012 compared to 2014 according to the changes in guidelines. This change did not affect disease-free survival.

De-Escalated Neoadjuvant Trastuzumab-Emtansine With or Without Endocrine Therapy Versus Trastuzumab With Endocrine Therapy in HR+/HER2+ Early Breast Cancer: 5-Year Survival in the WSG-ADAPT-TP Trial.

PURPOSE: Neoadjuvant chemotherapy is standard of care in human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (EBC), irrespective of the hormone receptor status. Trastuzumab-emtansine (T-DM1), antibody-drug conjugate, is highly effective in HER2+ EBC; however, no survival data are available for de-escalated antibody-drug conjugate-based neoadjuvant therapy without conventional chemotherapy. PATIENTS AND METHODS: In the WSG-ADAPT-TP (ClinicalTrials.gov identifier: NCT01779206) phase II trial, 375 centrally reviewed patients with hormone receptor-positive (HR+)/HER2+ EBC (clinical stage I-III) were randomly assigned to 12 weeks of T-DM1 with or without endocrine therapy (ET) or trastuzumab + ET once every 3 weeks (ratio 1:1:1). Adjuvant chemotherapy (ACT) omission was allowed in patients with pathologic complete response (pCR). In this study, we report the secondary survival end points and biomarker analysis. Patients who received at least one dose of study treatment were analyzed. Survival was analyzed using the Kaplan-Meier method, two-sided log-rank statistics, and Cox regression models stratified for nodal and menopausal status. P values < .05 were considered statistically significant. RESULTS: T-DM1, T-DM1 + ET, and trastuzumab + ET induced similar 5-year invasive disease-free survival (iDFS; 88.9%, 85.3%, 84.6%; Plog-rank = .608) and overall survival rates (97.2%, 96.4%, 96.3%; Plog-rank = .534). Patients with pCR versus non-pCR had improved 5-year iDFS rates (92.7% v 82.7%; hazard ratio, 0.40 [95% CI, 0.18 to 0.85]). Among the 117 patients with pCR, 41 did not receive ACT; 5-year iDFS rates were similar in those with (93.0% [95% CI, 84.0 to 97.0]) and without ACT (92.1% [95% CI, 77.5 to 97.4]; Plog-rank = .848). Translational research revealed that tumors with PIK3CA wild type, high immune marker expression, and luminal-A tumors (by PAM50) had an excellent prognosis with de-escalated anti-HER2 therapy. CONCLUSION: The WSG-ADAPT-TP trial demonstrated that pCR after 12 weeks of chemotherapy-free de-escalated neoadjuvant therapy was associated with excellent survival in HR+/HER2+ EBC without further ACT. Despite higher pCR rates for T-DM1 ± ET versus trastuzumab + ET, all trial arms had similar outcomes because of mandatory standard chemotherapy after non-pCR. WSG-ADAPT-TP demonstrated that such de-escalation trials in HER2+ EBC are feasible and safe for patients. Patient selection on the basis of biomarkers or molecular subtypes may increase the efficacy of systemic chemotherapy-free HER2-targeted approaches.

Impact of RNA Signatures on pCR and Survival after 12-Week Neoadjuvant Pertuzumab plus Trastuzumab with or without Paclitaxel in the WSG-ADAPT HER2+/HR- Trial.

PURPOSE: To identify associations of biological signatures and stromal tumor-infiltrating lymphocytes (sTIL) with pathological complete response (pCR; ypT0 ypN0) and survival in the Phase II WSG-ADAPT HER2+/HR- trial (NCT01817452). EXPERIMENTAL DESIGN: Patients with cT1-cT4c, cN0-3 HER2+/HR- early breast cancer (EBC) were randomized to pertuzumab+trastuzumab (P+T, n = 92) or P+T+paclitaxel (n = 42). Gene expression signatures were analyzed in baseline biopsies using NanoString Breast Cancer 360 panel (n = 117); baseline and on-treatment (week 3) sTIL levels were available in 119 and 76 patients, respectively. Impacts of standardized gene expression signatures on pCR and invasive disease-free survival (iDFS) were estimated by logistic and Cox regression. RESULTS: In all patients, ERBB2 [OR, 1.70; 95% confidence interval (CI), 1.08-2.67] and estrogen receptor (ER) signaling (OR, 1.72; 95% CI, 1.13-2.61) were favorable, whereas PTEN (OR, 0.57; 95% CI, 0.38-0.87) was unfavorable for pCR. After 60 months median follow-up, 13 invasive events occurred (P+T: n = 11, P+T+paclitaxel: n = 2), none following pCR. Gene signatures related to immune response (IR) and ER signaling were favorable for iDFS, all with similar HR about 0.43-0.55. These patterns were even more prominent in the neoadjuvant chemotherapy-free group, where additionally BRCAness signature was unfavorable (HR, 2.00; 95% CI, 1.04-3.84). IR signatures were strongly intercorrelated. sTILs (baseline/week 3/change) were not associated with pCR or iDFS, though baseline sTILs correlated positively with IR signatures. CONCLUSIONS: Distinct gene signatures were associated with pCR versus iDFS in HER2+/HR- EBC. The potential role of IR in preventing recurrence suggests that patients with upregulated IR signatures could be candidates for de-escalation concepts in HER2+ EBC.

Hypofractionated Whole Breast Irradiation and Boost-IOERT in Early Stage Breast Cancer (HIOB): First Clinical Results of a Prospective Multicenter Trial (NCT01343459).

Background and purpose: To investigate intraoperative electron radiation therapy (IOERT) as a tumor bed boost during breast conserving surgery (BCS) followed by hypofractionated whole breast irradiation (HWBI) on age-correlated in-breast recurrence (IBR) rates in patients with low- to high-risk invasive breast cancer. Material and methods: BCS and IOERT (11.1 Gy) preceded a HWBI (40.5 Gy) in 15 fractions. Five-year IBR-rates were compared by a sequential ratio test (SQRT) with best evidences in three age groups (35−40 y and 41−50 y: 3.6%, >50 y: 2%) in a prospective single arm design. Null hypothesis (H0) was defined to undershoot these benchmarks for proof of superiority. Results: Of 1445 enrolled patients, 326 met exclusion criteria, leaving 1119 as eligible for analysis. After a median follow-up of 50 months (range 0.7−104), we detected two local recurrences, both in the age group >50 y. With no observed IBR, superiority was demonstrated for the patient groups 41−50 and >50 y, respectively. For the youngest group (35−40 y), no appropriate statistical evaluation was yet possible due to insufficient recruitment. Conclusions: In terms of five-year IBR-rates, Boost-IOERT followed by HWBI has been demonstrated to be superior in patients older than 50 and in the age group 41−50 when compared to best published evidence until 2010.

Does the Presence of Circulating Tumor Cells in High-Risk Early Breast Cancer Patients Predict the Site of First Metastasis-Results from the Adjuvant SUCCESS A Trial.

The prognostic relevance of circulating tumor cells (CTCs) in breast cancer is well established. However, little is known about the association of CTCs and site of first metastasis. In the SUCCESS A trial, 373 out of 3754 randomized high-risk breast cancer patients developed metastatic disease. CTC status was assessed by the FDA-approved CellSearch®-System (Menarini Silicon Biosystems, Bologna, Italy) in 206 of these patients before chemotherapy and additionally in 159 patients after chemotherapy. CTCs were detected in 70 (34.0%) of 206 patients before (median 2 CTCs, 1-827) and in 44 (27.7%) of 159 patients after chemotherapy (median 1 CTC, 1-124); 16 (10.1%) of 159 patients were CTC-positive at both timepoints. The site of first distant disease was bone-only, visceral-only, and other-site-only in 44 (21.4%), 60 (29.1%), and 74 (35.9%) patients, respectively, while 28 (13.6%) patients had multiple sites of first metastatic disease. Patients with CTCs at both timepoints more often showed bone-only first distant disease (37.5% vs. 21.0%) and first distant disease at multiple sites (31.3% vs. 12.6%) than patients without CTCs before and/or after chemotherapy (p = 0.027). In conclusion, the presence of CTCs before and after chemotherapy is associated with multiple-site or bone-only first-distant disease and may trigger intensified follow-up and perhaps further treatment.

Endocrine Therapy Response and 21-Gene Expression Assay for Therapy Guidance in HR+/HER2- Early Breast Cancer.

PURPOSE: To our knowledge, WSG-ADAPT-HR+/HER2- (ClinicalTrials.gov identifier: NCT01779206; n = 5,625 registered) is the first trial combining the 21-gene expression assay (recurrence score [RS]) and response to 3-week preoperative endocrine therapy (ET) to guide systemic therapy in early breast cancer. MATERIALS AND METHODS: Baseline and postendocrine Ki67 (Ki67post) were evaluated centrally. In the endocrine trial, all patients received exclusively ET: patients with pathologic regional lymph node status (pN) 0-1 (ie, 0-3 involved lymph nodes) entered control arm if RS ≤ 11 and experimental arm if RS12-25 with ET response (Ki67post ≤ 10%). All other patients (including N0-1 RS12-25 without ET response) received dose-dense chemotherapy (CT) followed by ET in the CT trial. Primary end point of the endocrine trial was noninferiority of 5-year invasive disease-free survival (5y-iDFS) in experimental (v control) arm; secondary end points included distant DFS, overall survival, and translational research. RESULTS: Intention-to-treat population comprised 2,290 patients (n = 1,422 experimental v n = 868 control): 26.3% versus 34.6% premenopausal and 27.4% versus 24.0% pN1. One-sided 95% lower confidence limit of the 5y-iDFS difference was -3.3%, establishing prespecified noninferiority (P = .05). 5y-iDFS was 92.6% (95% CI, 90.8 to 94.0) in experimental versus 93.9% (95% CI, 91.8 to 95.4) in control arm; 5-year distant DFS was 95.6% versus 96.3%, and 5-year overall survival 97.3% versus 98.0%, respectively. Differences were similar in age and nodal subgroups. In N0-1 RS12-25, outcome of ET responders (ET alone) was comparable with that of ET nonresponders (CT) for age > 50 years and superior for age ≤ 50 years. ET response was more likely with aromatase inhibitors (mostly postmenopausal) than with tamoxifen (mostly premenopausal): 78.1% versus 41.1% (P < .001). ET response was 78.8% in RS0-11, 62.2% in RS12-25, and 32.7% in RS > 25 (n = 4,203, P < .001). CONCLUSION: WSG-ADAPT-HR+/HER2- demonstrates that guiding systemic treatment by both RS and ET response is feasible in clinical routine and spares CT in pre- and postmenopausal patients with ≤ 3 involved lymph nodes.

De-escalated Neoadjuvant Chemotherapy in Early Triple-Negative Breast Cancer (TNBC): Impact of Molecular Markers and Final Survival Analysis of the WSG-ADAPT-TN Trial.

PURPOSE: Although optimal treatment in early triple-negative breast cancer (TNBC) remains unclear, de-escalated chemotherapy appears to be an option in selected patients within this aggressive subtype. Previous studies have identified several pro-immune factors as prognostic markers in TNBC, but their predictive impact regarding different chemotherapy strategies is still controversial. EXPERIMENTAL DESIGN: ADAPT-TN is a randomized neoadjuvant multicenter phase II trial in early patients with TNBC (n = 336) who were randomized to 12 weeks of nab-paclitaxel 125 mg/m2 + gemcitabine or carboplatin d 1,8 q3w. Omission of further (neo-) adjuvant chemotherapy was allowed only in patients with pathological complete response [pCR, primary endpoint (ypT0/is, ypN0)]. Secondary invasive/distant disease-free and overall survival (i/dDFS, OS) and translational research objectives included quantification of a predictive impact of markers regarding selection for chemotherapy de-escalation, measured by gene expression of 119 genes (including PAM50 subtype) by nCounter platform and stromal tumor-infiltrating lymphocytes (sTIL). RESULTS: After 60 months of median follow-up, 12-week-pCR was favorably associated (HR, 0.24; P = 0.001) with 5y-iDFS of 90.6% versus 62.8%. No survival advantage of carboplatin use was observed, despite a higher pCR rate [HR, 1.04; 95% confidence interval (CI), 0.68-1.59]. Additional anthracycline-containing chemotherapy was not associated with a significant iDFS advantage in pCR patients (HR, 1.29; 95% CI, 0.41-4.02). Beyond pCR rate, nodal status and high sTILs were independently associated with better iDFS, dDFS, and OS by multivariable analysis. CONCLUSIONS: Short de-escalated neoadjuvant taxane/platinum-based combination therapy appears to be a promising strategy in early TNBC for using pCR rate as an early decision point for further therapy (de-) escalation together with node-negative status and high sTILs. See related commentary by Sharma, p. 4840.

Identification and characterization of 12 microsatellite loci in Cnidium dubium (Apiaceae) using next-generation sequencing.

PREMISE OF THE STUDY: We present a set of 12 polymorphic nuclear microsatellite loci, identified for the first time within the herbaceous plant species Cnidium dubium (Schkuhr) Thell. using next-generation sequencing. METHODS AND RESULTS: To characterize these loci, 40 plants were analyzed genetically. The number of alleles ranged from 2 to 23, with an average of 8.3 alleles per locus. Mean observed and expected heterozygosities ranged from 0.25 to 0.95 and 0.30 to 0.94, respectively. CONCLUSIONS: All 12 nuclear microsatellite loci showed scorable and polymorphic fragments after polymerase chain reaction. The new marker set can be used for future studies of genetic diversity and differentiation as well as estimation of gene flow and spatial genetic structures.

Smoking complicates the course of non-infectious uveitis.

BACKGROUND: Data concerning the association of smoking and uveitis are limited. The aim of this study was to evaluate the effect of tobacco smoking on uveitis activity and complications of noninfections uveitis and the need for immunosuppressive therapy. METHODS: We conducted an observational cross-sectional study in 350 patients with noninfectious uveitis. All patients completed a questionnaire concerning smoking habits. Primary outcome measure was uveitis activity in smokers as compared to nonsmokers; secondary outcome measures were need for immunosuppression and uveitis complications. RESULTS: In all 115 patients (32.9%) were smokers. Smokers had an increased risk for active uveitis (OR 1.8; 95% CI, 1.2-2.9; p = 0.007). Smokers with anterior uveitis had anterior chamber cells more often than nonsmokers (p = 0.008) and required significantly more topical steroid eyedrops (p = 0.002). Uveitis developed at a younger age in smokers than in nonsmokers (p = 0.027). The number of smokers who needed any second-line immunosuppression (p = 0.642) and the number of immunosuppressive agents required (p = 0.794) did not differ from that for nonsmokers. The number of pack-years significantly increased the risk of macular edema (p = 0.020) und cataract (p = 0.022). CONCLUSIONS: Smoking is associated with uveitis activity, leading to increased need for steroid eyedrops and increased incidence of cataract and macular edema. The results highlight the need to encourage uveitis patients to stop or at least to reduce their smoking.

The use of breast ultrasound for prediction of pathologic complete response in different subtypes of early breast cancer within the WSG-ADAPT subtrials.

OBJECTIVE: We assessed the value of breast ultrasound (US) performed at week 3 and 6 and at the end (EOT) of neoadjuvant therapy (NAT) for prediction of pathologic complete response (pCR, ypT0/is ypN0) in patients with HR+/HER2+, HR-/HER2-or HR-/HER2+ early breast cancer enrolled in the WSG-ADAPT subtrials. METHODS: US was performed at week 3 and 6 of NAT and at EOT in 401, 517, and 553 patients, respectively. Tumors with complete or partial response by US (RECIST 1.1) were classified as responders and those with stable or progressive disease as non-responders. RESULTS: pCR rate was higher in US responders than in non-responders. US tended to yield the highest positive predictive value in HR-/HER2+ (69%) and HR-/HER2-tumors (65%) at week 3, and the highest negative predictive value in HR+/HER2+ tumors at week 6 and at EOT (88.9% and 86.9%, respectively) and in HR-/HER2-tumors at EOT (87.9%). Multivariable analysis of patients with US at week 3 and 6 identified tumor subtype (HR-/HER2+ vs HR+/HER2+; odds ratio (OR) 2.77, 95%CI 1.45-5.29, and OR 4.17, 95%CI 2.26-7.68, respectively) and each 10% change in lesion dimension on US from baseline (OR 1.15, 95%CI 1.08-1.24, and OR 1.25, 95%CI 1.16-1.35, respectively) as parameters associated with pCR. CONCLUSIONS: Our data support the use of week 3 and EOT US for prediction of pCR in response-guided NAT and in planning of breast-conserving surgery. Change in tumor diameter on US as a continuous variable could be a valuable alternative to categorical RECIST 1.1 criteria.

Immune Markers and Tumor-Related Processes Predict Neoadjuvant Therapy Response in the WSG-ADAPT HER2-Positive/Hormone Receptor-Positive Trial in Early Breast Cancer.

Prognostic or predictive biomarkers in HER2-positive early breast cancer (EBC) may inform treatment optimization. The ADAPT HER2-positive/hormone receptor-positive phase II trial (NCT01779206) demonstrated pathological complete response (pCR) rates of ~40% following de-escalated treatment with 12 weeks neoadjuvant ado-trastuzumab emtansine (T-DM1) ± endocrine therapy. In this exploratory analysis, we evaluated potential early predictors of response to neoadjuvant therapy. The effects of PIK3CA mutations and immune (CD8 and PD-L1) and apoptotic markers (BCL2 and MCL1) on pCR rates were assessed, along with intrinsic BC subtypes. Immune response and pCR were lower in PIK3CA-mutated tumors compared with wildtype. Increased BCL2 at baseline in all patients and at Cycle 2 in the T-DM1 arms was associated with lower pCR. In the T-DM1 arms only, the HER2-enriched subtype was associated with increased pCR rate (54% vs. 28%). These findings support further prospective pCR-driven de-escalation studies in patients with HER2-positive EBC.

TP53 mutations are associated with primary endocrine resistance in luminal early breast cancer.

BACKGROUND: Whereas the genomic landscape of endocrine-resistant breast cancer has been intensely characterized in previously treated cases with local or distant recurrence, comparably little is known about genomic alterations conveying primary non-responsiveness to endocrine treatment in luminal early breast cancer. METHODS: In this study, 622 estrogen receptor-expressing breast cancer cases treated with short-term preoperative endocrine therapy (pET) from the WSG-ADAPT trial (NCT01779206) were analyzed for genetic alterations associated with impaired endocrine proliferative response (EPR) to 3-week pET with tamoxifen or aromatase inhibitors. EPR was categorized as optimal (post-pET Ki67 <10%) versus slightly, moderately, and severely impaired (post-pET Ki67 10%-19%, 20%-34%, and ≥35%, respectively). Recently described gene mutations frequently found in previously treated advanced breast cancer were analyzed (ARID1A, BRAF, ERBB2, ESR1, GATA3, HRAS, KRAS, NRAS, PIK3CA, and TP53) by next-generation sequencing. Amplifications of CCND1, FGFR1, ERBB2, and PAK1 were determined by digital PCR or fluorescence in situ hybridization. RESULTS: ERBB2 amplification (p = 0.0015) and mutations of TP53 (p < 0.0001) were significantly associated with impaired EPR. Impaired EPR in TP53-mutated breast cancer cases was independent from the Oncotype DX Recurrence Score group and was seen both with tamoxifen- and aromatase inhibitor-based pET (p = 0.0005 each). CONCLUSION: We conclude that impaired EPR to pET is suitable to identify cases with primary endocrine resistance in early luminal breast cancer and that TP53-mutated luminal cancers might not be sufficiently treated by endocrine therapy alone.

Immune cell composition and functional marker dynamics from multiplexed immunohistochemistry to predict response to neoadjuvant chemotherapy in the WSG-ADAPT-TN trial.

BACKGROUND: The association of early changes in the immune infiltrate during neoadjuvant chemotherapy (NACT) with pathological complete response (pCR) in triple-negative breast cancer (TNBC) remains unexplored. METHODS: Multiplexed immunohistochemistry was performed in matched tumor biopsies obtained at baseline and after 3 weeks of NACT from 66 patients from the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer - Triple Negative Breast Cancer (WSG-ADAPT-TN) trial. Association between CD4, CD8, CD73, T cells, PD1-positive CD4 and CD8 cells, and PDL1 levels in stroma and/or tumor at baseline, week 3 and 3-week change with pCR was evaluated with univariable logistic regression. RESULTS: Compared with no change in immune cell composition and functional markers, transition from 'cold' to 'hot' (below-median and above-median marker level at baseline, respectively) suggested higher pCR rates for PD1-positive CD4 (tumor: OR=1.55, 95% CI 0.45 to 5.42; stroma: OR=2.65, 95% CI 0.65 to 10.71) and PD1-positive CD8 infiltrates (tumor: OR=1.77, 95% CI 0.60 to 5.20; stroma: OR=1.25, 95% CI 0.41 to 3.84; tumor+stroma: OR=1.62, 95% CI 0.51 to 5.12). No pCR was observed after 'hot-to-cold' transition in PD1-positive CD8 cells. pCR rates appeared lower after hot-to-cold transitions in T cells (tumor: OR=0.26, 95% CI 0.03 to 2.34; stroma: OR=0.35, 95% CI 0.04 to 3.25; tumor+stroma: OR=0.00, 95% CI 0.00 to 1.04) and PD1-positive CD4 cells (tumor: OR=0.60, 95% CI 0.11 to 3.35; stroma: OR=0.22, 95% CI 0.03 to 1.92; tumor+stroma: OR=0.32, 95% CI 0.04 to 2.94). Higher pCR rates collated with 'altered' distribution (levels below-median and above-median in tumor and stroma, respectively) of T cell (OR=3.50, 95% CI 0.84 to 14.56) and PD1-positive CD4 cells (OR=4.50, 95% CI 1.01 to 20.14). CONCLUSION: Our exploratory findings indicate that comprehensive analysis of early immune infiltrate dynamics complements currently investigated predictive markers for pCR and may have a potential to improve guidance for individualized de-escalation/escalation strategies in TNBC.