West German Study Research Articles

Abstract PS09-01: Individual patient data meta-analysis of clinical and translational biomarkers for prediction of pathological complete response (pCR) after de-escalated therapy in HER2+ breast cancer in four trials of the West German Study Group

Abstract Background Introduction of anti-HER2 therapies substantially improved outcomes for HER2-positive early breast cancer (HER2+ eBC). However, a considerable proportion of patients (pts) may still be overtreated with systemic chemotherapy (CTx) combinations. Establishing safe de-escalation strategies to avoid toxicities requires precise patient selection. Therefore, we set out to determine predictors for efficacy and survival in the unique setting of four de-escalation trials investigating short (12-week) neoadjuvant treatments (NAT) in HER2+ eBC. We investigated the prognostic ability of clinical and translational biomarkers for pCR to identify pts with the best prognosis after de-escalated systemic CTx-free NAT. Methods 756 pts who received de-escalated NAT were analyzed: trastuzumab + pertuzumab (T + P, n=92) and T + P + paclitaxel (pac, n=42) in ADAPT-HR-/HER2+ (NCT01817452); trastuzumab emtansine (T-DM1, n=118), T-DM1 + endocrine therapy (ET, n=125), and T + ET (n=129) in ADAPT-HR+/HER2+ (NCT01779206), T + P + pac (n=107) and T + P + ET (n=100) in TP-II (NCT03272477); and T + P + pembrolizumab (n=43) in Keyriched-1 (NCT03988036) in HER2-enriched (HER2-E) subtype by PAM50. The primary endpoint of each trial was pCR (ypT0/is ypN0). Survival was a secondary endpoint in all trials but Keyriched-1; survival data for TP-II are pending. Baseline gene expression was analyzed by BC360 assay; intrinsic molecular subtypes were determined using the PAM50 predictor. Stromal tumor infiltrating lymphocytes (sTILs) were evaluated at baseline and at week 3 of NAT. sTILs were categorized using a 30% threshold and the low cellularity category ( < 500 invasive tumor cells) at week 3. Prognostic markers for pCR were identified with univariate and multivariable logistic regression models with backstep algorithm excluding variables with p≥0.1; considered variables included age, sTILs (baseline, 3-weeks), cT, cN, grade, hormone receptor and HER2 status, intrinsic subtype, and standardized ERBB2 and ESR1 gene expression. These analyses were performed separately for NAT involving systemic CTx (i.e. containing pac, n=149) and systemic CTx-free NAT (n=607). Results Overall pCR rate was 39.1% (CTx: 66.4%; CTx-free: 32.5%). Multivariable analysis identified predictors of pCR after CTx-free NAT: low cellularity at week 3 (vs < 30% sTILs: OR 3.21, 95%CI 1.85-5.57), ERBB2 (OR 1.90, 95%CI 1.41-2.55), HER2 3+ (vs 1+/2+ and ISH+: OR 8.01, 95%CI 1.65-38.99), LumA/LumB/Basal subtype (vs HER2-E: OR 0.57, 95%CI 0.34-0.97), cT2 (vs 1: OR 0.54, 95%CI 0.33-0.89), and cN1-3 (vs 0, OR 0.46, 95%CI 0.27-0.78). In CTx-containing NAT, only ERBB2 (OR 2.08, 95%CI 1.28-3.40) and additionally ESR1 (OR 0.38, 95%CI 0.23-0.61) were prognostic for pCR. Updated analysis including expanded gene expression data from ADAPT-HR+/HER2+ and a prognostic score for pCR after CTx-free NAT developed using machine learning methods will be presented at the meeting. Conclusions This pooled analysis demonstrated a 66% pCR rate after a short (12-week) de-escalated NAT in HER2+ eBC. In one-third of patients (with mainly stage I cancer, higher HER2 expression by immunohistochemistry and gene expression analysis, and low cellularity at 3 weeks), pCR can be achieved without systemic CTx. Identified biomarkers could pave the way for developing new patient selection strategies to spare CTx-associated acute and late toxicities in a clinically meaningful number of patients. Citation Format: Monika Graeser, Oleg Gluz, Christine zu Eulenburg, Sherko Küemmel, Raquel von Schumann, Matthias Christgen, Rachel Wuerstlein, Enrico Pelz, Hans-Heinrich Kreipe, Peter Schmid, Marc Thill, Michael Braun, Jochem Potenberg, Claudia Schumacher, Joke Tio, Andreas Hartkopf, Marianne Just, Christian Schem, Kerstin Lüdtke-Heckenkamp, Eva-Maria Grischke, Felix Hilpert, Angela Kentsch, Ronald Kates, Ulrike Nitz, Nadia Harbeck. Individual patient data meta-analysis of clinical and translational biomarkers for prediction of pathological complete response (pCR) after de-escalated therapy in HER2+ breast cancer in four trials of the West German Study Group [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS09-01.

Abstract PO2-19-07: PROOFS – Pre-/perimenopausal patients with HR+/HER2- EBC with intermediate to high clinical and low genomic risk, treated by endocrine treatment (ET) plus ovarian function suppression (OFS) or chemotherapy followed by ET

Abstract Background During the past years, clinical routine has shifted away from relying solely on clinicopathologic factors toward increasing use of multigene expression assays in guiding treatment decisions regarding adjuvant chemotherapy (CT) for hormone receptor-positive (HR+), HER2-negative (HER2-) early breast cancer (EBC) with 0 to 3 positive lymph nodes. In case of a low genomic risk, there is strong consensus in favor of endocrine treatment (ET) alone for postmenopausal patients, regardless of clinical risk (supported by data from planB, ADAPT, RxPonder, TailorX, MINDACT). However, there is still uncertainty regarding optimal therapy for pre- and perimenopausal patients with a similar clinical/genomic risk profile. Since the observed benefit of CT in this patient group may be partly attributable to CT-induced ovarian function suppression (OFS), some of these patients could be spared CT by adding OFS to endocrine therapy. The West German Study Group (WSG) initiated the PROOFS-registry to create a real-world database on how to optimally treat these patients. Eligibility Criteria PROOFS (NCT05792150) aims at the long-term follow up of pre- or perimenopausal patients with HR+/HER2- EBC with an intermediate to high clinical risk of recurrence and low genomic risk measured by MammaPrint(R). Additional endocrine response assessment (Ki67) after a short preoperative endocrine therapy is encouraged. Up to 25% of the study population may have node-positive disease. Participants undergo standard-of-care treatment at physician´s discretion and according to clinical routine, which may include CT neoadjuvant or adjuvant + ET, ET + OFS in premenopausal, or ET +/- OFS in perimenopausal women. Specific Aims PROOFS aims to give insights in the real-world use of OFS and to confirm an excellent outcome in pre-/perimenopausal women with HR+/HER2- early BC with an intermediate to high clinical risk of recurrence and low genomic risk treated by ET +/- OFS alone (without CT). In addition, quality of life is captured. Statistical Methods The primary objective is to demonstrate the 5-year distant recurrence-free interval (dRFI) in patients treated by ET +/- OFS alone. The null hypothesis H(0) is: 5-year dRFI < 92%. Secondary endpoints for all patients are 5- and 10-year dRFI, distant disease-free survival (dDFS), overall survival (OS), breast cancer-free interval (BCFI), quality of life (QLQ BR23 and QLQ-C30) and therapy adherence. Cox regression models, Kaplan-Meier method and log-rank tests will be applied for survival analysis. Linear mixed models will be utilized to quantitatively describe the course of quality of life-scores as well as therapy adherence, and to conduct group comparisons. Present and Target Accrual The study is open for recruitment of 1500 patients (approximately 20% receiving CT and 80% receiving ET +/- OFS) at up to 100 centers in Germany (June 2023: 24 open for recruitment). Funding AGENDIA N.V., Amsterdam Contact Information rachel.wuerstlein@med.uni-muenchen.de Citation Format: Rachel Wuerstlein, Lotta Ada Fischer, Nadia Harbeck, Monika Graeser, Ulrike Nitz, Matthias Christgen, Sherko Kuemmel, Christine zu Eulenburg, Matthias Warm, Oleg Gluz. PROOFS – Pre-/perimenopausal patients with HR+/HER2- EBC with intermediate to high clinical and low genomic risk, treated by endocrine treatment (ET) plus ovarian function suppression (OFS) or chemotherapy followed by ET [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-07.

P53 Expression in Luminal Breast Cancer Correlates With TP53 Mutation and Primary Endocrine Resistance

TP53 mutation is associated with primary endocrine resistance in luminal breast cancer (BC). Nuclear accumulation of p53, as determined by immunohistochemistry (IHC), is a surrogate marker for TP53 mutation. The immunohistochemical p53 index that defines a p53-positive status is not well established. This study determined the optimal p53 index cutoff to identify luminal BCs harboring TP53 mutations. In total, 364 luminal BCs from the West German Study Group ADAPT trial (NCT01779206) were analyzed for TP53 mutations by next-generation sequencing and for p53 expression by IHC (DO-7 antibody). P53 indices were determined by automated image analysis. All tumors were from patients treated with short-term preoperative endocrine therapy (pET; tamoxifen or aromatase inhibitor) before tumor resection. IHC evaluation included needle biopsies before therapy (baseline) and resections specimens after therapy (post-pET). Optimal p53 index cutoffs were defined with Youden statistics. TP53 mutations were detected in 16.3% of BC cases. The median p53 indices were significantly higher in TP53-mutated BCs compared to BCs harboring wild-type TP53 (baseline: 47.0% vs 6.4%, P < .001; post-pET: 50.1% vs 1.1%, P < .001). Short-term pET decreased p53 indices in BCs harboring wild-type TP53 (P < .001) but not in TP53-mutated BCs (P = .102). For baseline biopsies, the optimal p53 index cutoff was ≥34.6% (specificity 0.92, sensitivity 0.63, Youden index 0.54, accuracy: 0.87). For post-pET specimens, the optimal cutoff was ≥25.3% (specificity 0.95, sensitivity 0.65, Youden index 0.60, accuracy: 0.90). Using these cutoffs to define the p53 status, p53-positive BCs were >2-fold more common in pET nonresponders compared to pET responders (baseline: 37/162, 22.8% vs 18/162, 11.1%, P = .007; post-pET: 36/179, 20.1% vs 16/179, 8.9%, P = .004). In summary, IHC for p53 identifies TP53-mutated luminal BCs with high specificity and accuracy. Optimal cutoffs are ≥35% and ≥25% for treatment-naïve and endocrine-pretreated patients, respectively.

Top 3 abstracts concerning hormone-receptor-positive early breast cancer

SummaryThe three top abstracts at the 2020 virtual San Antonio Breast Cancer Symposium regarding hormone-receptor-positive early breast cancer, from our point of view, were the long-awaited results from PenelopeBand RxPONDER as well as the data from the ADAPT trial of the West German Study Group. PenelopeBfailed to show any benefit by adjuvant palbociclib when added to standard endocrine therapy in patients without pathologic complete response after neoadjuvant chemotherapy. RxPONDER demonstrated that postmenopausal patients with early hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2−) breast cancer, 1–3 positive lymph nodes and an Oncotype DX Recurrence Score of less than 26 can safely be treated with endocrine therapy alone. In contrast, in premenopausal women with positive nodes, adjuvant chemotherapy plays still a role even in case of low genomic risk. Whether the benefit by chemotherapy is mainly an indirect endocrine effect and if ovarian function suppression would be similarly effective, is still a matter of debate. The HR+/HER2− part of the ADAPT umbrella trial investigated the role of a Ki-67 response to a short endocrine therapy before surgery in addition to Oncotype DX—performed on the pretreatment biopsy—to identify low-risk patients who can safely forgo adjuvant chemotherapy irrespective of menopausal status.

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

BackgroundThe 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.MethodsMultiplexed immunohistochemistry was performed in matched...

Abstract GS4-04: Endocrine therapy alone in patients with intermediate or high-risk luminal early breast cancer (0-3 lymph nodes), Recurrence Score &amp;lt;26 and Ki67 response after preoperative endocrine therapy: Primary outcome results from the WSG-ADAPT HR+/HER2- trial

Abstract Background: In HR+/HER2- N0 early breast cancer (EBC), patients (pts) with Recurrence Score™ (RS)&amp;lt;26 (postmenopausal) and &amp;lt;16 (premenopausal) have excellent prognosis and do not benefit fromadditional chemotherapy. However, prognostic impact of RS in N+ disease and importance of Ki67response after short preoperative endocrine therapy (ET) in the context of genomic signatures remainunclear. For the first time, we present survival results from the large prospective phase III WSG-ADAPTHR+/HER- trial combining both static (RS in baseline core biopsy) and dynamic (Ki67 response)biomarkers to optimize adjuvant therapy in luminal EBC. Methods: 5625 pts were registered and 4691 finally treated by ET (n=2356) or CT (n=2335) within ADAPTHR+/HER2-. ET-trial ITT population comprised 2290 pts: n=868 RS0-11, n=1422 RS12-25/ET-response(30% premenopausal, 26% N1). 5y-iDFS was 93.9% (95%-CI: [91.8% to 95.4%]) in RS0-11 and 92.6%(95%-CI: [90.8% to 94.0%]) in RS12-25/ET-responders. Since the one-sided upper 95% confidence limitof the 5y-iDFS difference was 3.3%, the pre-specified criterion to accept the primary NI-hypothesis wasmet (p=.05).5y-dDFS was 96.3% [94.6% to 97.5%] vs. 95.6% [94.2% to 96.7%]) in RS0-11 vs. RS12-25/ET-responders,respectively (95%-CI for 5y-dDFS difference: [-1.2% to 2.6%]). 5y-OS was also excellent and similar(98.0% [96.7% to 98.9%] vs. 97.3% [96.1 to 98.1%]) in RS0-11 vs. RS12-25/ET-responders, respectively(95% CI for the 5y-OS difference: [-0.7% to 2.2%]). Results: 5625 pts were registered and 4691 finally treated by ET (n=2356) or CT (n=2335) within ADAPTHR+/HER2-. ET-trial ITT population comprised 2290 pts: n=868 RS0-11, n=1422 RS12-25/ET-response(30% premenopausal, 26% N1). 5y-iDFS was 93.9% (95%-CI: [91.8% to 95.4%]) in RS0-11 and 92.6%(95%-CI: [90.8% to 94.0%]) in RS12-25/ET-responders. Since the one-sided upper 95% confidence limit of the 5y-iDFS difference was 3.3%, the pre-specified criterion to accept the primary NI-hypothesis was met (p=.05) 5y-dDFS was 96.3% [94.6% to 97.5%] vs. 95.6% [94.2% to 96.7%]) in RS0-11 vs. RS12-25/ET-responders, respectively (95%-CI for 5y-dDFS difference: [-1.2% to 2.6%]). 5y-OS was also excellent and similar (98.0% [96.7% to 98.9%] vs. 97.3% [96.1 to 98.1%]) in RS0-11 vs. RS12-25/ET-responders, respectively (95% CI for the 5y-OS difference: [-0.7% to 2.2%]). Conclusions: In pN0-1 luminal EBC pts receiving ET alone, pts with RS12-25/ET-response had 5y-iDFSwell above 90% and very close to RS0-11 pts. Both groups had excellent similar dDFS and OS. DynamicET response thus complements RS as a key selection criterion for omission of chemotherapy in pN0-1HR+/HER2- EBC. Citation Format: Nadia Harbeck, Oleg Gluz, Sherko Kuemmel, Matthias Christgen, Michael Braun, Bahriye Aktas, Kerstin Luedtke-Heckenkamp, Helmut Forstbauer, Eva-Maria Grischke, Claudia Schumacher, Maren Darsow, Katja Krauss, Benno Nuding, Marc Thill, Jochem Potenberg, Christoph Uleer, Mathias Warm, Hans H. Fischer, Wolfram Malter, Michael Hauptmann, Ronald Kates, Monika Graeser, Rachel Wuerstlein, Steve Shak, Rick Baehner, Hans Kreipe, Ulrike Nitz, West German Study Group. Endocrine therapy alone in patients with intermediate or high-risk luminal early breast cancer (0-3 lymph nodes), Recurrence Score &amp;lt;26 and Ki67 response after preoperative endocrine therapy: Primary outcome results from the WSG-ADAPT HR+/HER2- 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 GS4-04.

Abstract OT-01-02: Adaptlate -a randomized, controlled, open-label, phase-iii trial on adjuvant dynamic marker - adjusted personalized therapy comparing abemaciclib combined with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy in (clinical or genomic) high risk, hr+/her2- early breast cancer

Abstract Goals: The WSG ADAPT trial program is one of the first new generation trials addressing the issue of individualization of (neo)-adjuvant decision-making in early breast cancer (EBC) in a subtype-specific manner. The first WSG ADAPT umbrella trial (NCT01779206) aimed to establish early predictive molecular surrogate markers for response after a short 3-week induction treatment and to omit chemotherapy in a large cohort of early high risk HR+/HER2- patients. The aim of the ADAPTlate phase-III-trial is to improve adjuvant therapy for patients at high risk for late disease recurrence, who have completed definite locoregional therapy (with or without neoadjuvant or adjuvant chemotherapy) and are under adjuvant endocrine treatment. This high-risk population does not derive optimal benefit from standard ET, often develops secondary resistance against ET and consequently late recurrences. With ADAPTlate, it is planned to evaluate whether patients with high-risk EBC derive additional benefit from adding abemaciclib to ET even 2-6 year after their initial diagnosis. Abemaciclib has been shown to improve outcome in metastatic breast cancer and recently, even in early breast cancer when given as part of primary therapy. Methods: WSG-ADAPTcycle is a prospective, multi-center, interventional, two-arm, non-blinded, randomized, controlled adjuvant phase III trial (NCT not yet assigned). It investigates whether patients with HR+/HER2- EBC identified as high-risk during screening (based on clinical or genomic risk) derive additional benefit from 2 years of the CDK4/6 inhibitor abemaciclib combined with ET compared to ET alone. Starting Q3 2020 (enrollment 36 months, 50 sites), 1250 patients will be screened and 903 randomized in a ratio 3:2 (602 to abemaciclib + ET; 301 to standard ET). Pre-/postmenopausal patients with histologically confirmed invasive HR+/HER2- EBC and 2-6 years after primary diagnosis, with either known high clinical risk (c/pN 2-3 OR high CTS score in pN 0-1 OR non-pCR after neoadjuvant chemotherapy in cN 1 or G3 tumors OR G3 and Ki-67 ≥ 40% in pN 0-1) or known high genomic risk (Oncotype Dx® / RS &amp;gt;25 in c/pN 0, RS &amp;gt;18 in c/pN 1 OR high risk Prosigna®, EPclin® or Mammaprint® in pN 0-1) or intermediate clinical, but unknown genomic risk (luminal B-like (G3 or Ki-67 ≥20%) in c/pN 0-1 AND Oncotype DX® in screening either RS &amp;gt;25 in c/pN 0 or RS &amp;gt;18 in c/p N1) will be eligible. Treatment duration is 2 years for the interventional abemaciclib + ET (premenopausal: AI+GnRH) arm, followed by at least 3-6 years ET alone. Patients in control arm will receive 5-8-years ET at investigator´s choice. ePROs are collected using CANKADO. Primary objective is to demonstrate superiority of invasive disease-free survival (iDFS) of abemaciclib + ET vs. standard ET. Secondary objectives include overall survival (OS), distant disease-free survival (dDFS), occurrence of CNS metastases, quality of life (EORTC QLQ-C30, QLQ-BR23, EQ-5D-5L) and translational research. Translational analyses: Exploratory tissue biomarker research will be conducted to assess alterations in molecular markers (e.g., ESR1, PIK3CA, CCND1, CDKN2A, RB1). In addition, ctDNA/ctRNA from optional blood samples will be assessed for mutations and gene expression relevant for HR+/HER2- EBC using the most appropriate technology at the time of testing. Conclusions: ADAPTlate seeks to evaluate whether enhancing ET with a CDK 4/6 inhibitor is superior to ET alone in patients with clinical or genomic high risk EBC even 2-6 years after their initial diagnosis. Translational research aims at assessing potential mechanisms of resistance to endocrine and/or CDK4/6 targeted therapy. Citation Format: Oleg Gluz, Tom Degenhardt, Norbert Marschner, Matthias Christgen, Hans Heinrich Kreipe, Ulrike Nitz, Ronald Kates, Timo Schinkoethe, Monika Graeser, Rachel Würstlein, Sherko Kuemmel, Nadia Harbeck, West German Study Group. Adaptlate -a randomized, controlled, open-label, phase-iii trial on adjuvant dynamic marker - adjusted personalized therapy comparing abemaciclib combined with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy in (clinical or genomic) high risk, hr+/her2- early breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-01-02.

Abstract GS4-03: Neoadjuvant nab-paclitaxel weekly versus dose-dense paclitaxel followed by dose-dense EC in high risk HR+/HER2- early BC by: Results from the neoadjuvant part of ADAPT HR+/HER2- trial

Abstract Background: Pathological complete response (pCR) is associated with improved outcome in patients with high-risk HR+/HER2- breast cancer (BC) but the use of (neo)adjuvant chemotherapy in early HR+/HER2- BC remains controversial. Oncotype DX / Recurrence Score (RS) and dynamic Ki67 response after short preoperative endocrine therapy are potentially predictive for pCR. Still, no prospective data are available so far to predict chemotherapy efficacy in this key patient group. Use of dose-dense chemotherapy is associated with improved outcome in meta-analysis, but its use in the neoadjuvant setting is less studied. Furthermore, use of nab-paclitaxel instead of solvent-based paclitaxel has shown promising results in some studies. Here, we present for the first time data from a randomized prospective trial comparing these risk-selection strategies according to RS and Ki67 decrease in high-risk HR+/HER2- BC. Methods: High-risk BC patients [cN0-1 with RS&amp;gt;25 or (RS 12-25 AND (centrally measured) post-endocrine Ki67 &amp;gt;10%] OR [cN2-3 status] OR [G3 AND Ki67&amp;gt;40%] were randomized to (neo)adjuvant 4x paclitaxel175 q2w or 8xnab-paclitaxel 125 mg/m2q1w followed by 4x E90C600 q2w. pCR was defined as no invasive tumor in breast and lymph nodes. Results: 858 patients with available surgery data randomized to neoadjuvant Pac-EC (N=423) or nab-Pac-EC (N=435) were analyzed. Median age was 51 years; median RS was 30 (N=572); 34% had node-positive; 46% (locally) G3 tumors. Baseline characteristics were well balanced between study arms. Patients receiving nab-Pac-EC had higher pCR than those with Pac-EC (20.3% vs. 12.3%, p=.002); patients with RS&amp;lt;25 (about 27%) had a lower pCR rate than those with RS&amp;gt;25 (6.5% vs. 15.8%, p=.003). The association of RS with pCR appeared more pronounced in premenopausal women, but a test of interaction was not significant; RS was about 3 points higher (mean 32.9 vs. 29.8, p&amp;lt;.001) in postmenopausal cases (p=.001). Clinical tumor stage cT2-4 was reported in 65%, with a lower pCR rate than in cT1 tumors (14% vs. 20%, p=.02). RS was moderately correlated (R=.45) with baseline Ki67. In multivariable analysis with tumor stage, RS, Ki67, menopausal status, and ER and PR positivity, higher RS and cT1 stage were favorable for pCR. Excluding RS, higher Ki67 and lower ER (as well as cT1) were favorable. In patients with RS&amp;lt;25, there was no pCR with Pac-EC (0/72 pCR); pCR was almost 20% with RS&amp;gt;25 and nab-Pac-EC. Further details and data including impacts of Ki67 dynamics and additional markers on pCR will be presented at the meeting. Conclusions: Use of neoadjuvant nab-paclitaxel instead of solvent-based paclitaxel appears promising within a short (16-weeks) dose-dense chemotherapy schedule in high-risk HR+/HER2- BC. For the first time, data from a large neoadjuvant randomized trial confirm RS could help to select patients for neoadjuvant chemotherapy in high-risk HR+/HER2- breast cancer (BC). Citation Format: Sherko Kuemmel, Oleg Gluz, Ulrike Nitz, Michael Braun, Matthias Christgen, Kerstin Luedtke-Heckenkamp, Raquel von Schumann, Maren Darsow, Helmut Forstbauer, Jochem Potenberg, Eva-Maria Grischke, Bahriye Aktas, Claudia Schumacher, Ronald Kates, Monika Graeser, Rachel Wuerstlein, Christoph Uleer, Michael Hauptmann, Steve Shak, Rick Baehner, Hans Kreipe, Nadia Harbeck, West German Study Group. Neoadjuvant nab-paclitaxel weekly versus dose-dense paclitaxel followed by dose-dense EC in high risk HR+/HER2- early BC by: Results from the neoadjuvant part of ADAPT HR+/HER2- 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 GS4-03.

Utility of the 21-Gene Recurrence Score in Node-Positive Breast Cancer.

The 21-gene Recurrence Score (RS) assay has been validated as both a prognostic and predictive tool in node-negative (pN0), estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer. A large body of evidence supports the clinical utility of the RS in the node positive (pN+) population as well. Retrospective analyses of archived tissue from multiple clinical trials have found the RS to be prognostic in both endocrine therapy (ET)-treated and chemotherapy-treated patient with pN+ disease. Distribution of RS results in pN+ patients have also been consistent with those of pN0 populations. Data from the SWOG 8814 trial and large population-based registries further support the prognostic and potential predictive value of the RS. Specifically, patients with 1 to 3 positive nodes and RS less than 18 derived negligible benefit from adjuvant chemotherapy in these studies. In the prospective West German Study Group PlanB and ADAPT trials, pN+ patients with RS less than 11 and RS 25 or less, respectively, who were treated with ET alone experienced excellent outcomes. Finally, 5-year results of the RxPONDER clinical trial randomizing patients with 1 to 3 positive nodes and RS 25 or less to ET alone vs ET plus chemotherapy confirmed an absence of chemotherapy benefit in postmenopausal patients. Clinical practice guidelines support use of the RS in the pN+, ER+/HER2- population, and many institutions have adopted the RS to guide clinical decisionmaking, resulting in a net reduction of adjuvant chemotherapy use. This review highlights the existing data supporting the prognostic and predictive ability of the RS in pN+ disease, current practice patterns related to RS use in this population, and emerging applications.

Differential impact of prognostic parameters in hormone receptor-positive lobular breast cancer.

Invasive lobular breast cancer (BC) is the second most common BC subtype. Prognostic parameters (tumor classification, lymph node status, histologic grade, Oncotype DX recurrence score [RS], progesterone receptor status, and Ki67 index) were retrospectively studied in a large, prospective clinical trial encompassing 2585 patients who had hormone receptor-positive early BC (the West German Study Group PlanB trial). BCs were centrally reviewed and classified as lobular (n=353; 14%) or nonlobular (n=2232; 86%). The median follow-up was 60 months. Five-year disease-free survival (DFS) estimates were obtained using the Kaplan-Meier method. Prognostic parameters were evaluated using Cox proportional hazard models. Lobular BC was associated with higher tumor classification, higher lymph node status, lower histologic grade, lower Ki67 index, and low or intermediate RS. The prevalence of high RS (RS range, 26-100) was 3-fold lower in patients who had lobular BC compared with those who had nonlobular BC (8% vs 24%; P<.001). However, 5-year DFS estimates for lobular and nonlobular BC were similar (92.1% and 92.3%, respectively; P=.673). In multivariate analyses, prognostic parameters for DFS in lobular BC included grade 3 (hazard ratio, 5.06; 95% CI, 1.91-13.39) and a pathologic lymph node status (pN) of pN3 (hazard ratio, 12.16; 95% CI, 3.87-38.24), but not RS. By contrast, prognostic parameters in nonlobular BC included grade 3 (hazard ratio, 1.65; 95% CI, 1.11-2.44), pN3 (hazard ratio, 3.68; 95% CI, 1.60-8.46), and high RS (hazard ratio, 2.49; 95% CI, 1.69-3.68). Lobular BC is associated with low and intermediate RS, although 5-year DFS is similar to that of nonlobular BC. The effect of the RS in lobular BC appears to be distinct from that in nonlobular BC. For risk assessment, the RS needs to be complemented by clinicopathologic parameters for therapy decision making.

ERBB2 mRNA Expression and Response to Ado-Trastuzumab Emtansine (T-DM1) in HER2-Positive Breast Cancer.

Trastuzumab emtansine (T-DM1) is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer (BC) and for residual disease after neoadjuvant therapy; however, not all patients benefit. Here, we hypothesized that the heterogeneity in the response seen in patients is partly explained by the levels of human epidermal growth factor receptor 2 gene (ERBB2) mRNA. We analyzed ERBB2 expression using a clinically applicable assay in formalin-fixed paraffin-embedded (FFPE) tumors (primary or metastatic) from a retrospective series of 77 patients with advanced HER2+ BC treated with T-DM1. The association of ERBB2 levels and response was further validated in 161 baseline tumors from the West German Study (WGS) Group ADAPT phase II trial exploring neoadjuvant T-DM1 and 9 in vitro BC cell lines. Finally, ERBB2 expression was explored in 392 BCs from an in-house dataset, 368 primary BCs from The Cancer Genome Atlas (TCGA) dataset and 10,071 tumors representing 33 cancer types from the PanCancer TCGA dataset. High ERBB2 mRNA was found associated with better response and progression-free survival in the metastatic setting and higher rates of pathological complete response in the neoadjuvant setting. ERBB2 expression also correlated with in vitro response to T-DM1. Finally, our assay identified 0.20–8.41% of tumors across 15 cancer types as ERBB2-high, including gastric and esophagus adenocarcinomas, urothelial carcinoma, cervical squamous carcinoma and pancreatic cancer. In particular, we identified high ERBB2 mRNA in a patient with HER2+ advanced gastric cancer who achieved a long-lasting partial response to T-DM1. Our study demonstrates that the heterogeneity in response to T-DM1 is partly explained by ERBB2 levels and provides a clinically applicable assay to be tested in future clinical trials of breast cancer and other cancer types.

Abstract P4-10-05: Predictive value of HER2 expression, early response and tumor infiltrating lymphocytes (TILs) on efficacy of de-escalated pertuzumab+trastuzumab in the neoadjuvant WSG-ADAPT-HER2+/HR- trial

Abstract Purpose: Only limited data are available on predictive markers for use of chemotherapy-free, anti-HER2 combinations in HER2-positive early breast cancer (eBC), in particular within the molecularly distinct HER2+/HR- subgroup. Background: In the ADAPT HER2+/HR- trial, a promising pCR of about 43-45% was found in patients treated by 4 cycles of pertuzumab and trastuzumab with either defined early response (low tumor cellularity or relative Ki-67 decrease ≥30%) or indeterminate early response (e.g. no visible tumor by ultrasound), compared to under 10% in early non-responders. In addition to early response, HER2 protein expression and stromal TIL (s-TIL) dynamics after one cycle of therapy are promising tools for identification of patients with high likelihood of pathological complete response (pCR) after therapy with double anti-HER2 blockade (e.g. by lapatinib+trastuzumab) or T-DM1. Methods: Patients with cT1-cT4c, cN0-3 early HER2+/HR- BC (n=134) were treated with 4 cycles of P+T +/- paclitaxel d1,8,15 q3w. Primary endpoint of the study was pCR (ypT0/is, ypN0). All tumors were HR-negative (ER and PR&amp;lt;1%) and locally HER2 positive, i.e., 2+ with positive FISH or 3+ by immunohistochemistry (IHC). HR and HER2 status were confirmed by central pathology prior to randomization. Tumors were classified as “HER2-low” if HER2-1+ or HER2-2+ by either local or central IHC assessment, otherwise “HER2-high”. s-TILs were measured semi-quantitively according to current international consensus in triplicate at baseline and on-treatment (at cycle 2); the median of the three measurements was taken to define the quantities TIL-0 and TIL-3, respectively. “Lymphocyte-dominant subtype” at baseline and cycle 2 were defined as TIL-0≥40% and TIL-3≥40%, respectively. The present analysis characterizes the predictive impact of early response HER2 protein expression, and s-TILs on pCR under dual anti-HER2 therapy for the first time within a prospective neoadjuvant trial specific to the HER2+/HR- BC subtype. Results: As previously reported, pCR was 34.4% without chemotherapy and 90.5% with chemotherapy. TIL-0 and TIL-3 were available in n=119/134 and n=103/134 patients, respectively. TIL-0 and TIL-3 were not significantly associated with pCR in the whole cohort or within the T+P arm, either modeled as a continuous variable or in terms of binary variables representing lymphocyte-dominant subtype or defined by the respective population medians. HER2-high expression was found in 87% of patients. In the T+P arm, pCR was much higher in HER2-high than HER2-low patients (40.3% vs. 0%, p=.003). In the T+P arm, 24 and 38 of 92 patients were classified as non- and responders, unclassified early response was observed in 30 of 92 patients. pCR in these groups were 8.3% vs. 44.7% vs. 42.9% respectively. Higher baseline TILs were positively associated with early response. Clinically meaningful pCR of 49% after only 4 cycles of chemotherapy-free P+T was seen in those patients with early response after one cycle of therapy and HER2-high classification, compared to 11.8% in the HER2-high/non-responder group). Conclusions: At present, a combination of baseline high HER2 expression with low cellularity after one cycle of neoadjuvant therapy – rather than s-TIL determination (at baseline or in response to therapy) – appears to be a simple and feasible tool for identification of candidates for de-escalated treatment in HER2+/HR- disease. Further research on high-precision determination of HER2-high expression (by immunohistochemistry vs. mRNA-based tools) is strongly needed for optimal patient selection for future chemotherapy de-escalation trials. Citation Format: Oleg Gluz, Cornelia Kolberg-Liedtke, Claudia Biehl, Matthias Christgen, Sherko Kuemmel, Eva-Maria Grischke, Doris Augustin, Michael Braun, Jochem Potenberg, Monika Graeser, Ronald Kates, Rachel Wuerstlein, Friedrich Feuerhake, Ulrike Nitz, Hans Kreipe, Nadia Harbeck, West German Study Group. Predictive value of HER2 expression, early response and tumor infiltrating lymphocytes (TILs) on efficacy of de-escalated pertuzumab+trastuzumab in the neoadjuvant WSG-ADAPT-HER2+/HR- trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-05.

Abstract P2-16-05: Efficacy of response- and toxicity-guided neoadjuvant chemotherapy in elderly early breast cancer patients: Results of WSG ADAPT elderly sub-trial

Abstract Introduction: More than 1/3 of early breast cancers (EBC) are diagnosed in women ≥ 70 years. Although polychemotherapy has been shown to be more effective than monochemotherapy also in these patients, only limited prospective data on efficacy of neoadjuvant therapy are available so far. Here, we present results of the prospective ADAPT Elderly sub-study from the WSG ADAPT umbrella protocol. Methods: Patients ≥70 years with high-risk HR+/HER2- EBC (i.e. Recurrence Score (RS)&amp;gt;25 or RS 12-25 with post-endocrine Ki67 of &amp;gt;10% or ≥cN2) or HR-/HER2- EBC were treated by 2 cycles of liposomal doxorubicin (Myocet® 60 mg/m2)/cyclophosphamide 600 mg/m2 (MC). In case of clinical response by ultrasound (&amp;gt;50% reduction in the sum of two largest diameters) and no AE grade 3-4, patients received an additional 2 cycles MC, otherwise they were switched to 6 cycles of paclitaxel (80 mg/m2) weekly. A sample size of n=150 was planned to demonstrate non-inferiority of the response- and toxicity-guided regimen vs. 4 cycles MC in responding patients (25% assumed pCR). The study was stopped early due to slow recruitment. Results: Between 09/2014 and 10/2015, 83 EBC patients from 31 centers were registered; 78 started with therapy (40 HR+/HER2-; 38 HR-/HER2-). Median age was 74 years. 64% had G3 tumors, 66% cT24, and 34% cN+. Median Ki67 was 40%. 75/78 pts underwent stratification after 2 cycles; 1 pt withdrew consent: 45(61%) were responders with no severe toxicities, 29 (39%) non-responders or suffered toxicity grade 3-4. Surgical information is available in 72 patients (43 responder/no toxicity, 29 no response/toxicity groups respectively). pCR was observed in 7 patients in the responder/no toxicity group (i.e. 16% irrespective of HR status) and in n=3 patients in the no response/toxicity group (10%). Updated efficacy and safety data will be presented at the meeting. Discussion: In one of the largest neoadjuvant chemotherapy-studies specifically for elderly pts with HER2- EBC, we observed a lower than expected pCR rate after 4 cycles of anthracycline-containing neoadjuvant chemotherapy. Taxane-based standard chemotherapy may thus be preferable in this population. Nevertheless, neoadjuvant chemotherapy seems feasible in elderly pts with high-risk HER2- EBC and should further be explored in the context of potential pCR-based (de)escalation strategies. Citation Format: Sherko Kuemmel, Oleg Gluz, Matthias Christgen, Jochem Potenberg, John Hackmann, Raquel von Schumann, Monika Graeser, Marina Mangold, Rachel Wuerstlein, Ronald Kates, Hans H. Kreipe, Ulrike Nitz, Nadia Harbeck, West German Study Group. Efficacy of response- and toxicity-guided neoadjuvant chemotherapy in elderly early breast cancer patients: Results of WSG ADAPT elderly sub-trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-05.

Abstract PD5-10: Impact of immune markers on response to neoadjuvant de-escalated T-DM1 or trastuzumab with/or without endocrine therapy in HR+/HER2+ early breast cancer: A translational subproject of the WSG-ADAPT-HER2+/HR+ trial

Abstract Background: Among patients with highly heterogeneous HER2+ breast cancer (BC), pathological complete response (pCR) (ypT0/is/ypN0) is associated with improved prognosis. The prospective, phase-II neoadjuvant 3-arm WSG HER2+/HR+ trial (ADAPT-TP) showed pCR rates of about 41.0% after 4xT-DM1+/-ET and 15% after trastuzumab+ET. Pre-planned translational analysis of ADAPT-TP has revealed several biomarkers with impact on pCR, such as PIK3CA mutation status, HER2-enriched subtype (by PAM50), Bcl-2 and most notably immune biomarkers (e.g.CD8/tumor center). In particular, higher CD8 protein expression values either at baseline and/or after one cycle (3w) of neoadjuvant therapy were favorable for pCR. Moreover, CD8 and PDL1 dynamics were indicators of early therapy response, and dynamical response was itself favorable for pCR. The impact of immune biomarkers suggests that tumor infiltrating lymphocytes (TILs) could serve as predictive markers for de-escalated anti-HER2 therapy, in particular T-DM1. Methods: Semi-quantitative, triplicate TIL measurements were performed in tissue obtained at baseline (TIL-0) and at 3 weeks (TIL-3). At each timepoint, the median of the three measurements was used for analysis. CD8 and PD-L1 expression measurements were obtained by mRNA at baseline at both time points by immunohistochemistry (IHC). Associations of semiquantitative TIL-0/TIL-3 levels with pCR and with other clinical/pathological measurements were analyzed using logistic regression, rank correlations, t and chi-square statistics. Results: TIL-0 and TIL-3 were available in 355/375 and 301/375 randomized patients, respectively. Associations of TIL-0, TIL-3 and TIL-dynamics (increase from TIL-0 to TIL-3) with CD8 and PD-L1 (including dynamics) and with clinical factors (tumor size, nodal status, ER and PR status, grade, patient age, Ki67 and menopausal status) revealed several prominent relationships: Both TIL-0 and TIL-3 were at least moderately correlated with IHC measurements of CD8 (at center, not at invasive margin) and of PD-L1 at both timepoints. At cycle 2, the correlation of TILs and CD8 was strong, particularly in the T-DM1 arms (r=.7, p&amp;lt;.001). CD8 by mRNA was moderately correlated with TIL-0. Correlations between clinical factors and TILs at both timepoints were weak. These associations with known factors influencing pCR suggest a possible direct association of TILs with pCR; logistic regression using standardized TIL-0 revealed a modest (standardized) odds ratio of about 1.4 for pCR for TIL-0 in the T-DM1 arms, though not in the whole cohort. In particular, patients receiving T-DM1 with TIL0≥40% (about 8%) had pCR of 70% vs. 40% pCR for others (p=.016). We observed a dynamic increase of TILs during T-DM1 treatment of about 10 percentage points. However, neither these dynamics nor TIL-3 were significantly associated with pCR (in contrast to CD8 protein expression at cycle 2). Interpretation: To the best of our best knowledge, these are the first prospective data regarding the predictive value of TILs and TIL dynamics in HR+/HER2+ BC treated with de-escalated anti-HER2 therapy. Very high TIL levels (&amp;gt;40%) were associated with an excellent pCR rate of 70% in TDM1treated patients. However, CD8 expression and dynamics of CD8 were more strongly predictive for efficacy of de-escalated treatment than TILs – despite promising data on baseline and/or on-treatment TILs as markers for improved prognosis and higher sensitivity to (dual) anti-HER2 blockade (with or without chemotherapy) in unselected HER2+ BC. Further research on static and dynamic immune markers (according to HR+ and HR-/HER2+ subtypes) is needed prior to final conclusions regarding the clinical impact of TILs in early HER2+ BC. Citation Format: Claudia Biehl, Cornelia Kolberg-Liedtke, Oleg Gluz, Friedrich Feuerhake, Matthias Christgen, Ronald Kates, Eva-Maria Grischke, Helmut Forstbauer, Michael Braun, Mathias Warm, John Hackmann, Christoph Uleer, Bahriye Aktas, Claudia Schumacher, Sherko Kuemmel, Sanne L de Haas, Regula Deurloo, Rachel Wuerstlein, Ulrike Nitz, Hans H. Kreipe, Nadia Harbeck, West German Study Group. Impact of immune markers on response to neoadjuvant de-escalated T-DM1 or trastuzumab with/or without endocrine therapy in HR+/HER2+ early breast cancer: A translational subproject of the WSG-ADAPT-HER2+/HR+ trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD5-10.

ADAPTcycle: Adjuvant dynamic marker-adjusted personalized therapy comparing endocrine therapy plus ribociclib versus chemotherapy in intermediate-risk HR+/HER2- early breast cancer.

TPS596 Background: WSG (West German Study Group)-ADAPTcycle is a prospective, multi-center, interventional, two-arm, open-label, controlled (neo)adjuvant, non-blinded, randomized phase III trial (EudraCT 2018-003749-40). It investigates whether HR+/HER2- intermediate-risk patients (pts) (about 20 % of HR+/HER2- early breast cancer, EBC) identified during screening (OncotypeDX and 3-week endocrine therapy (ET)) derive additional benefit from 2-years of the CDK4/6 inhibitor ribociclib plus ET compared to chemotherapy (CT) (followed by adjuvant ET). Co-primary endpoints are disease-free and distant disease-free survival. Methods: Starting Q1 2019 (enrollment 36 months, 80 sites), 5600 pts will be screened and 1670 randomized in a 3:2 ratio (1002 to ribociclib + ET; 668 to standard CT followed by ET). Pre-/postmenopausal pts with histologically confirmed invasive HR+/HER2- EBC at clinically enhanced risk (cT2-4 or Ki67 &gt; 20 % or G3 or cN+) are eligible if they fulfill the ADAPT intermediate-risk group criteria: Recurrence Score (RS) ≤ 25 and poor endocrine response or RS &gt; 25 and good endocrine response in p/cN0-1 pts or RS ≤ 25 with good endocrine response in c/pN2-3 pts. Endocrine responsiveness is determined by Ki67 response (drop to ≤ 10 %) after 3-week ET. Treatment duration is 2 years for the ribociclib + ET (premenopausal: AI + GnRH) arm and 16-24 weeks for the CT arm; treatment can be given in the neoadjuvant or adjuvant setting. 5-year follow-up consists of standard adjuvant ET. Patient reported outcomes (ePROs) are collected using CANKADO; ECG monitoring is performed using a novel CANKADO-based methodology. For translational analyses, tumor tissue will be collected at baseline (prior to ET), after 3-weeks ET (+/- 1w). Additional samples are required if residual tumor is diagnosed in case of neoadjuvant treatment and at time of recurrence. Exploratory tissue biomarker research will be conducted to assess alterations of molecular markers (e. g., ESR1, PIK3CA, CCND1, CDKN2A, RB1). Circulating DNA and tumor cells from blood samples will be used to assess mutations, gene expression, etc. Clinical trial information: 2018-003749-40.

De-Escalation Strategies in Human Epidermal Growth Factor Receptor 2 (HER2)–Positive Early Breast Cancer (BC): Final Analysis of the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early BC HER2- and Hormone Receptor–Positive Phase II Randomized Trial—Efficacy, Safety, and Predictive Markers for 12 Weeks of Neoadjuvant Trastuzumab Emtansine With or Without

Purpose Human epidermal growth factor receptor 2 (HER2)-positive/hormone receptor (HR)-positive breast cancer is a distinct subgroup associated with lower chemotherapy sensitivity and slightly better outcome than HER2-positive/HR-negative disease. Little is known about the efficacy of the combination of endocrine therapy (ET) with trastuzumab or with the potent antibody-cytotoxic, anti-HER2 compound trastuzumab emtansine (T-DM1) with or without ET for this subgroup. The West German Study Group trial, ADAPT (Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer) compares pathologic complete response (pCR) rates of T-DM1 versus trastuzumab with ET in early HER2-positive/HR-positive breast cancer. Patients and Methods In this prospective, neoadjuvant, phase II trial, 375 patients with early breast cancer with HER2-positive and HR-positive status (n = 463 screened) were randomly assigned to 12 weeks of T-DM1 with or without ET or to trastuzumab with ET. The primary end point was pCR (ypT0/is/ypN0). Early response was assessed in 3-week post-therapeutic core biopsies (proliferation decrease ≥ 30% Ki-67 or cellularity response). Secondary end points included safety and predictive impact of early response on pCR. Adjuvant therapy followed national standards. Results Baseline characteristics were well balanced among the arms. More than 90% of patients completed the therapy per protocol. pCR was observed in 41.0% of patients treated with T-DM1, 41.5% of patients treated with T-DM1 and ET, and 15.1% with trastuzumab and ET ( P < .001). Early responders (67% of patients with assessable response) achieved pCR in 35.7% compared with 19.8% in nonresponders (odds ratio, 2.2; 95% CI, 1.24 to 4.19). T-DM1 was associated with a significantly higher prevalence of grade 1 to 2 toxicities, especially thrombocytopenia, nausea, and elevation of liver enzymes. Overall toxicity was low; seventeen therapy-related severe adverse events (T-DM1 arms v trastuzumab plus ET; 5.3% v 3.1%, respectively) were reported. Conclusion The ADAPT HER2-positive/HR-positive trial demonstrates that neoadjuvant T-DM1 (with or without ET) given for only 12 weeks results in a clinically meaningful pCR rate. Thus, a substantial number of patients are spared the adverse effects of systemic chemotherapy.

Reducing chemotherapy use in clinically high-risk, genomically low-risk pN0 and pN1 early breast cancer patients: five-year data from the prospective, randomised phase 3 West German Study Group (WSG) PlanB trial

BackgroundThe prospective phase 3 PlanB trial used the Oncotype DX® Recurrence Score® (RS) to define a genomically low-risk subset of clinically high-risk pN0-1 early breast cancer (EBC) patients for treatment with adjuvant endocrine therapy (ET) alone. Here, we report five-year data evaluating the prognostic value of RS, Ki-67, and other traditional clinicopathological parameters.MethodsA central tumour bank was prospectively established within PlanB. Following an early amendment, hormone receptor (HR)+ , pN0-1 RS ≤ 11 patients were recommended to omit chemotherapy. Patients with RS ≥ 12, pN2-3, or HR-negative/HER2-negative disease were randomised to anthracycline-containing or anthracycline-free chemotherapy. Primary endpoint: disease-free survival (DFS). PlanB Clinicaltrials.gov identifier: NCT01049425.FindingsFrom 2009 to 2011, PlanB enrolled 3198 patients (central tumour bank, n = 3073) with the median age of 56 years, 41.1% pN+, and 32.5% grade 3 EBC. Chemotherapy was omitted in 348/404 (86.1%) eligible RS ≤ 11 patients. After 55 months of median follow-up, five-year DFS in ET-treated RS ≤ 11 patients was 94% (in both pN0 and pN1) versus 94% (RS 12–25) and 84% (RS > 25) in chemotherapy-treated patients (p < 0.001); five-year overall survival (OS) was 99 versus 97% and 93%, respectively (p < 0.001). Nodal status, central/local grade, tumour size, continuous Ki-67, progesterone receptor (PR), IHC4, and RS were univariate prognostic factors for DFS. In a multivariate analysis including all univariate prognostic markers, only pN2-3, central and local grade 3, tumour size >2 cm, and RS, but not IHC4 or Ki-67 were independent adverse factors. If RS was excluded, IHC4 or both Ki-67 and PR entered the model. The impact of RS was particularly pronounced in patients with intermediate Ki-67 (>10%, <40%) tumours.InterpretationThe excellent five-year outcomes in clinically high-risk, genomically low-risk (RS ≤ 11) pN0-1 patients without adjuvant chemotherapy support using RS with standardised pathology for treatment decisions in HR+ HER2-negative EBC. Ki-67 has the potential to support patient selection for genomic testing.

The West German Study Group Breast Cancer Intrinsic Subtype study: a prospective multicenter decision impact study utilizing the Prosigna assay for adjuvant treatment decision-making in estrogen-receptor-positive, HER2-negative early-stage breast cancer

Purpose: The West German Study Group (WSG) Breast Cancer Intrinsic Subtype (BCIST) study was designed to assess the influence of Prosigna gene signature assay results on physicians’ adjuvant treatment recommendations by determining the extent of change in pre-test treatment recommendations following assay results. Secondary objectives were to assess the influence of Prosigna results on physicians’ confidence in their therapeutic recommendations and on patients’ decisional conflict status, anxiety levels, and functional status. Methods: This prospective, observational, decision impact study enrolled consecutive postmenopausal patients with estrogen-receptor (ER)-positive, HER2-negative, lymph-node-negative early-stage breast cancer in 11 centers in Germany. Physicians based their pre-test adjuvant treatment recommendations on standard clinico-pathological parameters. Tumor specimens were assayed using the Prosigna test in a WSG central pathology laboratory following manufacturer’s guidelines. An independent pathology laboratory performed subsequent Prosigna assays on tumor sections to assess assay result concordance with the central laboratory. Physicians completed treatment confidence questionnaires prior to and after receiving Prosigna test results. Patients completed standardized questionnaires on decisional conflict, anxiety, and health status both before and after Prosigna testing. Results: The present study population consisted predominantly of low-to-intermediate risk patients (N = 198). Prosigna had 29.3% discordance in intrinsic subtyping with local immunohistochemistry test results. After Prosigna test results, a change in the adjuvant therapy recommendation occurred in 36 (18.2%) patients; 22 (11.1%) patients switched from no chemotherapy to chemotherapy. After Prosigna test results, physicians expressed increased confidence in their prognostic assessment in 87.9% of patients, and increased confidence in their treatment recommendation in 89.4%. Patients reported improved anxiety and emotional/functional well-being after receiving Prosigna test results. Conclusions: Use of the Prosigna assay led to a change in 18.2% of adjuvant treatment decisions. Prosigna testing was associated with increased patient and physician confidence in treatment decisions, and with decreased patient anxiety and improved well-being. Any comparison of the therapeutic decision-making impacts of different genomic assays must account for potential confounding factors.

Abstract OT3-2-03: Prospective observational study of clinical outcomes for the NanoString® technologies Prosigna™ test by the West German Study Group

Abstract Background: Current diagnostic tools for breast cancer (BC), including screening, diagnostic breast imaging and biopsy, do not provide information about subtype classification. However, the subtype classification is crucial for the assessment of the recurrence risk and for the choice of optimal adjuvant treatment. A vast amount of data from recent research, clinical trials, and peer reviewed publications support the value of intrinsic subtyping based on gene expression analyses to assess prognosis and treatment options for patients with early BC. Trial design: The multicenter (n=8), prospective study examines whether the Prosigna™ test influences physician and patient adjuvant treatment selection over and above currently used prognostic factors. It also examines the impact of the test results on patients’ reported outcomes including their decisional conflict status, anxiety levels, and functional status. Prosigna™ is a standardized test measuring the expression levels of 50 classifier genes in formalin-fixed, paraffin-embedded tissue samples and provides a subtype classification based on the fundamental biology of individual patient’s tumor (intrinsic subtyping), as well as a prognostic score (risk of recurrence (ROR) score) that predicts the probability of cancer recurrence over 10 years. Eligibility criteria: Postmenopausal women with resected N0, estrogen-receptor-positive (ER) (by immunohistochemistry (IHC); &amp;gt;1% of stained tumor cells is considered positive), HER2-negative (IHC and/or in-situ fluorescence hybridization by local laboratory), early-stage invasive BC (T1-T2, pN0 (i+/mol+), M0). Patients must be able to give consent and must be eligible for treatment with adjuvant chemotherapy (Ctx) (ECOG performance status ≤1). Patients with non-invasive (e.g. Paget’s disease, DCIS), ER-negative or HER2-positive BC must not be included. Metastatic disease and contraindications for adjuvant Ctx (age, ECOG &amp;gt;1, significant comorbidities) are exclusion criteria. Patients unable to complete patient reported outcome surveys will be excluded. Specific aims: Primary endpoint is the proportion of patients whose choice of treatment is changed as a result of receiving the Prosigna™ result. Secondary endpoints include the proportion of patients whose choice of treatment is changed stratified by ROR groups (low, intermediate, high) and who have cancer recurrence risk proximal to the cutoff points between risk strata (± 5% from cutoff point). Investigators’ confidence in treatment recommendations before/after Prosigna™ results and change in patients’ decisional conflict status, anxiety levels, and functional status, stratified by cancer recurrence risk strata, will be investigated. Rate and severity of treatment-related adverse events stratified by whether patient received adjuvant Ctx and agreement in molecular subtyping between Prosigna™ and local IHC will be evaluated. Statistical methods: Sample size of 200 produces a one-sided 95% lower-limit CI with a distance from the sample proportion to the lower limit that is equal to 0.05 when the sample proportion is 0.25. Present and target accrual: A total of 200 patients will be included, current accrual is n=111 as of 3rd June 2014. Citation Format: Rachel Wuerstlein, Karl Sotlar, Burkhard Otremba, Oleg Gluz, Enrico Pelz, Daniel Hofmann, Ronald E Kates, Isabelle Witzel, Christian Schindlbeck, Wolfgang Janni, Christian Schem, Hans Tesch, Nadia Harbeck. Prospective observational study of clinical outcomes for the NanoString® technologies Prosigna™ test by the West German Study Group [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-2-03.

Abstract P3-10-12: Pilot Phase of the Randomized PlanB Trial: Prospective Comparison of Molecular Classification, Oncotype DX® and Clinical-Pathological Characteristics in Hormone-Receptor (HR) Positive Primary Breast Cancer

Abstract Background: Despite progress in adjuvant breast cancer (BC) treatment, overtreatment due to decisions based on conventional prognostic factors (lymph nodes (LN), grade, tumor size) alone remains an important clinical problem. Recurrence Score®, RS is validated using pre-specified analyses, genes, cutt-offs in several randomized patient collectives as a potent prognostic and predictive marker in HR positive BC. Here, we present the first WSG-Plan B trial preplanned correlation analysis of central grade, nodal status, RS, and luminal A/B subtypes. Material and Methods: The West German Study Group (WSG) Plan B trial (planned n=2,448) is a randomized Phase-III-trial evaluating anthracyline-free adjuvant chemotherapy (Cht) (6x TC) vs. standard 4xEC-4xDOC in high-risk N0 and N+ HER2-negative BC. In HR+ BC with 0-3 LN, RS is the decision criterion for (&amp;gt;11) or against (≥11) Cht randomization. Tumor blocks are prospectively evaluated by a central pathologist for grade, histology and Ki-67. In HR+ disease, molecular subtypes (luminal A vs. B) are grouped using a Ki-67 cut-off of 13.25% (Cheang et al, JNCI 2009) and 20% (Penault-Llorca et al JCO 2009). Exploratory analysis with Elston-Ellis central grade and Ki-67 based (mitosis measured by Ki-67) grade will be performed. Results: As of June 2010, 1375 patients in 96 centers have been registered and 1067 randomized into Plan B. In 298 patients, RS results and clinical-pathological characteristics were available. In 266 patients complete information on all factors was available (132 N0, 134 N+). RS groups using the pre-specified trial cut-offs of 0-11, 12-25 and &amp;lt;25 were 21%, 59%, and 20%, respectively, with a median of 18. RS groups using the standard cutt-offs (&amp;lt;18/18-30/&amp;gt;30) were 48%, 38%, 14%. Central grade 1, 2, or 3 was observed in 4%, 50%, and 46% of cases. We observed a modest (Spearman) correlation between central grade and RS (e.g 83.8% of G3 tumors with RS &amp;gt;25, rs=0.331, P&amp;lt;0.001), Ki-67 based grade (rs=0.34, P&amp;lt;0.001), and Ki-67 as continuous variable (median 20), (rs=0.438, P&amp;lt;0.001). No significant correlation was observed between nodal groups (0 vs. 1-3 vs. 4+) and RS groups (e.g. RS≥11 in N0/1-3/4+: 17.8%/22.6%/25.0%; p=0.253) Modest correlations were found for luminal A/B subtypes by both Ki-67 cut-off's (13.25%; 20%) and RS groups using our conservative trial cut-off (12/12-25/&amp;gt;25), and guideline-recommended &amp;lt;18/18-30/&amp;gt;30 (see table 1).Discussion: For the first time, we demonstrate a modest but significant correlation between centrally assed tumor grade, molecular classes by IHC Ki-67 cutt offs, and RS, particularly in the high RS group. However, our data also indicate that there is substantial discordance between the methods and thus an urgent need for optimzing risk-stratification classifiers. Table 1. Association of RS and molecular subtypes Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-12.