Search

Introduction Patients’ satisfaction after breast reconstruction can be evaluated with validated questionnaires as the Breast-Q questionnaire. The Breast-Q questionnaire includes different domains; one of them is “satisfaction with the result”. Material and methods: In the multicentre, prospective studies PRO (patient related outcome)-BRA (clinicaltrials.gov: NCT01885572) and PRO-Pocket (clinicaltrials.gov: NCT03868514), patient satisfaction was assessed using the Breast-Q questionnaire. In the PRO-Bra study, 269 patients underwent subpectoral surgery using the TiLOOP® Bra polypropylene mesh (pfm medical ag, Germany). In the "PRO-Pocket" study, 311 patients underwent prepectoral surgery using the TiLOOP® Bra Pocket polypropylene mesh. For the evaluation, those patients from the PRO-Bra and PRO-Pocket studies who completed a Breast-Q questionnaire 6 and/or 12 months after surgery were included. The BreastQ score is measured from 0 to 100, with a score of 100 corresponding to "very satisfied". Satisfaction with the result of the breast reconstruction was evaluated. Results: In the PRO-Bra study, a total of 221 and 203 patients completed a Breast-Q at 6 months and/or 12 months FU, respectively. The mean age and BMI of the patients with completed Breast-Q were comparable between the two studies (PRO-Bra: 49.3 [±11.6] years, 22.9 kg/m2 [±3.5]; PRO-Pocket: 47.7 [±11.7] years, 24.5 kg/m2 [±4.3]). In the PRO-Pocket study, a total of 258 and 266 patients completed a Breast-Q at 6 months and/or 12 months FU, respectively. In the PRO-Bra study the mean score of satisfaction with the result at 6 months follow-up (FU) was 74.5 (±19.9), in the PRO-Pocket 79.1 (±19.1), at 12 months FU the mean scores were 76.3 (±18.9) for PRO-Bra and 78.2 (±20.4) for PRO-Pocket. Furthermore, stratification according to age (cutoff 50 years) or BMI (cutoff 25 kg/m2) did not reveal any differences between the subgroups or the two studies (see Table). PRO-Bra PRO-Pocket mean score (±SD) 6 months 12 months 6 months 12 months BMI ≤ 25 75.1 (±19.7) 76.4 (±17.8) 77.7 (±19.9) 78.9 (±19.8) BMI > 25 72.1 (±20.7) 76.1 (±22.9) 82.1 (±16.9) 76.8 (±21.8) age ≤ 50 76.4 (±18.7) 77.0 (±18.9) 80.1 (±18.7) 78.1 (±19.6) age > 50 71.5 (±21.5) 75.3 (±19.0) 77.5 (±19.5) 78.4 (±21.8) Conclusion: Our data so far show high patient satisfaction with overall outcome of the surgery. In addition, patients’ satisfaction with the result was comparable after subpectoral as well as prepectoral implant placement. This is particularly important in the PRO-Pocket study, as approximately 60% of the operations and the follow-up period took place during the COVID-19 pandemic. Citation Format: Stefan Paepke, Anne Andrulat, Christine Ankel, Lelia Bauer, Kristin Baumann, Jens-Uwe Blohmer, Andree Faridi, Visnja Fink, Claudia Gerber-Schaefer, Daphne Gschwantler-Kaulich, Jörg Heil, Sherko Kuemmel, Anette Kossmann-Meiré, Ralf Ohlinger, Marc Thill. Satisfaction of patients after implant-based subpectoral reconstruction with a titanized polypropylene mesh (TiLOOP® Bra) compared to prepectoral reconstruction with a titanzied polypropylene pocket (TiLOOP® Bra Pocket) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-13.

Invasive lobular breast cancer (ILC) is a special breast cancer (BC) subtype and is mostly hormone receptor (HR)-positive and ERBB2 non-amplified. Endocrine therapy restrains tumor proliferation and is the mainstay of lobular BC treatment. Mutation of ERBB2 has been associated with recurrent ILC. However, it is unknown whether ERBB2 mutation impacts on the otherwise exquisite responsiveness of early ILC to endocrine therapy. We have recently profiled n = 622 HR-positive early BCs from the ADAPT trial for mutations in candidate genes involved in endocrine resistance, including ERBB2. All patients were treated with short-term preoperative endocrine therapy (pET, tamoxifen or aromatase inhibitors) before tumor resection. Tumor proliferation after endocrine therapy (post-pET Ki67 index) was determined prospectively by standardized central pathology assessment supported by computer-assisted image analysis. Sustained or suppressed proliferation were defined as post-pET Ki67 ≥10% or10%. Here, we report a subgroup analysis pertaining to ILCs in this cohort. ILCs accounted for 179/622 (28.8%) cases. ILCs were enriched in mutations in CDH1 (124/179, 69.3%, P 0.0001) and ERBB2 (14/179, 7.8%, P 0.0001), but showed fewer mutations in TP53 (7/179, 3.9%, P = 0.0048) and GATA3 (11/179, 6.1%, P 0.0001). Considering all BCs irrespective of subtypes, ERBB2 mutation was not associated with proliferation. In ILCs, however, ERBB2 mutations were 3.5-fold more common in cases with sustained post-pET proliferation compared to cases with suppressed post-pET proliferation (10/75, 13.3% versus 4/104, 3.8%, P = 0.0248). Moreover, ERBB2 mutation was associated with high Oncotype DX recurrence scores (P = 0.0087). In summary, our findings support that ERBB2 mutation influences endocrine responsiveness in early lobular BC.

Supplementary Table 1 lists genes comprising the RNA expression signatures measured with the BC360 panel

Supplementary Figure 3 shows association between RNA signatures and overall survival

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

Supplementary Data from 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

Supplementary Figure from 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: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.

Supplementary Table from 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

It has been suggested that the benefit of adjuvant chemotherapy (CT) in premenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2−) early breast cancer may be related, at least in part, to CT-induced ovarian function suppression (OFS) in this subgroup of patients. Although this hypothesis has not been directly tested in large randomized clinical trials, the observations from prospective studies have been remarkably consistent in showing a late benefit of CT among the subgroup of patients who benefit (ie, women who were close to menopause). The hypothesis has important clinical implications, as it may be possible to spare the associated adverse effects of adjuvant CT in a select group of women with early breast cancer, in favor of optimizing OFS and endocrine therapy (ET), without compromising clinical outcomes. Such an approach has the added benefit of preserving the key quality of life outcomes in premenopausal women, particularly by preventing the irreversible loss of ovarian function that may result from CT use. For this reason, we convened an international panel of clinical experts in breast cancer treatment to discuss the key aspects of the available data in this area, as well as the potential clinical implications for patients. This article summarizes the results of these discussions and presents the consensus opinion of the panel regarding optimizing the use of OFS for premenopausal women with HR+, HER2− early breast cancer.

ObjectiveThe international Charité-MAYO Conference aims to promote international dialog on diagnostics, management, scientific breakthroughs, and state-of-the-art surgical procedures in gynecology and gynecologic oncology and senology. Live surgeries are a fundamental tool of interdisciplinary and international exchange of experts in their respective fields. Currently, there is a controversial and emotional debate about the true value, risks, and safety of live surgical broadcasts. The aim of the current study is to analyze peri-operative risks in patients who were operated live during the Charité-MAYO Conferences.MethodsLive surgeries were performed by the core Charité team consisting of gynecologic oncologic surgeons, breast and plastic surgeons, partly in collaboration with visiting gynecologic oncologic surgeons. We performed a retrospective analysis of live surgeries performed during seven Charité-MAYO Conferences from 2010 to 2019 held in Berlin, Germany. Patients’ files and tumor databases were analyzed as required and patients were contacted to update their long-term follow-up.ResultsSixty-nine patients who were operated live were included. The types of surgery were as follows: urogynecologic procedures (n=13), breast surgery (n=21), and gynecologic oncology surgery for ovarian, uterine, vulvar or cervical cancer (n=35). Peri-operative complications were assessed according to the Clavien–Dindo classification. Despite a high rate of complete resection and the high frequency of multivisceral procedures, the rate of peri-operative complications was within the range published in the literature. Time of surgery and length of intensive unit care and hospital stay did not differ from data acquired at the home institution.ConclusionsBased on our analysis, live surgeries appear to be safe when performed within a multidisciplinary setting without an increase in surgical morbidity and mortality compared with historical controls and without compromise of patients’ outcome. This is the first analysis of its kind to set the basis for patient information and consent for this type of surgeries.

Background: De-escalating strategies seem promising inHER2-positive early breast cancer (EBC) and chemo-free regimens are thus of keyinterest. Recent data have underlined the role of tumor immunogenicity inresponse to de-escalated neoadjuvant anti-HER2 therapy. Therefore, theprospective single arm hypothesis-generating phase II KEYRICHED-1 trial (NCT03988036)investigates the pCR rate in patients with HER2-enriched EBC receiving fourcycles of the dual anti-HER2 blockade in combination with the checkpointinhibitor pembrolizumab. Initial studies with dual antibody-based HER2 blockadealone were able to achieve pCR-rates of 20-40%, which did not quite match the pCRrates obtained with concurrent chemotherapy. KEYRICHED-1 aims at achieving pCR-ratescomparable to standard chemotherapy-containing regimens by incorporating appropriatemolecular selection and immune oncology. Methods: A total of 48 pre- and postmenopausal patients with newly diagnosed HER22+ or 3+ EBC (stage I-III) and HER2-enriched (HER2-E) subtype by PAM50 wereenrolled in this single-arm study. All patients received four cycles of studytreatment with pembrolizumab (200mg), trastuzumab biosimilar (Trazimera®,loading dose 8mg/kg bodyweight (BW), maintenance dose 6mg/kg BW), and pertuzumab(loading dose 840mg/kg BW, maintenance dose 420mg/kg BW) q21d . Primaryendpoint was centrally confirmed pCR (ypT0/is, ypN0). The trial was planned asa Simon's two-Stage design (null and alternative pCR were 40% and 60%); interimanalysis after 16 patients had to show a pCR rate of at least 50% to continuerecruitment. Results: Between 05/2020 and 03/2021, 98 patients werescreened. N=52 (55%) had HER2-E subtype,of whom 48 patients entered thetreatment phase. Median patient age was 57 years (28-83). 65% had tumors > 2cm and 30% positive lymph node status. Centrally confirmed pCR rate in surgicalspecimens was 46% (95% CI 0.31-0.62) in the 43 patients of the per protocolpopulation, and 52% (95%CI 0.37-0.67) in all 46 evaluable patients (localassessment; two pCRs verified only by core biopsy) (p=0.22 and p=0.06 for nullhypothesis, respectively). Despite HER2-E subtype, no pCR was observed in the 4patients with immunohistochemical (IHC) HER2 2+/ISH-positive status in contrastto 20/39 (51.2%) pCRs in IHC HER2 3+ tumors. Centrally confirmed pCR rate in HR+/HER2+tumors was38.5% compared to 58.5% in HR-/HER2+ tumors. No new safety signals wereobserved. Conclusions: These are the first results of a neoadjuvant chemotherapy-free12-week de-escalation anti-HER2-regimen with trastuzumab and pertuzumab incombination with the PD-1 inhibitor pembrolizumab in patients with a HER2-E EBC.In the context of the WSG ADAPT HER2+ de-escalation trials the observed pCRrates compare favourably in HR+ as well as HR- HER2 EBC. Moreover, KEYRICHED-1demonstrates that with appropriate molecular patient selection clinicallymeaningful pCR rates in the range of those obtained with longer, more toxicchemotherapy-containing regimens can be achieved. Citation Format: Sherko Kuemmel, Oleg Gluz, Mattea Reinisch, Athina Kostara, Iris Scheffen, Monika Graeser, Kerstin Luedtke-Heckenkamp, Andreas Hartkopf, Felix Hilpert, Angela Kentsch, Carsten Ziske, Reinhard Depenbusch, Michael Braun, Jens Blohmer, Christine zu Eulenburg, Matthias Christgen, Stephan Bartels, Hans Kreipe, Enrico Pelz, Peter Schmid, Nadia Harbeck. KEYRICHED-1 - A prospective, multicenter, open label, neoadjuvant phase II single arm study with pembrolizumab in combination with dual anti-HER2 blockade with trastuzumab and pertuzumab in early breast cancer patients with molecular HER2-enriched intrinsic subtype [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-03.

Supplementary Figure from Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2− Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial

Purpose:Ribociclib plus endocrine therapy (ET) demonstrated a statistically significant progression-free survival and overall survival (OS) benefit in the phase III MONALEESA-7 trial of pre-/perimenopausal patients with hormone receptor (HR)-positive (HR+), HER2-negative (HER2−) advanced breast cancer (ABC). The median OS was not reached in the ribociclib arm in the protocol-specified final analysis; we hence performed an exploratory OS and additional outcomes analysis with an extended follow-up (median, 53.5 months).Patients and Methods:Patients were randomized to receive ET [goserelin plus nonsteroidal aromatase inhibitor (NSAI) or tamoxifen] with ribociclib or placebo. OS was evaluated with a stratified Cox proportional hazard model and summarized with Kaplan–Meier methods.Results:The intent-to-treat population included 672 patients. Median OS was 58.7 months with ribociclib versus 48.0 months with placebo [hazard ratio = 0.76; 95% confidence interval (CI), 0.61–0.96]. Kaplan–Meier estimated OS at 48 months was 60% and 50% with ribociclib and placebo, respectively. Subgroup analyses were generally consistent with the OS benefit, including patients who received NSAI and patients aged less than 40 years. Subsequent antineoplastic therapies following discontinuation were balanced between the ribociclib (77%) and placebo (78%) groups. Use of cyclin-dependent kinase 4/6 inhibitors after discontinuation was higher with placebo (26%) versus ribociclib (13%). Time to first chemotherapy was significantly delayed with ribociclib versus placebo. No drug–drug interactions were observed between ribociclib and either NSAI.Conclusions:Ribociclib plus ET continued to show significantly longer OS than ET alone in pre-/perimenopausal patients, including patients aged less than 40 years, with HR+/HER2− ABC with 53.5 months of median follow-up (ClinicalTrials.gov, NCT02278120).

Purpose:This phase II study determined the efficacy of lacnotuzumab added to gemcitabine plus carboplatin (gem-carbo) in patients with advanced triple-negative breast cancer (TNBC).Patients and Methods:Female patients with advanced TNBC, with high levels of tumor-associated macrophages not amenable to curative treatment by surgery or radiotherapy were enrolled. Lacnotuzumab was dosed at 10 mg/kg every 3 weeks, ± a dose on cycle 1, day 8. Gemcitabine (1,000 mg/m2) and carboplatin (dose in mg calculated by area under the curve [mg/mL/min] × (glomerular filtration rate [mL/min] + 25 [mL/min]) were dosed every 3 weeks. Treatment continued until unacceptable toxicity, disease progression, or discontinuation by physician/patient.Results:Patients received lacnotuzumab + gem-carbo (n = 34) or gem-carbo (n = 15). Enrollment was halted due to recruitment challenges owing to rapid evolution of the therapeutic landscape; formal hypothesis testing of the primary endpoint was therefore not performed. Median progression-free survival was 5.6 months [90% confidence interval (CI), 4.47–8.64] in the lacnotuzumab + gem-carbo arm and 5.5 months (90% CI, 3.45–7.46) in the gem-carbo arm. Hematologic adverse events were common in both treatment arms; however, patients treated with lacnotuzumab experienced more frequent aspartate aminotransferase, alanine aminotransferase, and creatine kinase elevations. Pharmacokinetic results showed that free lacnotuzumab at 10 mg/kg exhibited a typical IgG pharmacokinetic profile and target engagement of circulating colony-stimulating factor 1 ligand.Conclusions:Despite successful target engagement and anticipated pharmacokinetic profile, lacnotuzumab + gem-carbo showed comparable antitumor activity to gem-carbo alone, with slightly poorer tolerability. However, the data presented in this article would be informative for future studies testing agents targeting the CSF1–CSF1 receptor pathway in TNBC.

Supplementary Table from Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2− Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical 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.

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, Early recognition of endocrine resistance could be enabled by impaired suppression of proliferation after short‐term preoperative endocrine therapy (pET). Impaired endocrine proliferative response (EPR, post‐pET Ki67 ≥10%) sorts out cancers carrying TP53 mutations.

Aim We developed tailored axillary surgery (TAS) to reduce the axillary tumor volume in patients with clinically node-positive breast cancer to the point where radiotherapy can control it. The aim of this study was to quantify the extent of tumor load reduction achieved by TAS. Methods International multicenter prospective study embedded in a randomized trial. TAS is a novel pragmatic concept for axillary surgery de-escalation that combines palpation-guided removal of suspicious nodes with the sentinel procedure and, optionally, imaging-guided localization. Pre-specified study endpoints quantified surgical extent and reduction of tumor load. Results A total of 296 patients were included at 28 sites in four European countries, 125 (42.2%) of whom underwent neoadjuvant chemotherapy (NACT) and 71 (24.0%) achieved nodal pathologic complete response. Axillary metastases were detectable only by imaging in 145 (49.0%) patients. They were palpable in 151 (51.0%) patients, of whom 63 underwent NACT and 21 had residual palpable disease after NACT. TAS removed the biopsied and clipped node in 279 (94.3%) patients. In 225 patients with nodal disease at the time of surgery, TAS removed a median of five (IQR 3–7) nodes, two (IQR 1–4) of which were positive. Of these 225 patients, 100 underwent ALND after TAS, which removed a median of 14 (IQR 10–17) additional nodes and revealed additional positive nodes in 70/100 (70%) of patients. False-negative rate of TAS in patients who underwent subsequent ALND was 2.6%. Conclusions TAS selectively reduced the tumor load in the axilla and remained much less radical than ALND., Highlights • Tailored axillary surgery is a novel concept for clinically node-positive breast cancer • Tailored axillary surgery selectively removes positive lymph nodes • Tailored axillary surgery is much less radical than axillary dissection • Tailored axillary surgery removes the clipped node in the vast majority of patients

To characterise risk of anaphylaxis/hypersensitivity with intravenous pertuzumab plus trastuzumab (PH IV), the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC) or concomitant chemotherapy to support potential administration of PH FDC SC by healthcare professionals outside clinics.A cumulative search for anaphylaxis/hypersensitivity (Roche Standard Adverse Event Group Terms) was performed for all pivotal trials cited in the current EMA P IV/PH FDC SC summaries of product characteristics: MBC: NCT00567190, NCT02402712; EBC: NCT01358877, NCT00545688, NCT00976989, NCT02132949, NCT03493854 and NCT03674112. Occurrence, incidence and severity of events were analysed and a time-trend analysis (by cycle) was performed.This analysis includes 4772 patients who received PH IV and/or PH FDC SC. Incidence of all-grade (grade ≥3) anaphylaxis/hypersensitivity events: 3-11% (≤2%) for PH IV MBC trials; 1-13% (0-3%) for PH IV EBC trials; and 2-3% (1%; not related to PH FDC SC) for PH FDC SC EBC trials. Discontinuations due to anaphylaxis/hypersensitivity were rare for PH IV (generally1% except two arms of TRYPHAENA: 1% and 3%); no discontinuations of PH FDC SC have been recorded so far. Time-trend analysis showed that most events were reported during the first 6-8 cycles with concurrent chemotherapy, with a decrease in later cycles (except MetaPHER).PH IV and PH FDC SC were well tolerated, with few grade ≥3 anaphylaxis/hypersensitivity events reported with PH IV and no grade ≥3 related events with PH FDC SC. Most events occurred during chemotherapy.

Purpose Intravenous trastuzumab, pertuzumab, and docetaxel are first-line standard of care for patients with HER2-positive metastatic breast cancer (mBC). MetaPHER is the first study assessing the safety and tolerability of subcutaneous trastuzumab plus intravenous pertuzumab and chemotherapy in a global patient population with HER2-positive mBC. Methods In this open-label, single-arm, multicenter, phase 3b study, eligible patients were ≥ 18 years old with histologically/cytologically confirmed previously untreated HER2-positive mBC. All received ≥ 1 subcutaneous trastuzumab 600 mg fixed dose plus intravenous pertuzumab (loading dose: 840 mg/kg; maintenance: 420 mg/kg) and docetaxel (≥ 6 cycles; initial dose 75 mg/m2) every 3 weeks. The primary objective was safety and tolerability; secondary objectives included efficacy. Results At clinical cutoff, 276 patients had completed the study; median duration of follow-up was 27 months. The most common any-grade adverse events were diarrhea, alopecia, and asthenia; the most common grade ≥ 3 events were neutropenia, febrile neutropenia, and hypertension. There were no cardiac deaths and mean left ventricular ejection fraction was stable over time. Median investigator-assessed progression-free survival was 18.7 months; objective response rate was 75.6%. Conclusions Safety and efficacy with subcutaneous trastuzumab plus intravenous pertuzumab and docetaxel in mBC are consistent with historical evidence of intravenous trastuzumab with this combination. Findings further support subcutaneous administration not affecting safety/efficacy profiles of trastuzumab in HER2-positive BC with increased flexibility in patient care. A fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection has recently been approved for the treatment of HER2-positive early/mBC, further addressing the increasing relevance of and need for patient-centric treatment strategies. Trial registration NCT02402712

Introduction: RIBECCA is a national, multi-center, open-label, single-arm phase IIIb trial assessing the efficacy and safety of ribociclib in combination with letrozole in a patient population similar to the populations of MONALEESA-2, -3 and -7, including premenopausal and postmenopausal patients without pretreatment as well as patients with up to 3 previous treatment lines for advanced disease. Here we present the final analysis for the primary endpoint. Methods:The study enrolled women or men with metastatic or locally advanced breast cancer irrespective of their menopausal status, who were not amenable to curative treatment by surgery or radiotherapy. Histological or cytological confirmation of HR+, HER2- breast cancer was required. 502 patients were enrolled in two Cohorts. Cohort A (n=319): postmenopausal women and men without pretreatment for advanced disease; Cohort B (n=183): premenopausal women without pretreatment for advanced disease and pre- or postmenopausal women and men with ≤ 1 line of chemotherapy and/or ≤ 2 lines of endocrine therapy in the advanced situation. The primary endpoint was to assess the clinical benefit rate (CBR, defined as CR, PR or SD, or NCRNPD) at 24 weeks for the overall study population. Secondary endpoints included: progression free survival (PFS), overall survival (OS), safety, and changes in quality of life as assessed by EORTC QLQ-C30 and -BR23 questionnaires. Results: The study ended 84 weeks after the enrollment of the last patient. The median observation time was 10.6 months (0.1-38 months). Baseline characteristics: of 502 pts, 5 were male, 497 were female(46 pre-or perimenopausal, 451 postmenopausal); median age: 64 yrs; ECOG 0-1: 96.8%; 71.1 % of pts had bone metastases (40.8% bone only), 30.6% liver, 27.5% lung and 30.1% other metastases. 97.3% had at least 1 metastatic site: 48.7% had 1, 35.1% had 2, 12.9% had 3 and 1.6% had 4 metastatic sites, respectively. 78.9% received at least one prior antineoplastic therapy: 4.9% received neoadjuvant, 56.8% adjuvant and 37.8% palliative treatment as last antineoplastic therapy before study start. The most common treatment emergent AEs (all grades) were neutropenia and/or neutrophil count decreased (60.6%), nausea (42%), fatigue (39.2%), alopecia (35.1%), leukopenia or WBC decreased (30.7%), nasopharyngitis (28.5%), diarrhea (25.3%), ALT increased (22.9%) and AST increased (20.7%). The CBR at week 24 for the overall study population was 69.2%. Median PFS was 16.5 [95%CI 13.7; 19.3] months in the overall study population, 21.8 [15.4; 25.3] months and 9.3 [8.1; 16.3] months in Cohort A and B, respectively. At 72 weeks, the Kaplan-Meier estimate for OS was 86.8% [83.3; 89.6]. Because of the low number of events during the study period, median OS could not be determined. Conclusion: The results of the final analysis confirmed clinical benefit of ribociclib and letrozole in this patient population. No new safety signals emerged. Citation Format: Mattea Reinisch, Arndt Nusch, Thomas Decker, Andreas Hartkopf, Bernhard J Heinrich, Christian M Kurbacher, Roswitha Fuchs, Hans Tesch, Petra Krabisch, Sara Y Brucker, Tanja Fehm, Wolfgang Janni, Sherko Kuemmel, Diana Lüftner, Andreas Schneeweiss, Martin Schuler, Claudia Voges, Joerg Schubert, Peter A Fasching. Ribecca - a phase 3b, multi-center, open label study for women with estrogen receptor positive, locally advanced or metastatic breast cancer treated with ribociclib (lee011) in combination with letrozole: Final results [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 PS10-31.

BACKGROUND 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). METHODS 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. RESULTS 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

There is a strong biologic rationale that poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors may benefit a broader range of metastatic breast cancer (MBC) patients than covered by current approvals, which require a germline BRCA1/2 sequence variant affecting function. We report a patient with germline/somatic BRCA1/2 wild-type MBC, who had a dramatic response to the PARP inhibitor olaparib of at least 8 months’ duration. The patient is a 37-year-old woman with recurrent, hormone receptor-positive, HER2-negative MBC that had progressed despite hormonal therapy and palbociclib. Sensitivity to olaparib was likely conferred by a germline sequence variant affecting function in PALB2 (exon 1, c.18G>T, p.(=)). This case documenting activity of olaparib monotherapy in germline/somatic BRCA1/2 wild-type MBC illustrates that the clinical potential of PARP inhibition in MBC extends beyond currently approved indications to additional patients whose tumors have (epi)genetic changes affecting homologous recombination repair.

Background The phase Ib KEYNOTE-173 study was conducted to assess the safety and preliminary antitumor activity of neoadjuvant chemotherapy plus pembrolizumab in high-risk, early-stage, non-metastatic triple-negative breast cancer (TNBC). Patients and methods Six pembrolizumab plus chemotherapy regimens were evaluated (cohorts A–F). All cohorts received a pembrolizumab 200-mg run-in dose (cycle 1), then eight cycles of pembrolizumab in combination with a taxane with or without carboplatin for 12 weeks, and then doxorubicin and cyclophosphamide for an additional 12 weeks before surgery. Primary end points were safety and recommended phase II dose (RP2D); secondary end points were pathological complete response (pCR) rate, objective response rate, and event-free and overall survival. Exploratory end points were the relationship between outcome and potential biomarkers, such as tumor programmed death ligand 1 (PD-L1) expression (combined positive score) and stromal tumor-infiltrating lymphocyte levels (sTILs). Results Sixty patients were enrolled between 18 February 2016, and 28 February 2017. Dose-limiting toxicities occurred in 22 patients, most commonly febrile neutropenia (n = 10 across cohorts). Four cohorts (B, C, D, F) did not meet the RP2D threshold; two cohorts did (A, E). The most common grade ≥3 treatment-related adverse event was neutropenia (73%). Immune-mediated adverse events and infusion reactions occurred in 18 patients (30%) and were grade ≥3 in six patients (10%). The pCR rate (ypT0/Tis ypN0) across all cohorts was 60% (range 49%–71%). Twelve-month event-free and overall survival rates ranged from 80% to 100% across cohorts (100% for four cohorts). Higher pre-treatment PD-L1 combined positive score, and pre- and on-treatment sTILs were significantly associated with higher pCR rates (P = 0.0127, 0.0059, and 0.0085, respectively). Conclusion Combination neoadjuvant chemotherapy and pembrolizumab for high-risk, early-stage TNBC showed manageable toxicity and promising antitumor activity. In an exploratory analysis, the pCR rate showed a positive correlation with tumor PD-L1 expression and sTIL levels. Trial registration ClinicalTrials.gov identifier: NCT02622074.

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 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.

Background: Efficacy and quality of life (QoL) are key factors when selecting therapies for metastatic breast cancer (MBC) patients. The addition of targeted oral agents such as CDK4/6 inhibitors to endocrine therapy is the new standard for hormone receptor (HR)+ HER2- MBC and substantially prolongs progression-free survival. However more complex oral medication in oncology might require substantial improvement of patient management. Despite several advantages of an oral treatment, patients become increasingly self-responsible and physician/patient contact is reduced. Adherence, maintaining patients’ satisfaction, and early detection and management of side effects become important challenges and new ways of continuous support for oncological patients are needed. An eHealth-based platform could help to support therapy management and physician-patient interaction. Methods: PRECYCLE is a multicenter, randomized, phase IV trial in HR+ HER2- MBC. All patients (n = 960) receive the CDK4/6 inhibitor palbociclib either in first (62.5%) or later line (37.5%) together with endocrine therapy (AI, fulvestrant) according to national guidelines. Primary study aim is the time to deterioration (TTD) of QoL in patients supported by two eHealth systems with substantially different functionality. To date (05/07/2019), 250 patients have been registered in all 72 participating centers and 230 randomized to the different study arms: - CANKADO inform with only a CANKADO-based eHealth service with a personal login, documentation of daily drug intake and passive text information (disease, treatment), but no further functions. vs. - CANKADO active with the fully functional CANKADO-based eHealth treatment support system (+ drug diary, QoL, AEs, automated recommendations, etc.) To evaluate QoL, the FACT-B questionnaire is completed at every visit. Primary objective is to test the hypothesis of superiority for TTD with regards to QoL (FACT-G scale) in patients supported by an eHealth therapy management system (CANKADO active) versus in those merely receiving eHealth-based information (CANKADO inform). As little is known about relationships between behavioral patterns (e.g. adherence), genetic background, and drug efficacy. The trial also includes a large translational program that aims at the discovery and validation of biomarkers concerning efficacy, toxicity, adherence and QoL. Recruitment is ongoing. Citation Format: Tom Degenhardt, Peter Fasching, Diana Luftner, Volkmar Mueller, Christoph Thomssen, Christian Schem, Isabel Witzel, Thomas Decker, Hans Tesch, Sherko Kuemmel, Christoph Uleer, Rachel Wuerstlein, Christoph Riese, Timo Schinköthe, Ronald Kates, Johannes Schumacher, Nadia Harbeck, Marcus Schmidt. Impact of CANKADO-based eHealth-support on quality of life in metastatic breast cancer patients treated with palbociclib and endocrine therapy - Precycle [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 OT3-14-02.

Background: Breast cancer (BC) patients with ≥ 4 positive lymph nodes have a particularly poor prognosis with shorter disease free survival (DFS) and overall survival (OS) than pts with pN1a. However this is a highly heterogeneous group. The implementation of genomic signatures and/or Ki-67 status for hormone receptor positive BC pts with node negative or positive (≤ pN1a) disease enables identification of a subgroup of pts with favourable outcome and no survival benefit from chemotherapy (CTX). However, here is lack of information regarding pts with ≥ 4 positive lymph nodes, and so far all patients receive a recommendation for CTX. In addition, there are no predictive factors for use of dd CTX in this group so far. Methods: Between 1996–2000, 231 BC pts ≥ pN2a (median positive lymph nodes n= 6) with no evidence of distant metastases, were randomized to either adjuvant dd treatment with dd 3 × epirubicin (E, 90 mg/m2) + paclitaxel (P, 175 mg/m2) every 2 weeks (q2w) followed by 3 × cyclophosphamide (C)/methotrexate/5-fluorouracil (CMF, 600/40/600 mg/m2, q2w), or standard (st) treatment : 4 × E + C (C, 600 mg/m2) q3w followed by 3 × CMF q3w. Pts in the dd arm had a significantly better DFS (adjusted p = 0.027) with a non-significant trend to better OS (adjusted p = 0.058). Due to the recruitment period, there is no information on the HER2 status of the included pts (Reinisch et al, 2018). The BC360 panel analysis was performed on 147 tumor specimens (dd arm n= 75; st arm n= 72). Samples were run on the 770 gene BC360 panel with additional 6 spike-in genes. Genes related to adhesion and migration, immune activation, ER signaling, DNA damage and repair, apoptosis, and proliferation were analyzed. The survival analysis was used to create the forest plot incorporating a Cox proportional hazards model with the survival outcome as a dependent variable, the observed normalized gene expression or signature score data as a continuous covariate, and any grouping variable included as a strata variable in the model. Results: After quality control, 144/147 tumor specimens were available for the analysis (dd arm: 72; st arm; 72). The intrinsic subtype was equivalently distributed between the arms. The expression of PD-L1 (p = 0.025), PD-L2 (p = 0.007) and the presence of macrophages (p = 0.019) were positively correlated with an improved DFS in pts receiving dd but not st CTX. An improved OS was also associated with the presence of macrophages (p = 0.018) and the expression of TGF-β (p = 0.035) only in pts receiving dd CTX. Pts with a HER2 enriched subtype benefited from the use of dd CTX. Dd CTX does not influence the outcome in BRCAness and HRD positive pts regardless the applied CTX. Further prognostic and predictive factors correlated to a median FU of 20 years will be presented at the meeting. Conclusions: To our best knowledge, this is the first time the BC360 panel was run on samples of a cohort of high risk pts with ≥ pN2a with a median long term FU of 20 years. Our data may indicate that markers associated with immune activation are predictive factors for the use of dd therapies. High risk pts with different benefit from CTX may be identified. In pts with a HER2 enriched subtype not having received anti-HER2 therapy, the application of dd therapy may correlate with a better outcome. This analysis highlights the prognostic and predictive value of gene signatures to provide treatment guidance. Citation Format: Mattea Reinisch, Oleg Gluz, Beyhan Ataseven, Peter Schmid, Jens-Uwe Blohmer, Christine Dittmer-Grabwoski, Anna Rueland, Simona Bruzas, Christine Seiberling, Hakima Harrach, Daniel Gebauer, Alexander Traut, Sherko Kuemmel. Prognostic and predictive impact of genes and signatures measured with the BC360 panel (Nanostring) in node positive (≥pN2a) high risk patients (pts) receiving dose dense (dd) versus standard dosed chemotherapy in an adjuvant randomized trial with a long term follow-up (FU) [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 PD5-09.

Purpose: Ribociclib plus endocrine therapy (ET) demonstrated a statistically significant progression-free survival and overall survival (OS) benefit in the phase III MONALEESA-7 trial of pre-/perimenopausal patients with hormone receptor (HR)-positive (HR+), HER2-negative (HER2−) advanced breast cancer (ABC). The median OS was not reached in the ribociclib arm in the protocol-specified final analysis; we hence performed an exploratory OS and additional outcomes analysis with an extended follow-up (median, 53.5 months). Patients and Methods: Patients were randomized to receive ET [goserelin plus nonsteroidal aromatase inhibitor (NSAI) or tamoxifen] with ribociclib or placebo. OS was evaluated with a stratified Cox proportional hazard model and summarized with Kaplan–Meier methods. Results: The intent-to-treat population included 672 patients. Median OS was 58.7 months with ribociclib versus 48.0 months with placebo [hazard ratio = 0.76; 95% confidence interval (CI), 0.61–0.96]. Kaplan–Meier estimated OS at 48 months was 60% and 50% with ribociclib and placebo, respectively. Subgroup analyses were generally consistent with the OS benefit, including patients who received NSAI and patients aged less than 40 years. Subsequent antineoplastic therapies following discontinuation were balanced between the ribociclib (77%) and placebo (78%) groups. Use of cyclin-dependent kinase 4/6 inhibitors after discontinuation was higher with placebo (26%) versus ribociclib (13%). Time to first chemotherapy was significantly delayed with ribociclib versus placebo. No drug–drug interactions were observed between ribociclib and either NSAI. Conclusions: Ribociclib plus ET continued to show significantly longer OS than ET alone in pre-/perimenopausal patients, including patients aged less than 40 years, with HR+/HER2− ABC with 53.5 months of median follow-up (ClinicalTrials.gov, NCT02278120).

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

PURPOSENeoadjuvant systemic treatment (NST) elicits a pathologic complete response in 40%-70% of women with breast cancer. These patients may not need surgery as all local tumor has already been eradicated by NST. However, nonsurgical approaches, including imaging or vacuum-assisted biopsy (VAB), were not able to accurately identify patients without residual cancer in the breast or axilla. We evaluated the feasibility of a machine learning algorithm (intelligent VAB) to identify exceptional responders to NST.METHODSWe trained, tested, and validated a machine learning algorithm using patient, imaging, tumor, and VAB variables to detect residual cancer after NST (ypT+ or in situ or ypN+) before surgery. We used data from 318 women with cT1-3, cN0 or +, human epidermal growth factor receptor 2–positive, triple-negative, or high-proliferative Luminal B–like breast cancer who underwent VAB before surgery (ClinicalTrials.gov identifier: NCT02948764 , RESPONDER trial). We used 10-fold cross-validation to train and test the algorithm, which was then externally validated using data of an independent trial (ClinicalTrials.gov identifier: NCT02575612 ). We compared findings with the histopathologic evaluation of the surgical specimen. We considered false-negative rate (FNR) and specificity to be the main outcomes.RESULTSIn the development set (n = 318) and external validation set (n = 45), the intelligent VAB showed an FNR of 0.0%-5.2%, a specificity of 37.5%-40.0%, and an area under the receiver operating characteristic curve of 0.91-0.92 to detect residual cancer (ypT+ or in situ or ypN+) after NST. Spiegelhalter's Z confirmed a well-calibrated model ( z score –0.746, P = .228). FNR of the intelligent VAB was lower compared with imaging after NST, VAB alone, or combinations of both.CONCLUSIONAn intelligent VAB algorithm can reliably exclude residual cancer after NST. The omission of breast and axillary surgery for these exceptional responders may be evaluated in future trials.

Purpose: This phase II study determined the efficacy of lacnotuzumab added to gemcitabine plus carboplatin (gem-carbo) in patients with advanced triple-negative breast cancer (TNBC). Patients and Methods: Female patients with advanced TNBC, with high levels of tumor-associated macrophages not amenable to curative treatment by surgery or radiotherapy were enrolled. Lacnotuzumab was dosed at 10 mg/kg every 3 weeks, ± a dose on cycle 1, day 8. Gemcitabine (1,000 mg/m2) and carboplatin (dose in mg calculated by area under the curve [mg/mL/min] × (glomerular filtration rate [mL/min] + 25 [mL/min]) were dosed every 3 weeks. Treatment continued until unacceptable toxicity, disease progression, or discontinuation by physician/patient. Results: Patients received lacnotuzumab + gem-carbo (n = 34) or gem-carbo (n = 15). Enrollment was halted due to recruitment challenges owing to rapid evolution of the therapeutic landscape; formal hypothesis testing of the primary endpoint was therefore not performed. Median progression-free survival was 5.6 months [90% confidence interval (CI), 4.47–8.64] in the lacnotuzumab + gem-carbo arm and 5.5 months (90% CI, 3.45–7.46) in the gem-carbo arm. Hematologic adverse events were common in both treatment arms; however, patients treated with lacnotuzumab experienced more frequent aspartate aminotransferase, alanine aminotransferase, and creatine kinase elevations. Pharmacokinetic results showed that free lacnotuzumab at 10 mg/kg exhibited a typical IgG pharmacokinetic profile and target engagement of circulating colony-stimulating factor 1 ligand. Conclusions: Despite successful target engagement and anticipated pharmacokinetic profile, lacnotuzumab + gem-carbo showed comparable antitumor activity to gem-carbo alone, with slightly poorer tolerability. However, the data presented in this article would be informative for future studies testing agents targeting the CSF1–CSF1 receptor pathway in TNBC.

Background In unselected HER2+ early breast cancer (EBC), de-escalated chemotherapy-free neoadjuvant therapy (NAT) with dual HER2-blockade induces pCR rates of only 20%-40%. In order to achieve pCR rates by de-escalated therapy comparable to those achieved by chemotherapy-based regimens, patient selection and more effective chemotherapy-free regimens are thus key. KEYRICHED-1 (NCT03988036), a single-arm phase 2 study, is the first trial to investigate chemotherapy-free NAT with dual HER2 blockade and pembrolizumab in HER2-enriched HER2+ EBC. In a translational subproject, we analyzed gene signatures together with tumor cell proliferation and spatiotemporal immune cell profiling to identify predictive factors for pCR. Methods 48 pre- and postmenopausal patients with newly diagnosed HER2 2+ (ISH positive) or 3+ EBC (stage I-III) and HER2-enriched (HER2-E) subtype by PAM50 were included in the study. All patients received 4 cycles of pembrolizumab (200 mg), trastuzumab biosimilar ABP 980 (loading dose (LD) 8 mg/kg bodyweight (BW), maintenance dose (MD) 6 mg/kg BW), and pertuzumab (LD 840 mg/kg BW, MD 420 mg/kg BW) q21d. Primary objective was pCR (centrally confirmed absence of invasive tumor in breast and lymph nodes: ypT0/is, ypN0). NanoString Breast Cancer 360 panel was performed in baseline biopsies (n=42). ≥30% Ki67 decrease, < 500 invasive tumor cells or no evidence of tumor in week 3 biopsies (on treatment) were classified as early response. sTILs were analyzed at baseline (n=42) and week 3 (n=28). Ongoing analyses include whole exome sequencing and multiplexed immunohistochemistry for expression of PD1, PDL1, CD4, CD8, CD68, and CD20 levels in tumor and stroma at baseline and at week 3. Impact of standardized expression of single genes, signatures, and sTILs on pCR was evaluated with univariable and multivariate logistic regression analyses and summarized with odds ratios (OR) and 95% confidence intervals (95%CI). Results 42 patients with BC360 and sTILs data at baseline were included in the analysis. Median age was 55 years (range: 22-83), 11 patients (31%) had node-positive EBC. At baseline, 28 patients had sTIL levels ≥30% and 14 had sTILs < 30%; the corresponding pCR rates were 57.1% (n=16) and 28.6% (n=4, p=0.108). At week 3 (on treatment), 16 patients had sTIL levels ≥30%, 50% (n=8) had a pCR vs 8.3% in those with < 30% sTILs (one patient out of 12, p=0.039). 37 patients had early response, 54.1% of them (n=20) had a pCR vs 0% in early non-responders (n=5, p=0.049). In univariate analysis, IDO1, ERBB2, IFNγ, cytotoxic cells, cytotoxicity, CD8 T-cells, TIGIT, and tumor inflammation signatures were statistically significantly associated with pCR (OR 2.3-3.6); ERBB2, IDO1, IFNγ and CD8 T-cells remained significant after adjusting for hormone receptor (HR) and central HER2 status (OR 2.2-4.3). 70 single genes were predictive for pCR; none of them remained significant after false discovery rate adjustment (25%). In multivariable analysis for baseline markers including signatures, sTILs, HR and central HER2 status, only ERBB2 (OR 8.7, 95%CI 1.9-39.0, p=0.0046) and cytotoxic cells signatures (OR 4.6, 95%CI 1.6-13.5, p=0.0059) were predictive for pCR. Results of whole exome sequencing, and multiplexed immunohistochemistry analysis of immune cell markers will be presented at the Symposium. Conclusions Biomarker analysis in the unique KEYRICHED-1 cohort revealed that early response at week 3, ERBB2 and immune related signatures as well as on-therapy sTIL levels predict pCR after a chemotherapy-free combination of immunotherapy and dual HER2 blockade in HER2-enriched EBC. These results pave the way for validation in larger de-escalation trials investigating short, chemotherapy-free regimens in selected patients with HER2+ EBC. Funding for this research was provided by MSD Sharp & Dohme GmbH. Citation Format: Monika Graeser, Sherko Kuemmel, Oleg Gluz, Friedrich Feuerhake, Valery Volk, Daniel Ulbrich-Gebauer, Claudia Biehl, Mattea Reinisch, Athina Kostara9, Iris Scheffen, Kerstin Luedtke-Heckenkamp, Andreas Hartkopf, Felix Hilpert, Angela Kentsch, Carsten Ziske, Reinhard Depenbusch, Michael Braun, Jens-Uwe Blohmer, Christine zu Eulenburg, Matthias Christgen, Ronald Kates, Stephan Bartels, Hans-Heinrich Kreipe, Enrico Pelz, Peter Schmid, Nadia Harbeck. Combined biomarker analysis for prediction of pathological complete response (pCR) after 12 weeks of pembrolizumab + trastuzumab + pertuzumab in HER2-enriched early breast cancer: Keyriched-1 trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-03.