Long-term outcomes by lobular versus ductal histology in four NSABP adjuvant breast cancer trials.

We evaluated differences in long-term outcomes of invasive lobular carcinoma (ILC) vs breast cancers of no special type (NST) treated with anthracycline-based adjuvant chemotherapy using 4 National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized phase III trials (B-22, B-25, B-28, B-30). Our cohort included 11,251 patients with NST and 1,231 with ILC. Patients with ILC were older, had larger and more often estrogen receptor-positive tumors, and more positive lymph nodes. During early follow-up (0-5 years), patients with ILC had fewer recurrences (HR: 0.797; 95% confidence interval [CI] 0.685-0.929) and deaths (HR: 0.756; 95% CI 0.623-0.917). After 5 years patients with ILC had more recurrences (HR: 1.30; 95% CI 1.085-1.558) and deaths (HR: 1.044; 95% CI 0.898-1.214). Conditional probability analysis showed significant interactions between time-period and histologic type for recurrences (p < .001) and deaths (p < .001). Patients with ILC have elevated risk of late recurrence and death compared to patients with NST.

Clinical and Genomic Risk for Late Breast Cancer Recurrence and Survival.

BACKGROUND: The 21-gene recurrence score (RS) assay (Oncotype DX) is used to guide adjuvant chemotherapy use for patients with hormone receptor-positive, HER2 (human epidermal growth factor receptor 2)-negative, axillary node-negative breast cancer. Its role, however, in providing prognostic information for late distant recurrence when added to clinicopathologic prognostic factors is unknown. METHODS: A patient-specific meta-analysis including 10,004 women enrolled in three trials was updated using extended follow-up data from TAILORx, integrating the RS with histologic grade, tumor size, and age at surgery for the RSClin tool. Cox models integrating clinicopathologic factors and the RS were compared by using likelihood ratio (LR) tests. External validation of prognosis for distant recurrence in years 0 to 10 and 5 to 10 was performed in an independent cohort of 1098 women in a real-world registry. RESULTS: RSClin provided significantly more prognostic information than either the clinicopathologic factors (ΔLR chi-square, 86.2; P<0.001) or RS alone (ΔLR chi-square, 131.0; P<0.001). The model was prognostic in an independent cohort for distant recurrence by 10 years after diagnosis (standardized hazard ratio, 1.56; 95% confidence interval, 1.25 to 1.94), was associated with late distant recurrence risk between 5 and 10 years after diagnosis (standardized hazard ratio, 1.78; 95% confidence interval, 1.25 to 2.55), and approximated the observed 10-year distant recurrence risk (Lin concordance, 0.87) and 5- to 10-year distant recurrence risk (Lin concordance, 0.92). CONCLUSIONS: The 21-gene RS is prognostic for distant recurrence and overall survival in early breast cancer. A model integrating the 21-gene RS and clinicopathologic factors improved estimates of distant recurrence risk compared with either used individually and stratified late distant recurrence risk. (Funded by the National Cancer Institute, National Institutes of Health [U10CA180820, U10CA180794, UG1CA189859, U10CA180868, and U10CA180822] and others.).

Utility of the 70-Gene MammaPrint Assay for Prediction of Benefit From Extended Letrozole Therapy in the NRG Oncology/NSABP B-42 Trial.

PURPOSE: MammaPrint (MP) determines distant metastatic risk and may improve patient selection for extended endocrine therapy (EET). This study examined MP in predicting extended letrozole therapy (ELT) benefit in patients with early-stage breast cancer (BC) from the NSABP B-42 trial. PATIENTS AND METHODS: MP was tested in 1,866 patients randomly assigned to receive ELT or placebo. The primary end point was distant recurrence (DR). Secondary end points were disease-free survival (DFS) and BC-free interval (BCFI). Tumors were classified as MP high risk (MP-HR) or low risk (MP-LR). MP-LR tumors were further classified as ultralow risk (MP-UL) or low non-ultralow risk (MP-LNUL). RESULTS: There was no statistically significant difference in ELT benefit on DR between MP-HR and MP-LR (interaction P = .38). MP-LR tumors (n = 1,160) exhibited a statistically significant 10-year benefit of 3.7% for DR (hazard ratio [HR], 0.43 [95% CI, 0.25 to 0.74]; P = .002), whereas MP-HR tumors (n = 706) exhibited a nonsignificant 2.4% benefit (HR, 0.65 [95% CI, 0.34 to 1.24]; P = .19). The 10-year ELT benefit was significant for DFS (7.8%) and BCFI (7.0%) for MP-LR tumors, whereas MP-HR tumors did not significantly benefit (interaction DFS: P = .015, BCFI: P = .006). In exploratory analysis, the 10-year ELT benefit was significant and more pronounced in MP-LNUL (n = 908) tumors: 4.0% for DR, 9.5% for DFS, and 7.9% for BCFI; the benefit in MP-UL (n = 252) tumors was not significant: 3% for DR, 1.8% for DFS, and 4.1% for BCFI. CONCLUSION: The primary hypothesis of predictive ability of MP on DR was not confirmed. However, the secondary outcomes demonstrated MP was predictive of ELT response and identified a subset of patients with early-stage hormone receptor-positive BC (MP-LR) with improved outcomes from ELT. These data could have important clinical implications in patient selection beyond clinical risk assessment for EET.

NSABP FB-10: a phase Ib/II trial evaluating ado-trastuzumab emtansine (T-DM1) with neratinib in women with metastatic HER2-positive breast cancer.

BACKGROUND: We previously reported our phase Ib trial, testing the safety, tolerability, and efficacy of T-DM1 + neratinib in HER2-positive metastatic breast cancer patients. Patients with ERBB2 amplification in ctDNA had deeper and more durable responses. This study extends these observations with in-depth analysis of molecular markers and mechanisms of resistance in additional patients. METHODS: Forty-nine HER2-positive patients (determined locally) who progressed on-treatment with trastuzumab + pertuzumab were enrolled in this phase Ib/II study. Mutations and HER2 amplifications were assessed in ctDNA before (C1D1) and on-treatment (C2D1) with the Guardant360 assay. Archived tissue (TP0) and study entry biopsies (TP1) were assayed for whole transcriptome, HER2 copy number, and mutations, with Ampli-Seq, and centrally for HER2 with CLIA assays. Patient responses were assessed with RECIST v1.1, and Molecular Response with the Guardant360 Response algorithm. RESULTS: The ORR in phase II was 7/22 (32%), which included all patients who had at least one dose of study therapy. In phase I, the ORR was 12/19 (63%), which included only patients who were considered evaluable, having received their first scan at 6 weeks. Central confirmation of HER2-positivity was found in 83% (30/36) of the TP0 samples. HER2-amplified ctDNA was found at C1D1 in 48% (20/42) of samples. Patients with ctHER2-amp versus non-amplified HER2 ctDNA determined in C1D1 ctDNA had a longer median progression-free survival (PFS): 480 days versus 60 days (P = 0.015). Molecular Response scores were significantly associated with both PFS (HR 0.28, 0.09-0.90, P = 0.033) and best response (P = 0.037). All five of the patients with ctHER2-amp at C1D1 who had undetectable ctDNA after study therapy had an objective response. Patients whose ctHER2-amp decreased on-treatment had better outcomes than patients whose ctHER2-amp remained unchanged. HER2 RNA levels show a correlation to HER2 CLIA IHC status and were significantly higher in patients with clinically documented responses compared to patients with progressive disease (P = 0.03). CONCLUSIONS: The following biomarkers were associated with better outcomes for patients treated with T-DM1 + neratinib: (1) ctHER2-amp (C1D1) or in TP1; (2) Molecular Response scores; (3) loss of detectable ctDNA; (4) RNA levels of HER2; and (5) on-treatment loss of detectable ctHER2-amp. HER2 transcriptional and IHC/FISH status identify HER2-low cases (IHC 1+ or IHC 2+ and FISH negative) in these heavily anti-HER2 treated patients. Due to the small number of patients and samples in this study, the associations we have shown are for hypothesis generation only and remain to be validated in future studies. Clinical Trials registration NCT02236000.

Breast Cancer Index and Prediction of Extended Aromatase Inhibitor Therapy Benefit in Hormone Receptor-Positive Breast Cancer from the NRG Oncology/NSABP B-42 Trial.

PURPOSE: BCI (H/I) has been shown to predict extended endocrine therapy (EET) benefit. We examined BCI (H/I) for EET benefit prediction in NSABP B-42, which evaluated extended letrozole therapy (ELT) in patients with hormone receptor-positive breast cancer after 5 years of ET. EXPERIMENTAL DESIGN: A stratified Cox model was used to analyze RFI as the primary endpoint, with DR, BCFI, and DFS as secondary endpoints. Because of a nonproportional effect of ELT on DR, time-dependent analyses were performed. RESULTS: The translational cohort included 2,178 patients (45% BCI (H/I)-High, 55% BCI (H/I)-Low). ELT showed an absolute 10-year RFI benefit of 1.6% (P = 0.10), resulting in an underpowered primary analysis (50% power). ELT benefit and BCI (H/I) did not show a significant interaction for RFI (BCI (H/I)-Low: 10 years absolute benefit 1.1% [HR, 0.70; 95% confidence interval (CI), 0.43-1.12; P = 0.13]; BCI (H/I)-High: 2.4% [HR, 0.83; 95% CI, 0.55-1.26; P = 0.38]; Pinteraction = 0.56). Time-dependent DR analysis showed that after 4 years, BCI (H/I)-High patients had significant ELT benefit (HR = 0.29; 95% CI, 0.12-0.69; P < 0.01), whereas BCI (H/I)-Low patients were less likely to benefit (HR, 0.68; 95% CI, 0.33-1.39; P = 0.29; Pinteraction = 0.14). Prediction of ELT benefit by BCI (H/I) was more apparent in the HER2- subset after 4 years (ELT-by-BCI (H/I) Pinteraction = 0.04). CONCLUSIONS: BCI (H/I)-High versus BCI (H/I)-Low did not show a statistically significant difference in ELT benefit for the primary endpoint (RFI). However, in time-dependent DR analysis, BCI (H/I)-High patients experienced statistically significant benefit from ELT after 4 years, whereas (H/I)-Low patients did not. Because BCI (H/I) has been validated as a predictive marker of EET benefit in other trials, additional follow-up may enable further characterization of BCI's predictive ability.

Machine Learning Predicts Oxaliplatin Benefit in Early Colon Cancer.

PURPOSE: A combination of fluorouracil, leucovorin, and oxaliplatin (FOLFOX) is the standard for adjuvant therapy of resected early-stage colon cancer (CC). Oxaliplatin leads to lasting and disabling neurotoxicity. Reserving the regimen for patients who benefit from oxaliplatin would maximize efficacy and minimize unnecessary adverse side effects. METHODS: We trained a new machine learning model, referred to as the colon oxaliplatin signature (COLOXIS) model, for predicting response to oxaliplatin-containing regimens. We examined whether COLOXIS was predictive of oxaliplatin benefits in the CC adjuvant setting among 1,065 patients treated with 5-fluorouracil plus leucovorin (FULV; n = 421) or FULV + oxaliplatin (FOLFOX; n = 644) from NSABP C-07 and C-08 phase III trials. The COLOXIS model dichotomizes patients into COLOXIS+ (oxaliplatin responder) and COLOXIS- (nonresponder) groups. Eight-year recurrence-free survival was used to evaluate oxaliplatin benefits within each of the groups, and the predictive value of the COLOXIS model was assessed using the P value associated with the interaction term (int P) between the model prediction and the treatment effect. RESULTS: Among 1,065 patients, 526 were predicted as COLOXIS+ and 539 as COLOXIS-. The COLOXIS+ prediction was associated with prognosis for FULV-treated patients (hazard ratio [HR], 1.52 [95% CI, 1.07 to 2.15]; P = .017). The model was predictive of oxaliplatin benefits: COLOXIS+ patients benefited from oxaliplatin (HR, 0.65 [95% CI, 0.48 to 0.89]; P = .0065; int P = .03), but COLOXIS- patients did not (COLOXIS- HR, 1.08 [95% CI, 0.77 to 1.52]; P = .65). CONCLUSION: The COLOXIS model is predictive of oxaliplatin benefits in the CC adjuvant setting. The results provide evidence supporting a change in CC adjuvant therapy: reserve oxaliplatin only for COLOXIS+ patients, but further investigation is warranted.

Long-Term Follow-Up of the Anthracyclines in Early Breast Cancer Trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 [NRG Oncology]).

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The primary joint efficacy analysis of the Anthracyclines in Early Breast Cancer (ABC) trials reported in 2017 failed to demonstrate nonanthracycline adjuvant therapy was noninferior to anthracycline-based regimens in high-risk, early breast cancer. Full analyses of the studies had proceeded when the prespecified futility boundary was crossed at a planned futility analysis for the ability to demonstrate noninferiority of a nonanthracycline regimen with continued follow-up. These results were presented with 3.3 years of median follow-up. This manuscript reports results of the final analyses of the study efficacy end points conducted with 6.9 years of median follow-up. Long-term analysis of invasive disease-free survival (IDFS), the primary end point of the ABC trials, remains consistent with the original results, as noninferiority of the nonanthracycline regimens could not be declared on the basis of the original criteria. The secondary end point of recurrence-free interval, which excluded deaths not due to breast cancer as events, favored anthracycline-based regimens, and tests for heterogeneity were significant for hormone receptor status (P = .02) favoring anthracycline regimens for the hormone receptor-negative cohorts. There was no difference in overall survival, and review of the type of IDFS events in the groups suggested reductions in cancer recurrences achieved with anthracycline regimens were offset by late leukemias and deaths unrelated to breast cancer.

Gene Expression and Benefit of Chemotherapy in Women With Node-Negative, Estrogen Receptor-Positive Breast Cancer.

PURPOSE: The 21-gene recurrence score (RS) assay quantifies the likelihood of distant recurrence in women with estrogen receptor-positive, lymph node-negative breast cancer treated with adjuvant tamoxifen. The relationship between the RS and chemotherapy benefit is not known. METHODS: The RS was measured in tumors from the tamoxifen-treated and tamoxifen plus chemotherapy-treated patients in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B20 trial. Cox proportional hazards models were utilized to test for interaction between chemotherapy treatment and the RS. RESULTS: A total of 651 patients were assessable (227 randomly assigned to tamoxifen and 424 randomly assigned to tamoxifen plus chemotherapy). The test for interaction between chemotherapy treatment and RS was statistically significant (P = .038). Patients with high-RS (≥ 31) tumors (ie, high risk of recurrence) had a large benefit from chemotherapy (relative risk, 0.26; 95% CI, 0.13 to 0.53; absolute decrease in 10-year distant recurrence rate: mean, 27.6%; SE, 8.0%). Patients with low-RS (< 18) tumors derived minimal, if any, benefit from chemotherapy treatment (relative risk, 1.31; 95% CI, 0.46 to 3.78; absolute decrease in distant recurrence rate at 10 years: mean, -1.1%; SE, 2.2%). Patients with intermediate-RS tumors did not appear to have a large benefit, but the uncertainty in the estimate can not exclude a clinically important benefit. CONCLUSION: The RS assay not only quantifies the likelihood of breast cancer recurrence in women with node-negative, estrogen receptor-positive breast cancer, but also predicts the magnitude of chemotherapy benefit.

Replication of genetic associations of chemotherapy-related cardiotoxicity in the adjuvant NSABP B-31 clinical trial.

Background: The cardiotoxic effects of doxorubicin, trastuzumab, and other anticancer agents are well known, but molecular genetic testing is lacking for the early identification of patients at risk for therapy-related cardiac toxicity. Methods: Using the Agena Bioscience MassARRAY system, we genotyped TRPC6 rs77679196, BRINP1 rs62568637, LDB2 rs55756123, RAB22A rs707557, intergenic rs4305714, LINC01060 rs7698718, and CBR3 rs1056892 (V244M) (previously associated with either doxorubicin or trastuzumab-related cardiotoxicity in the NCCTG N9831 trial of anthracycline-based chemotherapy ± trastuzumab) in 993 patients with HER2+ early breast cancer from the NSABP B-31 trial of adjuvant anthracycline-based chemotherapy ± trastuzumab. Association analyses were performed with outcomes of congestive heart failure (N = 29) and maximum decline in left ventricular ejection fraction (LVEF) using logistic and linear regression models, respectively, under an additive model with age, baseline LVEF, and previous use of hypertensive medications as covariates. Results: Associations of maximum decline in LVEF in the NCCTG N9831 patients did not replicate in the NSABP B-31 patients. However, TRPC6 rs77679196 and CBR3 rs1056892 were significantly associated with congestive heart failure, p < 0.05, with stronger associations observed in patients treated with chemotherapy only (no trastuzumab) or in the combined analysis of all patients relative to those patients treated with chemotherapy + trastuzumab. Conclusions: TRPC6 rs77679196 and CBR3 rs1056892 (V244M) are associated with doxorubicin-induced cardiac events in both NCCTG N9831 and NSABP B-31. Other variants previously associated with trastuzumab-related decline in LVEF failed to replicate between these studies.

Ten-year update: NRG Oncology/National Surgical Adjuvant Breast and Bowel Project B-42 randomized trial: extended letrozole therapy in early-stage breast cancer.

BACKGROUND: The National Surgical Adjuvant Breast and Bowel Project B-42 trial evaluated extended letrozole therapy (ELT) in postmenopausal breast cancer patients who were disease free after 5 years of aromatase inhibitor (AI)-based therapy. Seven-year results demonstrated a nonstatistically significant trend in disease-free survival (DFS) in favor of ELT. We present 10-year outcome results. METHODS: In this double-blind, phase III trial, patients with stage I-IIIA hormone receptor-positive breast cancer, disease free after 5 years of an AI or tamoxifen followed by an AI, were randomly assigned to 5 years of letrozole or placebo. Primary endpoint was DFS, defined as time from random assignment to breast cancer recurrence, second primary malignancy, or death. All statistical tests are 2-sided. RESULTS: Between September 2006 and January 2010, 3966 patients were randomly assigned (letrozole: 1983; placebo: 1983). Median follow-up time for 3923 patients included in efficacy analyses was 10.3 years. There was statistically significant improvement in DFS in favor of letrozole compared with placebo (hazard ratio [HR] = 0.85, 95% confidence interval [CI] = 0.74 to 0.96; P = .01; 10-year DFS: placebo = 72.6%, letrozole = 75.9%, absolute difference = 3.3%). There was no difference in the effect of letrozole on overall survival (HR = 0.97, 95% CI = 0.82 to 1.15; P = .74). Letrozole statistically significantly reduced breast cancer-free interval events (HR = 0.75, 95% CI = 0.62 to 0.91; P = .003; absolute difference in cumulative incidence = 2.7%) and distant recurrences (HR = 0.72, 95% CI = 0.55 to 0.92; P = .01; absolute difference = 1.8%). The rates of osteoporotic fractures and arterial thrombotic events did not differ between treatment groups. CONCLUSIONS: The beneficial effect of ELT on DFS persisted at 10 years. Letrozole also improved breast cancer-free interval and distant recurrences without improving overall survival. Careful assessment of potential risks and benefits is necessary for selecting appropriate candidates for ELT.

Pathologic Complete Response and Individual Patient Prognosis After Neoadjuvant Chemotherapy Plus Anti-Human Epidermal Growth Factor Receptor 2 Therapy of Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer.

PURPOSE: The achievement of pathologic complete response (pCR) is strongly prognostic for event-free survival (EFS) and overall survival (OS) in patients with early breast cancer (EBC), and adapting postneoadjuvant therapy improves long-term outcomes for patients with HER2-positive disease not achieving pCR. We sought to investigate prognostic factors for EFS and OS among patients with and without pCR after neoadjuvant systemic treatment consisting of chemotherapy plus anti-HER2 therapy. MATERIALS AND METHODS: We used individual data from 3,710 patients randomly assigned in 11 neoadjuvant trials for HER2-positive EBC with ≥100 patients enrolled, available data for pCR, EFS, and OS, and follow-up ≥3 years. We assessed baseline clinical tumor size (cT) and clinical nodal status (cN) as prognostic factors using stratified (by trial and treatment) Cox models separately for hormone receptor-positive versus hormone receptor-negative disease, and for patients who had pCR (pCR+; ypT0/is, ypN0) versus patients who did not achieve a pCR (pCR-). RESULTS: The median follow-up overall was 61.2 months. In pCR+ patients, cT and cN were significant independent prognostic factors for EFS, whereas only cT was a significant predictor for OS. In pCR- patients, cT, cN, and hormone receptor status were significant independent predictors for both EFS and OS. Regardless of hormone receptor status, cT, and cN, the 5-year EFS/OS rates were higher in pCR+ patients than in pCR- patients. In most subsets with regards to hormone receptor and pCR status, cT and cN were independent prognostic factors for both EFS and OS, including pCR+ patients. CONCLUSION: These results confirm that patients achieving pCR have far better survival outcomes than patients who do not. The traditional poor prognostic features, namely tumor size and nodal status, remain important even after a pCR.

Long-term outcomes of dual vs single HER2-directed neoadjuvant therapy in NSABP B-41.

BACKGROUND: The primary aim of this randomized neoadjuvant trial in operable, HER2-positive breast cancer, was to determine the efficacy on pathologic complete response (pCR) of substituting lapatinib (L) for trastuzumab (T) or adding L to T, in combination with weekly paclitaxel (WP) following AC. Results on pCR were previously reported. Here, we report data on planned secondary endpoints, recurrence-free interval (RFI) post-surgery, and overall survival (OS). METHODS: All patients received standard AC q3 weeks × 4 cycles followed by WP (80 mg/m2) on days 1, 8, and 15, q28 days × 4 cycles. Concurrently with WP, patients received either T (4 mg/kg load, then 2 mg/kg) weekly until surgery, L (1250 mg) daily until surgery, or weekly T plus L (750 mg) daily until surgery. Following surgery, all patients received T to complete 52 weeks of HER2-targeted therapy. 522 of 529 randomized patients had follow-up. Median follow-up was 5.1 years. RESULTS: RFI at 4.5 years was 87.2%, 79.4% (p = 0.34; HR = 1.37; 95% CI 0.80, 2.34), and 89.4% (p = 0.37; HR = 0.70; 0.37, 1.32) for arms T, L, and TL, respectively. The corresponding five-year OS was 94.8%, 89.1% (p = 0.34; HR = 1.46; 0.68, 3.11), and 95.8% (p = 0.25; HR = 0.58; 0.22, 1.51), respectively. Patients with pCR had a much better prognosis, especially in the ER-negative cohort: RFI (HR = 0.23, p < 0.001) and OS (HR = 0.28, p < 0.001). CONCLUSIONS: Although pCR, RFI, and OS were numerically better with the dual combination and less with L, the differences were not statistically significant. However, achievement of pCR again correlated with improved outcomes, especially remarkable in the ER-negative subset. CLINICAL TRIALS REGISTRATION: NCT00486668.

Re-Evaluation of Pathologic Complete Response as a Surrogate for Event-Free and Overall Survival in Human Epidermal Growth Factor Receptor 2-Positive, Early Breast Cancer Treated With Neoadjuvant Therapy Including Anti-Human Epidermal Growth Factor Receptor 2 Therapy.

PURPOSE: Pathologic complete response (pCR) has prognostic importance and is frequently used as a primary end point, but doubts remain about its validity as a surrogate for event-free survival (EFS) and overall survival (OS) in human epidermal growth factor receptor 2 (HER2)-positive, early breast cancer. METHODS: We obtained individual-patient data from randomized trials of neoadjuvant anti-HER2 therapy that enrolled at least 100 patients, had data for pCR, EFS, and OS, and a median follow-up of at least 3 years. We quantified the patient-level association between pCR (defined as ypT0/Tis ypN0) and both EFS and OS using odds ratios (ORs, with ORs >1.00 indicating a benefit from achieving a pCR). We quantified the trial-level association between treatment effects on pCR and on EFS and OS using R2 (with values above 0.75 considered as indicating strong associations). RESULTS: Eleven of 15 eligible trials had data for analysis (3,980 patients, with a median follow-up of 62 months). Considering all trials, we found strong patient-level associations, with ORs of 2.64 (95% CI, 2.20 to 3.07) for EFS and 3.15 (95% CI, 2.38 to 3.91) for OS; however, trial-level associations were weak, with an unadjusted R2 of 0.23 (95% CI, 0 to 0.66) for EFS and 0.02 (95% CI, 0 to 0.17) for OS. We found qualitatively similar results when grouping trials according to different clinical questions, when analyzing only patients with hormone receptor-negative disease, and when using a more stringent definition of pCR (ypT0 ypN0). CONCLUSION: Although pCR may be useful for patient management, it cannot be considered as a surrogate for EFS or OS in neoadjuvant trials of HER2-positive, operable breast cancer.

Biomarker Data from the Phase III KATHERINE Study of Adjuvant T-DM1 versus Trastuzumab for Residual Invasive Disease after Neoadjuvant Therapy for HER2-Positive Breast Cancer.

PURPOSE: In KATHERINE, adjuvant T-DM1 reduced risk of disease recurrence or death by 50% compared with trastuzumab in patients with residual invasive breast cancer after neoadjuvant therapy (NAT) comprised of HER2-targeted therapy and chemotherapy. This analysis aimed to identify biomarkers of response and differences in biomarker expression before and after NAT. EXPERIMENTAL DESIGN: Exploratory analyses investigated the relationship between invasive disease-free survival (IDFS) and HER2 protein expression/gene amplification, PIK3CA hotspot mutations, and gene expression of HER2, PD-L1, CD8, predefined immune signatures, and Prediction Analysis of Microarray 50 intrinsic molecular subtypes, classified by Absolute Intrinsic Molecular Subtyping. HER2 expression on paired pre- and post-NAT samples was examined. RESULTS: T-DM1 appeared to improve IDFS versus trastuzumab across most biomarker subgroups, except the HER2 focal expression subgroup. High versus low HER2 gene expression in residual disease was associated with worse outcomes with trastuzumab [HR, 2.02; 95% confidence interval (CI), 1.32-3.11], but IDFS with T-DM1 was independent of HER2 expression level (HR, 1.01; 95% CI, 0.56-1.83). Low PD-L1 gene expression in residual disease was associated with worse outcomes with trastuzumab (HR, 0.66; 95% CI, 0.44-1.00), but not T-DM1 (HR, 1.05; 95% CI, 0.59-1.87). PIK3CA mutations were not prognostic. Increased variability in HER2 expression was observed in post-NAT versus paired pre-NAT samples. CONCLUSIONS: T-DM1 appears to overcome HER2 resistance. T-DM1 benefit does not appear dependent on immune activation, but these results do not rule out an influence of the tumor immune microenvironment on the degree of response.

Mixed invasive ductal lobular carcinoma is clinically and pathologically more similar to invasive lobular than ductal carcinoma.

BACKGROUND: Mixed invasive ductal lobular carcinoma (mDLC) remains a poorly understood subtype of breast cancer composed of coexisting ductal and lobular components. METHODS: We sought to describe clinicopathologic characteristics and determine whether mDLC is clinically more similar to invasive ductal carcinoma (IDC) or invasive lobular carcinoma (ILC), using data from patients seen at the University of Pittsburgh Medical Center. RESULTS: We observed a higher concordance in clinicopathologic characteristics between mDLC and ILC, compared to IDC. There is a trend for higher rates of successful breast-conserving surgery after neoadjuvant chemotherapy in patients with mDLC compared to patients with ILC, in which it is known to be lower than in those with IDC. Metastatic patterns of mDLC demonstrate a propensity to develop in sites characteristic of both IDC and ILC. A meta-analysis evaluating mDLC showed shared features with both ILC and IDC with significantly more ER-positive and fewer high grades in mDLC compared to IDC, although mDLCs were significantly smaller and included fewer late-stage tumours compared to ILC. CONCLUSIONS: These findings support clinicopathologic characteristics of mDLC driven by individual ductal vs lobular components and given the dominance of lobular pathology, mDLC features are often more similar to ILC than IDC. This study exemplifies the complexity of mixed disease.

Population, Clinical, and Scientific Impact of National Cancer Institute's National Clinical Trials Network Treatment Studies.

PURPOSE: In the United States, the National Cancer Institute National Cancer Clinical Trials Network (NCTN) groups have conducted publicly funded oncology research for 50 years. The combined impact of all adult network group trials has never been systematically examined. METHODS: We identified randomized, phase III trials from the adult NCTN groups, reported from 1980 onward, with statistically significant findings for ≥ 1 clinical, time-dependent outcomes. In the subset of trials in which the experimental arm improved overall survival, gains in population life-years were estimated by deriving trial-specific hazard functions and hazard ratios to estimate the experimental treatment benefit and then mapping this trial-level benefit onto the US cancer population using registry and life-table data. Scientific impact was based on citation data from Google Scholar. Federal investment costs per life-year gained were estimated. The results were derived through December 31, 2020. RESULTS: One hundred sixty-two trials comprised of 108,334 patients were analyzed, representing 29.8% (162/544) of trials conducted. The most common cancers included breast (34), gynecologic (28), and lung (14). The trials were cited 165,336 times (mean, 62.2 citations/trial/year); 87.7% of trials were cited in cancer care guidelines in favor of the recommended treatment. These studies were estimated to have generated 14.2 million (95% CI, 11.5 to 16.5 million) additional life-years to patients with cancer, with projected gains of 24.1 million (95% CI, 19.7 to 28.2 million) life-years by 2030. The federal investment cost per life-year gained through 2020 was $326 in US dollars. CONCLUSION: NCTN randomized trials have been widely cited and are routinely included in clinical guidelines. Moreover, their conduct has predicted substantial improvements in overall survival in the United States for patients with oncologic disease, suggesting they have contributed meaningfully to this nation's health. These findings demonstrate the critical role of government-sponsored research in extending the lives of patients with cancer.

Adjuvant trastuzumab emtansine in HER2-positive breast cancer patients with HER2-negative residual invasive disease in KATHERINE.

Following chemotherapy and human epidermal growth factor 2 (HER2)-targeted neoadjuvant therapy for HER2-positive early breast cancer, residual invasive breast cancer at surgery may be HER2-negative on retesting in some patients. We evaluated outcomes with T-DM1 and trastuzumab in patients randomized in the phase III KATHERINE trial based on HER2-positive central testing of the pre-treatment core biopsy with HER2-negative central testing on their corresponding surgical specimen after neoadjuvant treatment. In the 70/845 (8.3%) patients with HER2-negative residual disease on retesting at surgery, there were 11 IDFS events in the 42 trastuzumab-treated patients (26.2%) and none in the 28 T-DM1-treated patients, suggesting that T-DM1 should not be withheld in this patient population.

Definitive results of a phase III adjuvant trial comparing six cycles of FEC-100 to four cycles of AC in women with operable node-negative breast cancer: the NSABP B-36 trial (NRG Oncology).

PURPOSE: Results from adjuvant trials evaluating 6 cycles of epirubicin-based chemotherapy regimens suggested these programs may be more effective than 4 cycles of doxorubicin-based chemotherapy. METHOD: NSABP B-36 was a phase III clinical trial originally designed as a 2 × 2 factorial study comparing 6 cycles of 5-FU, epirubicin, and cyclophosphamide (FEC-100) to 4 cycles of conventional doxorubicin and cyclophosphamide (AC) with celecoxib or placebo. Shortly after activation, concerns regarding increased cardiovascular risks among selective COX-2 inhibitors resulted in a decision to remove the celecoxib/placebo from the trial. Women with histologically node-negative invasive breast cancer who had undergone primary surgery with a lumpectomy or total mastectomy were eligible. Primary endpoint was disease-free survival (DFS). RESULTS: Between May 2004 and July 2008, 2722 patients were enrolled. Administration of FEC-100 did not result in improvement in DFS compared to AC (HR 1.09; 95% CI 0.92-1.29, p value = 0.31). The effect of FEC-100 compared to AC on DFS was significantly different for receptor-positive (HR 1.32, 95% CI 1.05-1.66) compared to receptor-negative patients (HR 0.86, 95% CI 0.66-1.11) (treatment-by-receptor status interaction p value = 0.02). There was no statistically significant difference in the effect of treatment on overall survival (OS) with FEC-100 compared to AC (HR 1.06; 95% CI 0.84-1.35, p value = 0.61). Overall, Grade 3 and 4 adverse events were more frequent in the FEC-100 group. CONCLUSION: The results of B-36 do not support use of six-cycle anthracycline-based regimens in node-negative breast cancer. Prolongation of anthracycline-based therapy with FEC-100 does not improve DFS or OS, relative to AC for 4 cycles, and was associated with expected increases in toxicity. A statistically significant interaction between treatment and hormone receptor status favoring AC in hormone-receptor-positive breast cancers is consistent with the hypothesis that optimal duration of chemotherapy may be four cycles in these patients. Late cardiac events and deaths prior to recurrence or second cancer were infrequent on both arms, but slightly higher with FEC-100. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00087178.