The primary analysis of the FeDeriCa study (NCT03493854; Tan AR, et al. Lancet Oncol 2021) showed that PH FDC SC cycle 7 P and H serum trough concentrations were non-inferior to intravenous (IV) P and H, with comparable total pathological complete response rates and safety profiles when given as neoadjuvant therapy for HER2-positive EBC. Here we report long-term efficacy and safety data. Patients (pts) had HER2-positive operable, locally advanced or inflammatory stage II–IIIC BC and left ventricular ejection fraction ≥55%. They received eight cycles of neoadjuvant chemotherapy (one of two standard regimens chosen by the investigator) + P IV (840 mg loading dose then 420 mg maintenance) + H IV (8 mg/kg then 6 mg/kg) or PH FDC SC (1200 mg P/600 mg H then 600 mg each as FDC SC) every 3 weeks during cycles 5–8 in a 1:1 randomisation design. Pts continued adjuvant HER2-targeted treatment after surgery, per randomisation, to complete 18 cycles. Secondary endpoints included invasive disease-free survival (iDFS), event-free survival (EFS), distant recurrence-free interval (DRFI), overall survival (OS) and safety (focusing on cardiac adverse events). Data cut-off was 2 Jun, 2023; median follow-up was 51.4 months in the P + H IV arm and 51.2 months in the PH FDC SC arm. Long-term efficacy data are shown in the table. No new safety signals, including for cardiac safety, were observed.Table: 114PP + H IV n = 252PH FDC SC n = 248iDFSPts who underwent surgery, n239234Pts with event, n (%)23 (9.6)26 (11.1)Unstratified hazard ratio (HR)(95% confidence interval [CI])1.13 (0.64, 1.97)4-year event-free rate (95% CI)89.5 (85.4, 93.6)88.5 (84.3, 92.7)EFSPts, n252248Pts with event, n (%)29 (11.5)32 (12.9)HR (95% CI)1.20 (0.72, 1.98)4-year event-free rate (95% CI)88.5 (84.4, 92.5)86.6 (82.2, 90.9)DRFIPts, n252248Pts with event, n (%)18 (7.1)19 (7.7)HR (95% CI)1.17 (0.61, 2.24)4-year event-free rate (95% CI)92.5 (89.2, 95.8)91.9 (88.4, 95.4)OSPts, n252248Pts with event, n %12 (4.8)14 (5.6)HR (95% CI)1.26 (0.58, 2.72)4-year event-free rate (95% CI)95.5 (92.9, 98.1)94.1 (91.1, 97.1) Open table in a new tab The long-term efficacy of PH FDC SC was comparable to that of P + H IV. Safety remained similar to P + H IV and consistent with P + H + chemotherapy. Overall, these findings support the primary analysis results. PH FDC SC is established as a faster, more convenient, less invasive, pt- and healthcare professional-preferred alternative to P + H IV for pts with HER2-positive BC.

Axillary surgery in early breast cancer (BC) has become less radical. However, for patients (pts) undergoing NST, the optimal surgical treatment algorithm in the axilla remains uncertain and is influenced by response to NST. The significance of nodal micrometastases (ypN1mi) after NST remains controversial and detection of additional macrometastases could have impact on postneoadjuvant treatment decisions. The aim of our study was to retrospectively analyse ypN1mi occurrence in five neoadjuvant AGO B / GBG trials conducted between 2012 and 2019. Data from 3199 pts with early BC, who were enrolled in five NACT studies (GeparSepto, GeparOcto, GeparNuevo, GeparX, GeparOla), were retrospectively analyzed. Our study investigated axillary surgeries, the incidence of ypN1mi and their correlation with outcome. 3163/3199 (98.9%) patients underwent breast surgery and information available on axillary intervention and were included in our analysis. TNBC, HER2+ and HR+/HER2- BC were reported in 38.9%, 29.1% and 32.0% respectively. Nodal status upon clinical/imaging evaluation was cN0 in 66.5%, cN1 in 29.5% and cN2/cN3 in 3.9%. Sentinel lymph node biopsy (SLNB) prior to NST was performed in 44.1% (1395/3163) and after NST in 19.4%. 1746 pts did not have any axillary surgery prior to NST. After NST 612 pts had a SLNB only, 5 pts received a targeted lymph node biopsy (TLNB) only, 27 pts had a targeted axillary dissection (TAD) and 1288 pts received an axilla lymph node dissection (ALND) only. 125 pts had an ALND following SLNB, TLNB or TAD. Of the 2038 evaluable pts who had any LN surgery after NST 879 (43.1%) achieved a pathological complete response in the breast (ypT0) of which 47 (5.3%) had concurrent residual disease in the LNs (ypT0, ypN+). 2.7% had ypN1mi and 0.64% had ypN1mi as sole residual disease. During our retrospective study period, surgical standards changed to preferring SLNB in cN0 and allowing TAD in cN+ patients both after NST starting 2017 and 2019 respectively. Surgical approaches according to cN stage, axillary conversion rates according to subtypes and 5 year TTE data will be presented.

TROP-2 is involved in regulating cancer growth and invasion in different tumour types. It is also a potent therapeutic target, being addressed by antibody drug conjugates (ADC). This study evaluates the impact of TROP-2 on breast cancer prognosis in high-risk, node-positive BC of the German adjuvant intergroup node-positive (GAIN) cohort. Tissue microarrays (TMAs) were generated from FFPE-pre-therapeutic surgical resection tissue (n = 1358). Immunohistochemical staining was performed with human TROP-2 antibody SP295. Membranous and cytoplasmic expression of TROP-2 in invasive tumor cells was assessed. The Cutoff Finder web application was used for identification of the best cutoff point according to disease-free survival (DFS) and overall survival (OS). For n = 996 patients, data on hormone receptor (HR), HER2 and Ki67 status were available. The association of membranous (m)TROP-2 and cytoplasmic (c)TROP-2 expression with molecular intrinsic subgroups, TNM stages, age, proliferation and HR status were evaluated. For 1186 TMA spots valid TROP-2 evaluation was available. The Cutoff Finder identified 70 % as best cutoff for cTROP-2 expression. cTROP-2 ≤ 70 % was significantly associated with better grading (p < 0.001). In multivariate Cox regression analysis, cTROP-2 ≤ 70% was associated with improved DFS in HR+/HER2- (p = 0.006) and luminal A-like tumors (p = 0.013). For mTROP-2, a product score (IRS) of grouped percentage and staining intensity showed better DFS and OS for IRS > 3 (also identified by Cutoff Finder) in HER2+/HRany and HER2+/HR+ patients (uni-/multivariate). Detailed data incl. molecular subtypes will be presented. TROP-2 is commonly expressed in breast cancer with its cellular localization differentially affecting survival. The results are relevant for biomarker strategies for future therapeutic concepts. In the SASCIA trial investigating Sacituzumab TROP-2 is prospectively assessed.

Intermediate biopsies during neoadjuvant treatment might offer opportunities for prediction of pathological complete response (pCR) and patient outcome, which could be a basis for de-escalation of treatment. However, their relevance for clinical decisions is not clear. We evaluated intermediate biopsies that were taken during neoadjuvant treatment from 297 patients with invasive breast cancer from three prospective, randomized trials (GeparQuattro, -Quinto, -Sixto). We evaluated the presence of invasive breast cancer, tumor-infiltrating lymphocytes (TILs) and Ki-67 expression and compared the results to pre-treatment samples. We explored the association of residual cancer in the intermediate biopsies as well as dynamics in Ki-67 and TILs with pCR rates and disease-free survival. Of the 297 tumors, 87 (29%) samples were triple-negative (TNBC), 138 (46%) HR+/HER2- and 72 (24%) HER2+. We found invasive tumor cells in 70% of biopsies, with significant differences between the subtypes (HR+/HER2-: 84%; TNBC: 62%, HER2+: 51%; p<0.001). In the complete cohort, 8% of patients with invasive tumor cells in intermediate biopsies achieved a pCR after completion of treatment (pCR rate in patients with residual tumor: TNBC: 19%, HR+/HER2: 3%; HER2+: 11%). If no residual cancer was present, pCR rate was 50% in the complete cohort (TNBC: 48%, HR+/HER2-: 27%; HER2+: 66%). An increase in TILs from baseline biopsy to intermediate biopsy was associated with a higher probability of pCR in the overall study cohort (p=0.001). A similar or increased Ki-67 was associated with a low probability of pCR in the overall study cohort (p=0.004) and with a shorter disease-free survival in patients with TNBC (p=0.04). Intermediate biopsies can identify patients that are unlikely to achieve a pCR after therapy. After further validation, this may be useful for adaptation of treatment. For translational biomarker research, intermediate biopsies are useful tool to study mechanisms of therapy resistance and biomarker discovery. Additional studies will be needed to demonstrate if standardized sampling procedures can further improve response prediction through intermediate biopsies.

ET is the mainstay management for ER+ BC; guidelines recommend ET before chemotherapy in LA/mBC. Giredestrant, a highly potent, non-steroidal, oral selective ER antagonist and degrader (SERD), achieves robust ER occupancy and was well tolerated and active as a single agent and in combination with palbociclib, regardless of ESR1 mutation, in phase I/II studies. acelERA BC (NCT04576455) compares giredestrant and PCET for ER+, HER2– LA/mBC in the 2nd/3rd line. We report the primary results. Post- and pre-/peri-menopausal women, or men, ≥18 years with measurable disease or evaluable bone lesions, who progressed after 1–2 lines of systemic therapy (≤1 targeted, ≤1 chemotherapy regimen, prior fulvestrant allowed) were randomised 1:1 to giredestrant (30 mg PO QD) or fulvestrant/aromatase inhibitor per local guidelines (+LHRH agonist in pre-/peri-menopausal women, and men) until disease progression/unacceptable toxicity. Stratification was by visceral vs non-visceral disease, prior CDK4/6 inhibitor (yes/no) and prior fulvestrant (yes/no). The primary endpoint was investigator-assessed progression-free survival (INV-PFS). At cut-off (18/02/22), median follow-up was 7.89 months; 39% of pts had baseline ESR1 mutations; 71%/28% had 1/2 prior therapy lines. Efficacy/safety are shown in the table. Updated data with longer follow-up will be presented.Table: 211MOGiredestrantPCETn = 151n = 152INV-PFS HR (95% CI)0.81 (0.60, 1.10)Stratified log-rank P-value0.18INV-PFS HR (95% CI) in pts with baseline ESR1 mutation*0.60 (0.35, 1.03)CBR, %3221ORR, %137Safety, % pts with ≥1:n = 150n = 152AE8571Grade 3/4 AE1712ET-related Grade 3/4 AE43Grade 5 AE1†1‡Serious AE98Related serious AE21AE leading to treatment discontinuation12Treatment effect was consistent across most key subgroups Overall survival was immature * In circulating tumour DNA † 2 ischemic strokes; 1 related which became fatal after cut-off ‡ 1 pulmonary embolism AE, adverse event; CBR, clinical benefit rate; CI, confidence interval; HR, hazard ratio (stratified); ORR, objective response rate Open table in a new tab Treatment effect was consistent across most key subgroups Overall survival was immature * In circulating tumour DNA † 2 ischemic strokes; 1 related which became fatal after cut-off ‡ 1 pulmonary embolism AE, adverse event; CBR, clinical benefit rate; CI, confidence interval; HR, hazard ratio (stratified); ORR, objective response rate While acelERA BC did not meet its primary endpoint of INV-PFS, giredestrant showed a numerical improvement vs PCET. A higher CBR and ORR was also observed in favour of giredestrant. In pts with higher dependence on ER activity, such as those with ESR1 mutations, the PFS benefit was more pronounced. Giredestrant was well tolerated, with a safety profile comparable to PCET and consistent with known ET risks. Giredestrant continues to be investigated in other studies.

PENELOPE-B is a phase III study investigating the role of PAL + ET vs placebo + ET in HR+, HER2- early BC pts with high risk of relapse after neoadjuvant chemotherapy (NACT). Invasive disease-free survival was not improved with PAL + ET (Loibl JCO 2021). Estradiol (E2), follicle-stimulating hormone (FSH), anti-Müllerian hormone (AMH) values might be influenced by post-NACT PAL. Changes in hormones for pts treated with CDK4/6 inhibitors + ET are not well explored. 616 pts were premenopausal at baseline (BL, investigator-defined). Pts with serum samples at BL and at least before cycle (C) 7 or at end of treatment (EOT) were considered (N=576). 576 pts provided blood samples at BL, 526 before C7, 541 at EOT. Centrally assessed FSH>12.4 IU/l and E2<52.2 ng/L were defined as postmenopausal; fertile level of AMH as ≥0.22 ng/mL (central lab cut-offs). Analysed subgroups were pre- vs postmenopausal FSH/E2 at BL, age ≤40 vs >40 yrs, gonadotropin-releasing hormone analogue (GnRHa) use vs no. Median age was 43 (19-56) yrs; 46.8% pts had BMI <25, 53.2% ≥25. Hormone values are shown below. At BL, 41.6% of pts in the placebo vs 41.3% in the PAL arm had premenopausal hormone levels. Of these, 9.1 vs 13.5% (p=0.387) had postmenopausal hormone levels at C7. In pts ≤40 yrs 29.2 vs 29.5% at BL (p=1.000), 18.1 vs 23.4% at C7 (p=0.472) had postmenopausal values. More pts >40 yrs (BL 75.3%, C7 69.8%) vs ≤40 yrs (29.4, 20.7%) and without GnRHa (80.3, 72.2%) vs with (15.9, 12.1%) had postmenopausal hormone levels. Median AMH was under the detection limit at all time points. At BL 91.8 vs 93.6% had non-fertile levels of AMH (p=0.426), 94.4 vs 96.5% at C7 (p=0.298), without difference in subgroups. EOT analysis will be presented at the meeting.Table: 60MOMedian, IQRFSH IU/lE2 ng/LPALPp-valuePALPp-valueAll premenopausal at BL (investigator-defined)BL35.67.1-55.532.56.3-54.20.407dt2.5-13.0dt2.5-14.00.242C724.15.5-37.718.45.1-34.30.157dt2.5-10.0dt2.5-10.00.726Premenopausal E2 and FSH at BLBL5.63.2-11.25.53.1-9.00.5716.02.5-105.07.02.5-125.00.768C74.82.5-14.44.62.3-8.80.258dtdt-14.0dtdt-13.00.940≤40 yrsBL10.63.8-46.97.64.4-41.50.8788.0dt-74.07.5dt-55.00.910C78.02.9-32.15.22.7-16.90.1505.0dt-55.0dtdt-22.00.448GnRHa use, BLBL5.13.1-10.65.03.1-9.00.731dtdt-8.0dtdt-9.00.792C73.52.2-7.04.32.2-8.00.489dtdt-5.0dtdt-6.00.574Detectable threshold, dt: E2=5 ng/L; P, placebo Open table in a new tab Detectable threshold, dt: E2=5 ng/L; P, placebo PAL does not influence FSH, E2 and the ovarian reserve significantly when added to ET after NACT.

Due to its decisive role to select targeted treatment options in breast cancer, we investigated if machine learning (ML) models could identify HER2-positive tumours from routinely obtained haematoxylin and eosin (H&E)-stained whole slide images.

Benefit of chemotherapy (CT) addition to ET remains controversial in premenopausal (pre) patients (pts) with 0-3 positive LNs (N0-1) and RS ≤25. In ADAPT, excellent outcome was observed in young N0-1 pts and ET response after short-term preoperative ET and RS 12-25 with ET alone. Here, we investigate impact of age, RS, and OFS on ET response, in ADAPT and its validation in the first part of ongoing phase III ADAPTcycle trial.

Background: Different endogenous and exogenous mutational processes act over the evolutionary history of a malignant tumor, driven by abnormal DNA editing, mutagens or age-related DNA alterations, among others, to generate the specific mutational landscape of each individual tumor. The signatures of these mutational processes can be identified in large genomic datasets. We investigated the hypothesis that genomic patterns of mutational signatures are associated with the clinical behavior of breast cancer, in particular chemotherapy response and survival, with a particular focus on therapy-resistant disease. Patients and methods: Whole exome sequencing was carried out in 405 pretherapeutic samples from the prospective neoadjuvant multicenter GeparSepto study. We analyzed 11 mutational signatures including biological processes such as APOBEC-mutagenesis, homologous recombination deficiency (HRD), mismatch repair deficiency and also age-related or tobacco-induced alterations. Results: Different subgroups of breast carcinomas were defined mainly by differences in HRD-related and APOBEC-related mutational signatures and significant differences between hormone-receptor (HR)-negative and HR-positive tumors as well as correlations with age, Ki-67 and immunological parameters were observed. We could identify mutational processes that were linked to increased pathological complete response rates to neoadjuvant chemotherapy with high significance. In univariate analyses for HR-positive tumors signatures, S3 (HRD, P < 0.001) and S13 (APOBEC, P = 0.001) as well as exonic mutation rate (P = 0.002) were significantly correlated with increased pathological complete response rates. The signatures S3 (HRD, P = 0.006) and S4 (tobacco, P = 0.011) were prognostic for reduced disease-free survival of patients with chemotherapy-resistant tumors. Conclusion: The results of this investigation suggest that the clinical behavior of a tumor, in particular, response to neoadjuvant chemotherapy and disease-free survival of therapy-resistant tumors, could be predicted by the composition of mutational signatures as an indicator of the individual genomic history of a tumor. After additional validations, mutational signatures might be used to identify tumors with an increased response rate to neoadjuvant chemotherapy and to define therapy-resistant subgroups for future therapeutic interventions.

Obesity is associated with T-cell dysfunction and reduced antitumor immune response. In TNBC, high sTILs seem to predict pathologic complete response (pCR) and favorable prognosis only in normal weight patients (Desmedt et al. Cancer Res 2020). TNBC patients, who received anthracycline-taxane-based chemotherapy in GeparDuo, GeparTrio, GeparQuinto, GeparSixto, GeparSepto, and GeparOcto, with available BMI and pretreatment sTILs (centrally assessed) were considered. Patients with BMI <18.5 kg/m2 were excluded. Associations between BMI (normal weight, 18.5-<25 vs overweight/obese ≥25 kg/m2), sTILs (high ≥30% vs low <30) and pCR were assessed using Fisher`s exact test; between sTILs (continuous, dichtomized) and pCR (ypT0/is ypN0) according to BMI and interaction BMI*sTILs by logistic regression, between sTILs and disease-free survival (DFS) according to BMI and interaction BMI*sTILs by Cox regression. Of 1288 patients, 49.8% were normal weight, 50.2% overweight/obese; median age was 47 [21-78] vs 50 [21-76] years (p<0.001), cT3-4 12.0% vs 16.6% (p=0.021) and N+ 32.7% vs 37.0% (p=0.125). Normal weight patients had a higher pCR than overweight/obese patients (47.2% vs 39.9% p=0.009). Median sTILs was 30%, 50.4% of patients had high sTILs (normal weight 50.2% vs overweight/obese 50.6%, p=0.868). Higher level of sTILs was predictive for pCR both in normal weight (sTILs continuous OR 1.10, 95%CI 1.03-1.17, p=0.002) and in overweight/obese patients (OR 1.15, 95%CI 1.08-1.22, p<0.001). Interaction BMI*sTILs, p=0.302. Results were similar for dichotomized sTILs. Median follow-up was 54.7 months. Each 10% increase in sTILs was associated with an 11% reduction in the risk of a DFS event in normal weight (HR 0.89, 95%CI 0.82-0.95, p=0.001) and 8% in overweight/obese patients (HR 0.92, 95%CI 0.87-0.99, p=0.017). Interaction TILs*BMI, p=0.366. Our results do not confirm differences in the predictive and prognostic role of sTILs according to BMI in TNBC as described previously. A joint analysis to explore the source of observed heterogeneity is planned.

Hypoxia occurs in most solid tumors including BC and may negatively impact treatment response. We investigate the incidence of BACH1 (a key regulator of mitochondrial metabolism) and HIF1α (a hypoxia-inducible factor) expressions and their correlation with clinical outcomes in early HER2-negative BC. We correlated tumor BACH1 and HIF1α mRNA expression from available RNA-Seq data with pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS) in the GeparSepto trial (NCT01583426), which randomized pts with early-stage BC to either neoadjuvant solvent-based paclitaxel (P) or nP followed by EC. BACH1 and HIF1α values were analyzed as a continuous variable and categorized as low and high by median cut-off. Multivariate logistic (for pCR) and Cox (DFS and OS) regressions were used to adjust for age, cT, and cN. RNA-Seq expression data was available for 279 out of 810 HER2-negative BC pts, median age was 49 years (range 22-76) and median follow-up 49.8 months (range 2.3-62.4). There was a positive correlation between BACH1 and HIF1A expression levels (Pearson correlation 0.498). Overall, BACH1 and HIF1α continuous expressions were significantly associated with increased pCR (OR=4.21 [95%CI 1.44-12.30), p=0.009), OR=2.08 [95%CI 1.14-3.82], p=0.018, respectively) but did not impact survival in multivariate models. The table shows effects of BACH1 and HIF1α expression in nP vs P arm, both high BACH1 and HIF1α expressions were significant independent predictors of pCR and were associated with numerically better survivalTable: 21PEndpointBACH1HIF1αlowhighP**lowhighP**OR/HR* (95%C/I)POR/HR* (95%CI)POR/HR* (95%CI)POR/HR* (95%CI)PypT0 ypN00.84 (0.33-2.12)0.7162.86 (1.33-6.17)0.0070.0420.67 (0.26-1.70)0.3962.91 (1.32-6.42)0.0080.018DFS0.93 (0.46-1.87)0.8390.70 (0.32-1.53)0.3750.5341.58 (0.70-3.55)0.2720.62 (0.30-1.26)0.1870.096OS0.83 (0.33-2.09)0.6860.46 (0.16-1.36)0.1590.4532.07 (0.60-7.18)0.2500.46 (0.18-1.17)0.1010.067*OR/HR (nP vs P groups) in multivariate model **interaction test (BACH1 high/HIF1α high by nP arm) p value, multivariate model. Open table in a new tab . *OR/HR (nP vs P groups) in multivariate model **interaction test (BACH1 high/HIF1α high by nP arm) p value, multivariate model. HER2-negative BC with elevated BACH1 and HIF1α expression benefits from nP-based treatment. There was a positive correlation between increased BACH1 and HIF1α levels for predicting pCR. We suggest that high BACH1 and HIF1α expressions enhance the efficacy of nP treatment, perhaps through triggering the hypoxic tumor adaptation.

Background Improvement of systemic treatment of TNBC represents an unmet medical need. Recently, targeted therapy of regulatory immune pathways has become an important option in the treatment of numerous malignancies. Neodjuvant trials combining chemotherapy and checkpoint inhibitors (KEYNOTE-522 and IMPASSION-031) have demonstrated a meaningful benefit regarding pathological complete remission (pCR) for the addition of PD-1- and PD-L1-inhibitors to chemotherapy. In the neoadjuvant GeparNuevo trial only the subgroup of patients receiving a checkpoint inhibitor monotherapy window before the start of neodjuvant therapy achieved a pCR-benefit compared to neoadjuvant chemotherapy.

In the primary analysis of the neoadjuvant phase of the FeDeriCa study (NCT03493854; Tan AR, et al. Lancet Oncol 2021), PH FDC SC cycle 7 P + H serum trough concentrations were non-inferior to intravenous (IV) P + H, with comparable total pathological complete response rates and safety profiles. We present updated descriptive safety data that span the adjuvant phase of the study, with an additional 12 months beyond the primary analysis. Patients (pts) with HER2-positive operable, locally advanced or inflammatory stage II–IIIC BC and left ventricular ejection fraction (LVEF) ≥55% were randomised 1:1 to eight neoadjuvant chemotherapy cycles (investigator's choice between two standard regimens) + P IV (loading dose 840 mg, maintenance 420 mg) + H IV (8 mg/kg → 6 mg/kg) or chemotherapy + PH FDC SC (1200 mg P/600 mg H → 600 mg each as FDC SC) every 3 weeks during cycles 5–8. After surgery, pts continued adjuvant HER2-targeted treatment only, as randomised, to complete 18 cycles. Safety was assessed by NCI-CTCAE v4. Clinical cut-off was 10 July 2020. Adverse events (AEs) are shown in the table; the most common were diarrhoea, radiation skin injury and arthralgia. Infusion-/administration-related reactions within 24 hours were higher with PH FDC SC (17%) than with P + H IV (5%), all grade 1/2 and mostly due to local injection site reactions. No grade ≥3 anaphylaxis/hypersensitivity was reported in either arm.Table: 46PAEs; % of pts with ≥1:P + H IV (n = 252)PH FDC SC (n = 248)Any87%89%Grade ≥315%11%Serious3%4%To monitor46%45%Leading to death<1%*0CardiacPrimary†1%2%Secondary4%1%Safety population *Related cardiac failure †Clinically significant LVEF drops: 1% of pts per arm. Open table in a new tab Safety population *Related cardiac failure †Clinically significant LVEF drops: 1% of pts per arm. Overall safety and tolerability, including cardiac safety, of PH FDC SC in the adjuvant phase of FeDeriCa remained comparable to P + H IV, with the exception of AEs associated with the different routes of administration. Results are in line with the expectation that most AEs with PH FDC SC or P + H IV are observed during concomitant chemotherapy.

Pathological complete response (pCR) to neoadjuvant treatment in TNBC is strongly correlated with improved EFS and OS. Randomised trials have demonstrated increased pCR rates with the addition of checkpoint inhibitors to NACT in TNBC. Preclinical evidence suggests that AKT inhibition can enhance checkpoint inhibitor efficacy. The AKT inhibitor ipatasertib (IPAT) has shown promising activity in combination with paclitaxel as 1L therapy for metastatic TNBC. BARBICAN was designed to evaluate the clinical and biological effects of adding IPAT to NACT plus atezolizumab (atezo). International phase II, randomised trial in 146 patients (pts) with newly diagnosed, non-metastatic, high risk (node+ and/or tumour size ≥2 cm) TNBC. Patients were randomised (1:1) to receive one cycle of atezo (1200mg Q3W) ± IPAT (400mg D1-14), followed by 3 cycles of atezo (840mg Q2W) + weekly paclitaxel (80mg/m2) ± IPAT (400mg D1-21), followed by 4 cycles of atezo (840mg Q2W) + dose-dense doxorubicin (60mg/m2)/cyclophosphamide (600 mg/m2). Tumour biopsies were obtained at baseline, after each treatment phase and surgery. The primary clinical endpoint was pCR rate (ypT0/is ypN0). PD-L1 expression was assessed using the SP142 assay (1% cut-off). 144 pts received treatment, IPAT (n = 72) vs no ipatasertib (no-IPAT) (n = 72). There was no difference in pCR rates between treatment groups (chemo/atezo + IPAT, 49.3%, 95%CI, 36.8%-61.8%; chemo/atezo alone, 48.5%, 95%CI, 36.2%-61.0%). For IPAT vs no-IPAT, pCR was 66.7% vs 75.0% in the PD-L1-positive population (65 pts) and 32.4% vs 25.0% in the PD-L1-negative population (70 pts). pCR in node-positive pts was 55.6% (IPAT, 51.6%, no-IPAT 59.4%) compared to 43.1% (IPAT, 47.2%, no-IPAT 38.9%) in node-negative pts. Grade 3 or higher AE rates were 73.6% in the chemo/atezo + IPAT group and 40.3% in the chemo/atezo alone group, with rash, neutropenia, ALT increase, diarrhoea and mucosits being the most common. The majority of patients required IPAT dose modifications and the dose intensity was low. Addition of IPAT to neoadjuvant atezo plus chemotherapy did not improve pCR rates. IPAT dose intensity was low due to increased toxicity.

BACKGROUND:Current genetic and genomic tests measuring homologous recombination deficiency (HRD) show limited predictive value. This study compares the performance of an immunohistology-based RAD51 test with genetic/genomic tests to identify patients with HRD primary triple-negative breast cancer (TNBC) and evaluates its accuracy to select patients sensitive to platinum-based neoadjuvant chemotherapy (NACT). PATIENTS AND METHODS:This is a retrospective, blinded, biomarker analysis from the GeparSixto randomized clinical trial. TNBC patients received neoadjuvant paclitaxel plus Myocet®-nonpegylated liposomal doxorubicin (PM) or PM plus carboplatin (PMCb), both arms including bevacizumab. Formalin-fixed paraffin-embedded (FFPE) tumor samples were laid on tissue microarrays. RAD51, BRCA1 and γH2AX were quantified using an immunofluorescence assay. The predictive value of RAD51 was assessed by regression models. Concordance analyses were carried out between RAD51 score and tumor BRCA (tBRCA) status or genomic HRD score (Myriad myChoice®). Associations with pathological complete response (pCR) and survival were studied. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low). RESULTS:Functional HRD by RAD51-low was evidenced in 81/133 tumors (61%). RAD51 identified 93% tBRCA-mutated tumors and 45% non-tBRCA mutant cases as functional HRD. The concordance between RAD51 and genomic HRD was 87% [95% confidence interval (CI) 79% to 93%]. In patients with RAD51-high tumors, pCR was similar between treatment arms [PMCb 31% versus PM 39%, odds ratio (OR) 0.71, 0.23-2.24, P = 0.56]. Patients with RAD51-low tumors benefited from PMCb (pCR 66% versus 33%, OR 3.96, 1.56-10.05, P = 0.004; interaction test P = 0.02). This benefit maintained statistical significance in the multivariate analysis. Carboplatin addition showed similar disease-free survival in the RAD51-high [hazard ratio (HR) 0.40, log-rank P = 0.11] and RAD51-low (0.45, P = 0.11) groups. CONCLUSIONS:The RAD51 test identifies tumors with functional HRD and is highly concordant with tBRCA mutation and genomic HRD. RAD51 independently predicts clinical benefit from adding Cb to NACT in TNBC. Our results support further development to incorporate RAD51 testing in clinical decision-making.

Background: PreCycle (NCT03220178) is a multicenter, randomized phase IV Intergroup trial to evaluate the impact of eHealth-based Patient-Reported Outcome (PRO) assessment on quality of life (QoL) in patients with HR +/HER2− locally advanced or metastatic breast cancer treated with palbociclib and an aromatase inhibitor or palbociclib and fulvestrant. Patients willing to use the web/APP-eHealth solution CANKADO were eligible. Patients were randomized (2:1) to the active or inform arm (and stratified by line of treatment). In the inform arm, patients can document only their drug intake. Patients in the active arm are supported by CANKADO PRO–React, which additionally provides symptom-triggered questionnaires and corresponding recommendations to contact their physician. Primary endpoint is superiority for time to deterioration (TTD) of QoL in patients using ePRO.

Background: The predictive value of tumor mutational burden (TMB), alone or in combination with an immune gene expression profile (GEP), for response to neoadjuvant therapy in early triple negative breast cancer (TNBC) is currently not known, either for immune checkpoint blockade (ICB) or conventional chemotherapy. Patients and methods: We obtained both whole exome sequencing and RNA-Seq data from pretreatment samples of 149 TNBC of the recent neoadjuvant ICB trial, GeparNuevo. In a predefined analysis, we assessed the predictive value of TMB and a previously developed immune GEP for pathological complete remission (pCR). Results: Median TMB was 1.52 mut/Mb (range 0.02-7.65) and was significantly higher in patients with pCR (median 1.87 versus 1.39; P = 0.005). In multivariate analysis, odds ratios for pCR per mut/Mb were 2.06 [95% confidence intervals (CI) 1.33-3.20, P = 0.001] among all patients, 1.77 (95% a 1.00-3.13, P = 0.049) in the durvalumab treatment arm, and 2.82 (95% CI 1.21-6.54, P = 0.016) in the placebo treatment arm, respectively. We also found that both continuous TMB and immune GEP (or tumor infiltrating lymphocytes) independently predicted pCR. When we stratified patients in groups based on the upper tertile of TMB and median GEP, we observed a pCR rate of 82% (95% CI 60% to 95%) in the group with both high TMB and GEP in contrast to only 28% (95% CI 16% to 43%) in the group with both low TMB and GEP. Conclusions: TMB and immune GEP add independent value for pCR prediction. Our results recommend further analysis of TMB in combination with immune parameters to individually tailor therapies in breast cancer.