Patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)-targeted therapy have a worse prognosis than those who ...have no residual cancer. Trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy.
We conducted a phase 3, open-label trial involving patients with HER2-positive early breast cancer who were found to have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab. Patients were randomly assigned to receive adjuvant T-DM1 or trastuzumab for 14 cycles. The primary end point was invasive disease-free survival (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause).
At the interim analysis, among 1486 randomly assigned patients (743 in the T-DM1 group and 743 in the trastuzumab group), invasive disease or death had occurred in 91 patients in the T-DM1 group (12.2%) and 165 patients in the trastuzumab group (22.2%). The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group. Invasive disease-free survival was significantly higher in the T-DM1 group than in the trastuzumab group (hazard ratio for invasive disease or death, 0.50; 95% confidence interval, 0.39 to 0.64; P<0.001). Distant recurrence as the first invasive-disease event occurred in 10.5% of patients in the T-DM1 group and 15.9% of those in the trastuzumab group. The safety data were consistent with the known safety profile of T-DM1, with more adverse events associated with T-DM1 than with trastuzumab alone.
Among patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T-DM1 than with trastuzumab alone. (Funded by F. Hoffmann-La Roche/Genentech; KATHERINE ClinicalTrials.gov number, NCT01772472 .).
In the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-based chemotherapy improved pathological complete response (pCR) rates in patients with triple-negative breast ...cancer (TNBC). Here, we present survival data and the potential prognostic and predictive role of homologous recombination deficiency (HRD).
Patients were randomized to paclitaxel plus nonpegylated liposomal doxorubicin (Myocet®) (PM) or PM plus carboplatin (PMCb). The secondary study end points disease-free survival (DFS) and overall survival (OS) were analyzed. Median follow-up was 47.3 months. HRD was among the exploratory analyses in GeparSixto and was successfully measured in formalin-fixed, paraffin-embedded tumor samples of 193/315 (61.3%) participants with TNBC. Homologous recombination (HR) deficiency was defined as HRD score ≥42 and/or presence of tumor BRCA mutations (tmBRCA).
A significantly better DFS (hazard ratio 0.56, 95% CI 0.34–0.93; P = 0.022) was observed in patients with TNBC when treated with PMCb. The improvement of OS with PMCb was not statistically significant. Additional carboplatin did not improve DFS or OS in patients with HER2-positive tumors. HR deficiency was detected in 136 (70.5%) of 193 triple-negative tumors, of which 82 (60.3%) showed high HRD score without tmBRCA. HR deficiency independently predicted pCR (ypT0 ypN0) odds ratio (OR) 2.60, 95% CI 1.26–5.37, P = 0.008. Adding carboplatin to PM significantly increased the pCR rate from 33.9% to 63.5% in HR deficient tumors (P = 0.001), but only marginally in HR nondeficient tumors (from 20.0% to 29.6%, P = 0.540; test for interaction P = 0.327). pCR rates with carboplatin were also higher (63.2%) than without carboplatin (31.7%; OR 3.69, 1.46–9.37, P = 0.005) in patients with high HRD score but no tmBRCA. DFS rates were improved with addition of carboplatin, both in HR nondeficient (hazard ratio 0.44, 0.17–1.17, P = 0.086) and HR deficient tumors (hazard ratio 0.49, 0.23–1.04, P = 0.059).
The addition of carboplatin to neoadjuvant PM improved DFS significantly in TNBC. Long-term survival analyses support the neoadjuvant use of carboplatin in TNBC. HR deficiency in TNBC and HRD score in non-tmBRCA TNBC are predictors of response. HRD does not predict for carboplatin benefit.
Guidelines recommend atezolizumab plus nab-paclitaxel (A + nP) for first-line treatment of unresectable, locally advanced, or metastatic triple-negative breast cancer expressing programmed ...death-ligand 1 (PD-L1) on tumor-infiltrating immune cells (IC), based on IMpassion130. We report the final overall survival (OS) and safety of that study as per the prespecified analysis plan.
Patients were randomized to nP 100 mg/m2 (days 1, 8, and 15 of a 28-day cycle) with atezolizumab 840 mg (A + nP) or placebo (P + nP; days 1 and 15), until progression or unacceptable toxicity. Coprimary endpoints were progression-free survival intention-to-treat (ITT) and PD-L1 IC-positive populations and OS (tested hierarchically in the ITT population and, if significant, in the PD-L1 IC-positive population).
Each arm comprised 451 patients; 666 (73.8%) had died by the final OS analysis cut-off (median follow-up, 18.8 months; interquartile range, 8.9-34.7 months). Median OS in the ITT population was 21.0 months 95% confidence interval (CI), 19.0-23.4 months with A + nP, and 18.7 months (95% CI, 16.9-20.8 months) with P + nP stratified hazard ratio (HR), 0.87; 95% CI, 0.75-1.02; P = 0.077. Exploratory analysis in the PD-L1 IC-positive population showed a median OS of 25.4 months (95% CI, 19.6-30.7 months) with A + nP (n = 185) and 17.9 months (95% CI, 13.6-20.3 months) with P + nP (n = 184; stratified HR, 0.67; 95% CI, 0.53-0.86). Safety outcomes were consistent with previous analyses and the known toxicity profiles of each agent. Immune-mediated adverse events of special interest were reported in 58.7% and 41.6% of patients treated with A + nP and P + nP, respectively.
Although the OS benefit in the ITT population was not statistically significant, precluding formal testing, clinically meaningful OS benefit was observed with A + nP in PD-L1 IC-positive patients, consistent with prior interim analyses. This combination remained safe and tolerable with longer follow-up.
•Final OS data from IMpassion130 (A + nP in metastatic triple-negative breast cancer) agree with prior interim analyses.•OS benefit with A + nP versus P + nP in the ITT population was not statistically significant, precluding further testing.•Exploratory data not formally tested showed clinically meaningful OS benefit for A + nP in the PD-L1 IC-positive population.•Three-year OS rates in the PD-L1 IC-positive population were 35.8% with A + nP versus 22.2% with P + nP.•No new safety signals were seen with longer follow-up; adverse events were consistent with those known for each drug.
Combining immune-checkpoint inhibitors with chemotherapy yielded an increased response rates in patients with metastatic triple-negative breast cancer (TNBC). Therefore, we evaluated the addition of ...durvalumab to standard neoadjuvant chemotherapy (NACT) in primary TNBC.
GeparNuevo is a randomised phase II double-blind placebo-controlled study randomising patients with TNBC to durvalumab or placebo given every 4weeks in addition to nab-paclitaxel followed by standard EC. In the window-phase durvalumab/placebo alone was given 2 weeks before start of nab-paclitaxel. Randomisation was stratified by stromal tumour-infiltrating lymphocyte (sTILs). Patients with primary cT1b-cT4a-d disease, centrally confirmed TNBC and sTILs were included. Primary objective was pathological complete response (pCR) (ypT0 ypN0).
A total of 174 patients were randomised, 117 participated in the window-phase. Median age was 49.5years (range 23–76); 47 patients (27%) were younger than 40years; 113 (65%) had stage ≥IIA disease, 25 (14%) high sTILs, 138 of 158 (87%) were PD-L1-positive. pCR rate with durvalumab was 53.4% (95% CI 42.5% to 61.4%) versus placebo 44.2% (95% CI 33.5% to 55.3%; unadjusted continuity corrected χ2P=0.287), corresponding to OR=1.45 (95% CI 0.80–2.63, unadjusted Wald P=0.224). Durvalumab effect was seen only in the window cohort (pCR 61.0% versus 41.4%, OR=2.22, 95% CI 1.06–4.64, P=0.035; interaction P=0.048). In both arms, significantly increased pCR (P<0.01) were observed with higher sTILs. There was a trend for increased pCR rates in PD-L1-positive tumours, which was significant for PD-L1-tumour cell in durvalumab (P=0.045) and for PD-L1-immune cell in placebo arm (P=0.040). The most common immune-related adverse events were thyroid dysfunction any grade in 47%.
Our results suggest that the addition of durvalumab to anthracycline-/taxane-based NACT increases pCR rate particularly in patients treated with durvalumab alone before start of chemotherapy.
ClinicalTrials.gov number: NCT02685059.
In the phase III IMpassion130 trial, combining atezolizumab with first-line nanoparticle albumin-bound-paclitaxel for advanced triple-negative breast cancer (aTNBC) showed a statistically significant ...progression-free survival (PFS) benefit in the intention-to-treat (ITT) and programmed death-ligand 1 (PD-L1)-positive populations, and a clinically meaningful overall survival (OS) effect in PD-L1-positive aTNBC. The phase III KEYNOTE-355 trial adding pembrolizumab to chemotherapy for aTNBC showed similar PFS effects. IMpassion131 evaluated first-line atezolizumab–paclitaxel in aTNBC.
Eligible patients no prior systemic therapy or ≥12 months since (neo)adjuvant chemotherapy were randomised 2:1 to atezolizumab 840 mg or placebo (days 1, 15), both with paclitaxel 90 mg/m2 (days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. Stratification factors were tumour PD-L1 status, prior taxane, liver metastases and geographical region. The primary endpoint was investigator-assessed PFS, tested hierarchically first in the PD-L1-positive immune cell expression ≥1%, VENTANA PD-L1 (SP142) assay population, and then in the ITT population. OS was a secondary endpoint.
Of 651 randomised patients, 45% had PD-L1-positive aTNBC. At the primary PFS analysis, adding atezolizumab to paclitaxel did not improve investigator-assessed PFS in the PD-L1-positive population hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.60-1.12; P = 0.20; median PFS 6.0 months with atezolizumab–paclitaxel versus 5.7 months with placebo–paclitaxel. In the PD-L1-positive population, atezolizumab–paclitaxel was associated with more favourable unconfirmed best overall response rate (63% versus 55% with placebo–paclitaxel) and median duration of response (7.2 versus 5.5 months, respectively). Final OS results showed no difference between arms (HR 1.11, 95% CI 0.76-1.64; median 22.1 months with atezolizumab–paclitaxel versus 28.3 months with placebo–paclitaxel in the PD-L1-positive population). Results in the ITT population were consistent with the PD-L1-positive population. The safety profile was consistent with known effects of each study drug.
Combining atezolizumab with paclitaxel did not improve PFS or OS versus paclitaxel alone.
NCT03125902.
•The phase III IMpassion131 trial evaluated atezolizumab combined with paclitaxel as first-line therapy for aTNBC.•The primary endpoint was investigator-assessed PFS, tested hierarchically in the PD-L1+ and then ITT populations.•Neither PFS nor OS was improved with the combination of atezolizumab plus paclitaxel in either population.•These findings may result from imbalances in prognostic features or chance findings in a relatively small trial.•IMpassion131 results highlight the need for further research into immunotherapy for TNBC.
Pertuzumab (P) combined with trastuzumab (H)-based chemotherapy improves efficacy in early and advanced HER2-positive breast cancer. We assessed the tolerability, with particular focus on cardiac ...safety, of H and P with chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer.
In this multicenter, open-label phase II study, patients with operable, locally advanced, or inflammatory breast cancer were randomized 1 : 1 : 1 to receive six neoadjuvant cycles q3w (Arm A: 5-fluorouracil, epirubicin, cyclophosphamide FEC + H + P ×3 → docetaxel T + H + P ×3; Arm B: FEC ×3 → T + H + P ×3; Arm C: T + carboplatin + H TCH+P ×6). pCR was assessed at surgery and adjuvant therapy given to complete 1 year of H.
Two hundred twenty-five patients were randomized. During neoadjuvant treatment, two patients (2.7%; Arm B) experienced symptomatic left ventricular systolic dysfunction (LVSD) and 11 patients (Arm A: 4 5.6%; Arm B: 4 5.3%; Arm C: 3 3.9%) had declines in left ventricular ejection fraction of ≥10% points from baseline to <50%. Diarrhea was the most common adverse event. pCR (ypT0/is) was reported for 61.6% (Arm A), 57.3% (Arm B), and 66.2% (Arm C) of patients.
The combination of P with H and standard chemotherapy resulted in low rates of symptomatic LVSD.
Addition of immune checkpoint inhibitors to neoadjuvant chemotherapy (NACT) is a promising strategy in early breast cancer, but the optimal duration of therapy is currently unknown. In the GeparNuevo ...(NCT02685059) trial, addition of durvalumab to NACT as previously reported led to a moderate increase in pathological complete response (pCR) rate by an absolute 9% (P = 0.287).
Patients with cT1b-cT4a-d triple-negative breast cancer (TNBC) received durvalumab 1.5 g or placebo every 4 weeks added to nab-paclitaxel 125 mg/m2 weekly for 12 weeks, followed by durvalumab/placebo every 4 weeks plus epirubicin/cyclophosphamide every 2 weeks followed by surgery. Durvalumab was not continued after surgery. The primary objective was pCR. Secondary endpoints included invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS).
A total of 174 patients were randomised between June 2016 and October 2017. After a median follow-up of 43.7 months, 34 events had occurred. Despite a non-significant increase in the pCR rate, significant differences were observed for 3-year iDFS, DDFS and OS: iDFS was 85.6% with durvalumab versus 77.2% with placebo hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.24-0.97, stratified log-rank P = 0.036; DDFS 91.7% versus 78.4% (HR 0.31, 95% CI 0.13-0.74, P = 0.005); OS 95.2% versus 83.5% (HR 0.24, 95% CI 0.08-0.72, P = 0.006). pCR patients had 3-year iDFS of 95.5% with durvalumab and 86.1% without (HR 0.22, 95% CI 0.05-1.06). In the non-pCR cohort 3-year iDFS was 76.3% versus 69.7% (HR 0.67, 95% CI 0.29-1.54). Multivariable analysis confirmed a durvalumab effect independent of the pCR effect. No new safety signals occurred.
Durvalumab added to NACT in TNBC significantly improved survival despite a modest pCR increase and no adjuvant component of durvalumab. Additional studies are needed to clarify the optimal duration and sequence of checkpoint inhibitors in the treatment of early TNBC.
•Significant improvement of secondary endpoints iDFS, DDFS and OS by adding durvalumab to neoadjuvant chemotherapy.•Survival improvement although no adjuvant checkpoint inhibitor therapy was given.•Long-term effect is seen in pCR as well as non-pCR patients.•The improved survival outcome with checkpoint inhibitor therapy is only partially explained by the increased pCR rate.•Our results suggest that additional long-term antitumour effects are present.
The efficacy and toxicity of olaparib as combination therapy in early breast cancer (BC) patients with homologous recombinant deficiency (HRD) score high and/or germline (g) or tumour (t) BRCA1/2 ...mutation is not well described. GeparOLA (ClinicalTrials.gov, NCT02789332) investigated olaparib in combination with paclitaxel in HER2-negative early BC with HRD.
Patients with untreated primary HER2-negative cT2-cT4a-d or cT1c with either cN+ or pNSLN+ or cT1c and triple-negative breast cancer (TNBC) or cT1c and Ki-67>20% BC with HRD were randomised either to paclitaxel (P) 80 mg/m2 weekly plus olaparib (O) 100 mg twice daily for 12 weeks or P plus carboplatinum (Cb) area under the curve 2 weekly for 12 weeks, both followed by epirubicin/cyclophosphamide (EC). Stratification factors were hormone receptor (HR) status (HR+ versus HR−) and age (<40 versus ≥40 years). The primary endpoint was pathological complete response (pCR; ypT0/is ypN0). A two-sided one-group χ2-test was planned to exclude a pCR rate of ≤55% in the PO-EC arm. Secondary end points were other pCR definitions, breast conservation rate, clinical/imaging response, tolerability and safety.
A total of 107 patients were randomised between September 2016 and July 2018; 106 (PO N = 69; PCb N = 37) started treatment. Median age was 47.0 years (range 25.0-71.0); 36.2% had cT1, 61.0% cT2, 2.9% cT3, and 31.8% cN-positive tumours; grade 3 tumours: 86.8%; Ki-67>20%: 89.6%; TNBC: 72.6%; confirmed gBRCA1/2 mutation: 56.2%. The pCR rate with PO was 55.1% 90% confidence interval (CI) 44.5% to 65.3% versus PCb 48.6% (90% CI 34.3% to 63.2%). Analysis for the stratified subgroups showed higher pCR rates with PO in the cohorts of patients <40 years and HR+ patients.
GeparOLA could not exclude a pCR rate of ≤55% in the PO arm. PO was significantly better tolerated and the combination merits further evaluation.
•Randomised phase II GeparOLA study investigated olaparib plus paclitaxel (PO) in early HER2-negative HRD breast cancer.•Addition of olaparib to chemotherapy could not exclude pCR ≤55% but was significantly better tolerated than carboplatinum.•Stratified subgroup analysis shows higher pCR rates with PO in cohorts <40 years and those with HR-positive tumours.•Overall, pCR rate in the gBRCA1/2 carriers was significantly higher than in non-carriers.•Combination of olaparib with paclitaxel prompts further investigation of olaparib as part of NACT in primary HRD tumours.
Background
This study evaluated breast imaging procedures for predicting pathologic complete response (pCR = ypT0) after neoadjuvant chemotherapy (NACT) for breast cancer to challenge surgery as a ...diagnostic procedure after NACT.
Methods
This retrospective, exploratory, monocenter study included 150 invasive breast cancers treated by NACT. The patients received magnetic resonance imaging (MRI), mammography (MGR), and ultrasound (US). The results were classified in three response subgroups according to response evaluation criteria in solid tumors. To incorporate specific features of MRI and MGR, an additional category clinical near complete response (near-cCR) was defined. Residual cancer in imaging and pathology was defined as a positive result. Negative predictive values (NPVs), false-negative rates (FNRs), and false-positive rates (FPRs) of all imaging procedures were analyzed for the whole cohort and for triple-negative (TN), HER2-positive (HER2+), and HER2-negative/hormone-receptor-positive (HER2−/HR+) cancers, respectively.
Results
In 46 cases (31 %), pCR (ypT0) was achieved. Clinical complete response (cCR) and near-cCR showed nearly the same NPVs and FNRs. The NPV was highest with 61 % for near-cCR in MRI and lowest with 44 % for near-cCR in MGR for the whole cohort. The FNRs ranged from 4 to 25 % according to different imaging methods. The MRI performance seemed to be superior, especially in TN cancers (NPV 94 %; FNR 5 %). The lowest FPR was 10 % in MRI, and the highest FPR was 44 % in US.
Conclusion
Neither MRI nor MGR or US can diagnose a pCR (ypT0) with sufficient accuracy to replace pathologic diagnosis of the surgical excision specimen.
HER2 is one of the predominant therapeutic targets in breast cancer. The metastatic selection process may lead to discrepancies between the HER2 status of the primary tumor and circulating tumor ...cells (CTCs). This study analyzed the HER2 status of CTCs in patients with HER2-positive primary breast cancer at the time of diagnosis. Aim of the study was to assess potential discordance of HER2 status between primary tumor and CTCs, as this may have important implications for the use of HER2-targeted therapy.
The number and HER2 status of CTCs out of 30ml peripheral blood were assessed in 642 patients using the CellSearch System (Janssen Diagnostics, USA). The cutoff for CTC positivity was the presence of at least 1 CTC, and the cutoff for HER2 positivity of CTCs was the presence of at least 1 CTC with a strong HER2 staining.
258 (40.2%) of the 642 patients were positive for CTCs (median 2; range 1-1,689). 149 (57.8%) of these 258 patients had at least 1 CTC with strong HER2 staining. The presence of HER2-positive CTCs was not associated with tumor size (p = 0.335), histopathological grading (p = 0.976), hormone receptor status (ER: p = 0.626, PR: p = 0.263) or axillary lymph node involvement (p = 0.430). Overall, 83 (32.2%) of the CTC-positive patients exclusively had CTCs with strong HER2 staining, whereas 31 (12.0%) had only CTCs with negative HER2 staining. Within-sample variation in the HER2 status of CTCs was found in 86 (57.8%) of the 149 patients with more than 1 CTC.
This study demonstrated that discordance between the HER2 expression of CTCs and that of the primary tumor frequently occurs in early breast cancer. Future follow-up evaluation will assess whether this discrepancy may contribute to trastuzumab resistance.
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