Diskordanz der Prognosefaktoren beim frühen Mammakarzinom (Recurrence Score, zentrales Grading, Ki67) und deren Einfluss auf die frühe Rezidivierung in der prospektiven Phase III WSG-planB Studie

2015 ◽  
Vol 12 (02) ◽  
Author(s):  
O Gluz ◽  
N Harbeck ◽  
R Kates ◽  
H Kreipe ◽  
M Christgen ◽  
...  
Keyword(s):  
Recurrence Score ◽  
Phase Iii

scholarly journals Response to Induction Neoadjuvant Hormonal Therapy Using Upfront 21-Gene Breast Recurrence Score Assay—Results From the SAFIA Phase III Trial

2021 ◽  
pp. 811-819
Author(s):  
Khalid AlSaleh ◽  
Heba Al Zahwahry ◽  
Adda Bounedjar ◽  
Mohammed Oukkal ◽  
Ahmed Saadeddine ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Interim Analysis ◽  
Growth Factor Receptor ◽  
Recurrence Score ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Hormone Sensitivity ◽  
Epidermal Growth ◽  
Breast Recurrence

PURPOSE Luminal, human epidermal growth factor receptor 2–negative breast cancer represents the most common subtype of breast malignancies. Neoadjuvant strategies of operable breast cancer are mostly based on chemotherapy, whereas it is not completely understood which patients might benefit from neoadjuvant hormone therapy (NAHT). MATERIALS AND METHODS The SAFIA trial is a prospective multicenter, international, double-blind, neoadjuvant phase III trial, using upfront 21-gene Oncotype DX Breast Recurrence Score assay (recurrence score [RS] < 31) to select operable luminal human epidermal growth factor receptor 2–negative patients, for induction hormonal therapy HT (fulvestrant 500 mg with or without goserelin) before randomly assigning responding patients to fulvestrant 500 mg (with or without goserelin) plus either palbociclib (cyclin-dependent kinase 4/6 inhibitor) or placebo. The objectives of this interim analysis were to assess the feasibility of upfront RS determination on core biopsies in the Middle-East and North Africa region and evaluate the efficacy of induction NAHT in patients with an RS < 31. RESULTS At the time of this interim analysis, 258 patients with relative risk were accrued, including 202 patients (RS < 31% to 78.3%) treated with induction NAHT and 182 patients evaluable so far for response. The feasibility of performing the Oncotype DX assays on core biopsy specimens was optimal in 96.4% of cases. Overall, 93.4% of patients showed hormone sensitivity and no difference in NAHT efficacy was noticed between RS 0-10, 11-25, and 26-30. Interestingly, patients with high RS (26-30) showed a trend toward a higher major response rate ( P = .05). CONCLUSION The upfront 21-gene assay performed on biopsies is feasible in our population and has allowed us to select patients with high hormone sensitivity (RS < 31). This approach could be an alternative to upfront surgery without significant risk of progression, particularly during pandemic times.

Prognostic impact of recurrence score, endocrine response and clinical-pathological factors in high-risk luminal breast cancer: Results from the WSG-ADAPT HR+/HER2- chemotherapy trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 504-504
Author(s):  
Oleg Gluz ◽  
Ulrike Nitz ◽  
Matthias Christgen ◽  
Michael Braun ◽  
Kerstin Luedtke-Heckenkamp ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
High Risk ◽  
Recurrence Score ◽  
Phase Iii ◽  
Luminal Breast Cancer ◽  
Prognostic Impact ◽  
Treatment Intensification ◽  
Ki 67 ◽  
Prospective Phase ◽  
High Risk Cohort

504 Background: In HR+/HER2- N0-1 early BC, postmenopausal patients (pts) with RS™ > 25 and a substantial proportion of premenopausal pts seem to benefit from addition of adjuvant chemotherapy (CT) to endocrine therapy (ET). However, the magnitude of absolute benefit from this treatment intensification seems to depend on clinical-pathological and biological prognostic factors. For the first time, we present outcome from the CT part of the prospective phase III WSG-ADAPT HR+/HER- trial combining both static (RS in baseline core biopsy (CB) and dynamic (Ki67 response) biomarkers to optimize adjuvant therapy in luminal EBC. Methods: Pts with clinically high-risk HR+/HER2- EBC (cT2-4 OR clinically N+ OR G3 OR Ki67>15%) were initially treated by 3 (+/-1) weeks of standard ET (postmenopausal: mostly AI; premenopausal: TAM) before surgery or sequential CB. Pts with cN2-3 or G3/Ki67>40% were randomized directly to the CT trial. pN0-1 pts with RS0-11 OR RS12-25/ET-response (central Ki67postendocrine<10%) received ET alone; the remaining high-risk cohort was randomized to the CT trial: (neo)adjuvant dose-dense CT (4xPaclitaxelà4xEC q2w vs. 8xNab-Paclitaxel q1wà4xEC q2w) followed by ET. Primary endpoint is efficacy comparison of CT schedules for survival; secondary endpoints reported here involve impacts of key prognostic factors on survival. Kaplan-Meier and Cox proportional hazard models were used to estimate survival curves and hazard ratios. For this analysis, subgroups free of selection bias by RS/ET-response were defined. Results: 5625 pts were screened and 4621 (ITT) entered the trial. After 4.9y median follow-up, higher baseline and post-endocrine Ki-67 levels were associated with poorer iDFS (both p < 0.001). In the CT cohort (n = 2331), higher RS, nodal status, and tumor size were generally associated with poorer iDFS. However, iDFS differed between N1 and N0 status only among younger pts (<50 years). In pts with >4 positive LN (n = 390), lower RS was associated with improved iDFS (RS0-11 vs RS > 25: plog-rank= 0.016, 5y-iDFS 90% vs. 64%). In pts with RS > 25 (n = 965), low Ki67postendocrine, N0 status, and c/pT1 status were associated with improved iDFS. In particular, ET-responders had higher 5y-iDFS (84%) than ET-non-responders (77%; plog-rank= 0.040). Younger patients (<50 years old) with N0-1 RS 12-25/ ET-non-responders treated by CT had non-significantly poorer 5-year iDFS (89%) compared to those with ET-response treated by ET only (92%) (plog-rank= 0.249). Conclusion: First results from the prospective high risk cohort from a large prospective phase III ADAPT trial provide evidence for good prognosis in some pts with >4 positive LN and e.g. low RS. Moreover combination of lower post-endocrine Ki-67 and limited tumor burden may be a promising criterion for CT de-escalation strategies even in patients with high RS. Clinical trial information: NCT01779206.

10-year update of E2197: Phase III doxorubicin/docetaxel (AT) versus doxorubicin/cyclophosphamide (AC) adjuvant treatment of LN+ and high-risk LN- breast cancer and the comparison of the prognostic utility of the 21-gene recurrence score (RS) with clinicopathologic features.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1021-1021 ◽  
Author(s):  
Joseph A. Sparano ◽  
Anne O'Neill ◽  
Robert James Gray ◽  
Edith A. Perez ◽  
Lawrence N. Shulman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Menopausal Status ◽  
Disease Free Survival ◽  
Recurrence Score ◽  
Phase Iii ◽  
Clinicopathologic Characteristics ◽  
Accurate Predictor ◽  
Gene Assay ◽  
Node Positive Disease

1021 Background: At 5 years, AT did not improve disease free survival or overall survival and RS was a more accurate predictor of relapse than standard clinicopathologic characteristics for patients with hormone receptor (HR) positive tumors. Methods: A Phase III Intergroup trial tested adjuvant AT vs. AC. Women with 1-3 N + or N - and T-size > 1cm were randomized to 4 cycles of AT (60 mg/m2/60 mg/ m2) or AC (60 mg/m2/600 mg/m2) q 3 wk x 4. Patients(pts) with ER + and/ or PR + tumors received tam for 5 yrs. Pts were stratified by nodal, HR (ER+ PR+, ER+PR-, ER-PR+, ER-PR-, ER/PR unk) and menopausal status. The primary endpoint was DFS. A sample of 465 pts with HR + breast cancer with 0 to 3 positive axillary nodes who did (N =116) or did not have a recurrence had tumor tissue evaluated using the 21- gene assay. Grade and HR expression were evaluated locally and centrally. Results: 2952 pts were randomized between 7/30/98 and 1/21/00. 2883 were eligible and analyzable. Arms were balanced for age, HR, menopause, nodes, surgery, grade and T-size: median age 51; 64% ER +; 65% LN-; grade: 10% low, 38% int., 46% high; and median T-size - 2.0 cm. At a median follow-up of 11.5 years the DFS/OS results are shown in the table below. RS was a highly significant predictor of recurrence including node negative and node positive disease (P < .0001) and predicted recurrence more accurately than clinical variables. Conclusions: At 11.5 yrs. median follow-up, there remains no difference in DFS or OS, although there continue to be fewer events in the AT arm in the prespecified ER/PR negative subgroup. At 10 years, the RS continues to be a more accurate predictor of relapse than standard clinical features. [Table: see text]

Prospective comparison of recurrence score and independent central pathology assessment of prognostic tools in early breast cancer (BC): Focus on HER2, ER, PR, Ki-67 results from the phase III WSG-Plan B trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 552-552 ◽  
Author(s):  
Oleg Gluz ◽  
Hans Heinrich Kreipe ◽  
Matthias Christgen ◽  
Tom Degenhardt ◽  
Ronald E. Kates ◽  
...  
Keyword(s):  
High Risk ◽  
Recurrence Score ◽  
Phase Iii ◽  
Rt Pcr ◽  
Ki 67 ◽  
Negative Results ◽  
Prospective Comparison ◽  
Plan B ◽  
Central Pathology ◽  
Pai 1

552 Background: Use of multi-gene real-time PCR (RT-PCR) based assays e.g. Recurrence Score (RS) and single markers (grade, uPA/PAI-1, ER/PR, HER2, KI-67) is currently controversially discussed in early BC. Here, we present the final WSG-planB trial correlation analysis of risk assessment tools and first prospective comparison of independent central pathology IHC/FISH assessment and RT-PCR for single markers. Methods: Plan B trial (n=2,448 randomized for 6xTC vs. 4xEC-4xDOC in locally HER2- BC). RS has been used as selection criterion for cht omission in HR+ BC (if RS<11 in pN0 or pN1). uPA/PAI-1 was optionally obtained. Grade, ER/PR, HER2 (IHC/FISH), Ki-67 were evaluated by the independent trial pathologist in all tumors. Results: From 04/09 to 11/11, 3196 patients have been recruited and 2448 randomized. RS distribution in 2551 HR+ tumors: 0-11 (18%), 12-25 (60%), >25 (22%). In 354 pN0-1 patients, cht was omitted based on low risk RS (88% compliance). Central grade for n=3038 and IHC/FISH results are currently available in n=1476. Moderately significant correlations were only found between RS and both central grade (rs=0.313; p<0.001) as well as Ki-67 (rs=0.374; p<0.001) and a weak one for uPA/PAI-1, particularly due to poor correlations within the RS group <26. In 1476 locally HER2- cases, n=9 were found as 3+ and/or FISH+ by central analysis. In 6 HR+/HER2+ cases, RS revealed 2 positive, 2 equivocal and 2 negative results. In 7 cases positive for HER2 by RT-PCR central pathology revealed 4 negative results. 24 locally HR+ cases are assessed as HR- in central pathology (2%). Among these, 6 were ER positive by RT-PCR. Final correlation analyses will be presented at the meeting. Conclusions: These first prospective data demonstrate that high-risk status according to RS is predictive of high risk by other factors, but the converse is not true. Regarding controversial HER2 and HR status by RT-PCR and IHC/FISH, we found few cases with false-negative or positive RT-PCR results in HER2- BC by local pathology. However, these discrepancies could potentially have a substantial impact on clinical patient management.

Prediction of response to neoadjuvant hormonal therapy (NAHT) using upfront oncotype Dx recurrence score (RS): Results from the SAFIA phase III trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 594-594
Author(s):  
Khalid A Al-Saleh ◽  
Adda Bounedjar ◽  
Mohammed Oukkal ◽  
Hasen Mahfouf ◽  
Kamel Bouzid ◽  
...  
Keyword(s):  
Hormonal Therapy ◽  
Endocrine Resistance ◽  
Recurrence Score ◽  
Complete Response ◽  
Oncotype Dx ◽  
Phase Iii ◽  
Progression Rate ◽  
Luminal A ◽  
Double Blind ◽  
Minor Response

594 Background: While hormonal therapy (HT) is a fundamental treatment in breast cancer therapy, neoadjuvant NAHT is not considered standard. The SAFIA trial is a prospective international neoadjuvant Phase III investigating the potential role of the addition of palbociclib (P) in patients (pts) sensitive to HT. We report the results of induction Faslodex (+/- zoladex) in pts initially selected by RS < 31, in order to assess their individual HT sensitivity before double-blind randomization HT vs HT + P followed by surgery. Materials and Methods: A total of 308 pts (stages II and IIIA Luminal A/B HER2 negative) in 24 centers and 6 countries (Middle-East/Maghreb) underwent upfront RS to select pts for induction HT. Pts with RS < 31 received induction neoadjuvant fulvestrant (500 mg i.m Day 1, 14, 28 then q.4 weeks) + goseriline (3.6 mg s.c q.4 w for pre and peri-menopausal pts) for 4 months, followed by clinical and radiological assessment of the disease response before randomization. Response was defined as no progression: Complete Response-CR/ Partial Response-PR: > 50% and Minor Response-MR: < 50% to > 0%/ No Response-NR: progression > 0%. Results: A total of 70 pts (22%) with RS > 31 were excluded, leaving 238 eligible pts for NAHT, age (25-84); pre-peri/ post menopause: 135 (57%)/103 (43%); Luminal A/B: 112 (49%)/114 (51%); Stage II/IIIA: 196 (87%) / 29 (13%). One hundred and seventy-seven pts (177) have validated responses to induction NAHT: CR: 9 pts (5%) / MR: 105 pts (59%) for major response rate: 64% / MR: 56 pts (32%) / NR: 7 pts (4%); available RS 0-10: 23 pts (16%) / RS 11-18: 67 pts (47%) / RS 19-25: 34 pts (24%) / RS 26-30: 18 pts (13%). Correlations between Response to NAHT and RS are shown in the table below (not statistically significant). Conclusions: In our population, upfront Oncotype DX RS < 31 allowed to select pts for induction NAHT without loss of chances with a no-progression rate (CR+PR = MR) of 96%. No significant correlation was found between RS and response to NAHT. Upfront RS > 31 (22%) is selecting pts candidates for neoadjuvant chemotherapy with a potential high risk of endocrine resistance. Clinical trial information: ICRG1201 .

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

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS601-TPS601
Author(s):  
Nadia Harbeck ◽  
Oleg Gluz ◽  
Matthias Christgen ◽  
Monika Graeser ◽  
Felix Hilpert ◽  
...  
Keyword(s):  
Endocrine Therapy ◽  
Disease Free Survival ◽  
Recurrence Score ◽  
Response Assessment ◽  
Early Response ◽  
Tumor Burden ◽  
Phase Iii ◽  
Induction Treatment ◽  
Intermediate Risk ◽  
Open Label

TPS601 Background: The WSG ADAPT trial program represents the concept of individualization of (neo)-adjuvant decision-making in EBC in a subtype-specific manner. The first WSG ADAPT umbrella trial aimed to establish early predictive molecular surrogate markers for response after a short 3-week induction treatment. The goals of the WSG ADAPT trial program are early response assessment and subtype-specific therapy tailoring to those patients who are most likely to benefit. Methods: WSG-ADAPTcycle is a prospective, multi-center, interventional, two-arm, open-label, (neo)adjuvant, non-blinded, randomized, controlled phase III trial (NCT04055493). It investigates whether patients (pts.) with HR+/HER2- EBC identified during screening as intermediate risk (based on Oncotype DX and response to 3 weeks of preoperative endocrine therapy [ET]) derive additional benefit from 2 years of the CDK4/6 inhibitor ribociclib combined with ET compared to chemotherapy (CT) (followed by standard ET). Co-primary endpoints are disease-free survival (DFS) and distant DFS. It is planned to screen 5600 pts and to randomize 1670 pts in a 3:2 ratio (ribociclib + ET/CT). Study start was in July 2019 (80 sites, enrollment period 36 months) and until date of submission, 180 pts. have been screened and 40 randomized. Pts with HR+/HER2- EBC with clinically enhanced risk (cT2-4 or Ki67 20% or G3 or cN+) are eligible if they fulfill the ADAPT intermediate-risk group criteria: either Recurrence Score (RS) ≤25 and Ki67postendocrine>10%, RS >25 and Ki67postendocrine<10% in p/cN0-1 pts, or RS ≤25 and Ki67postendocrine<10% in c/pN2-3 pts. Treatment duration is 2 years for the ribociclib + ET (premenopausal: AI + GnRH) arm and 16-24 weeks for the CT arm; treatment is possible either in the neoadjuvant (ET + ribociclib duration 16 – 32 weeks) or adjuvant setting. ePROs are collected using CANKADO; ECG monitoring is performed using a novel cardiology-supported CANKADO-based eHealth method. Translational analyses: Exploratory tissue biomarker research will be conducted to assess alterations in molecular markers. In addition, ctDNA/ctRNA from optional blood samples will be assessed for mutations and gene expression. Conclusions: ADAPTcycle seeks to evaluate whether endocrine-based therapy with ET and a CDK 4/6 inhibitor is superior to CT followed by ET in patients with luminal EBC who may be undertreated with ET alone (based on either lack of endocrine responsiveness or high tumor burden). Clinical trial information: 2018-003749-40 .

Cctg MA.39 tailor RT: A randomized trial of regional radiotherapy in biomarker low-risk node-positive breast cancer (NCT03488693).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS602-TPS602 ◽  
Author(s):  
Wendy R. Parulekar ◽  
Tanya Berrang ◽  
Iwa Kong ◽  
Eileen Rakovitch ◽  
Valerie Theberge ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Mortality ◽  
Recurrence Score ◽  
Low Risk ◽  
Phase Iii ◽  
Primary Analysis ◽  
Risk Of Recurrence ◽  
Axillary Nodes ◽  
Her2 Breast Cancer ◽  
Patient Reported

TPS602 Background: Biomarker low risk, ER positive (+), HER2 negative (-) breast cancer with low burden nodal involvement may be associated with good outcomes (Woodward 2016, Mamounas 2017). There is conflicting data regarding the efficacy of regional radiotherapy after breast conserving surgery (BCS) or mastectomy in these patients (Kyndi 2008, Whelan 2015, Poortmans 2015, Liu 2015). Our hypothesis is that the risk of recurrence in patients with biomarker low risk, ER+, Her2- breast cancer and involvement of 1-3 lymph nodes where regional RT is omitted will not be inferior to the risk of recurrence in patients treated with regional RT. Methods: MA39 is a Canadian Cancer Trials Group led, NCTN sponsored, randomized phase III study comparing breast cancer recurrence free interval (BCRFI) in patients with ER+, Her2-, LN 1-3+ breast cancer that is low risk as defined by Oncotype Dx Recurrence Score < 18. Secondary objectives include a comparison of DFS, breast cancer mortality, OS, locoregional and distant recurrence free intervals, toxicity, arm volume and mobility measurements, patient reported outcomes and cost effectiveness. Key eligibility criteria include: age ≥ 40 years; BCS or mastectomy with axillary dissection and 1-3 positive axillary nodes; BCS and SLNB alone and 1-2 positive axillary nodes; mastectomy and SLNB alone and only 1 positive axillary node; planned endocrine therapy ≥ 5 years; adjuvant chemotherapy allowed. Statistical design: The primary analysis will be a test of non-inferiority (NI) in the intention to treat population. If the upper bound of a one-sided 95% interval for the hazard ratio for BCRFI is < 1.4, NI will be declared. Using a one-sided α of 0.05 and a power of 87%, it is anticipated that 278 events are required. With an expected 5 years of accrual and 4.5 years of follow-up, 2140 patients are needed for the final sample size. Conduct to Date: Study activation May 30 2018. Participation as of February 2019: Registrations 64 Randomizations 26. CIRB approval for continuation of MA.39 was received on January 11 2019. Clinical trial information: NCT03488693.

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