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BACKGROUND: The recurrence score based on the 21-gene breast-cancer assay has been clinically useful in predicting a chemotherapy benefit in hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary lymph-node–negative breast cancer. In women with positive lymph-node disease, the role of the recurrence score with respect to predicting a benefit of adjuvant chemotherapy is unclear. METHODS: In a prospective trial, we randomly assigned women with hormone-receptor–positive, HER2-negative breast cancer, one to three positive axillary lymph nodes, and a recurrence score of 25 or lower (scores range from 0 to 100, with higher scores indicating a worse prognosis) to endocrine therapy only or to chemotherapy plus endocrine (chemoendocrine) therapy. The primary objective was to determine the effect of chemotherapy on invasive disease–free survival and whether the effect was influenced by the recurrence score. Secondary end points included distant relapse–free survival. RESULTS: A total of 5083 women (33.2% premenopausal and 66.8% postmenopausal) underwent randomization, and 5018 participated in the trial. At the prespecified third interim analysis, the chemotherapy benefit with respect to increasing invasive disease–free survival differed according to menopausal status (P = 0.008 for the comparison of chemotherapy benefit in premenopausal and postmenopausal participants), and separate prespecified analyses were conducted. Among postmenopausal women, invasive disease–free survival at 5 years was 91.9% in the endocrine-only group and 91.3% in the chemoendocrine group, with no chemotherapy benefit (hazard ratio for invasive disease recurrence, new primary cancer [breast cancer or another type], or death, 1.02; 95% confidence interval [CI], 0.82 to 1.26; P = 0.89). Among premenopausal women, invasive disease–free survival at 5 years was 89.0% with endocrine-only therapy and 93.9% with chemoendocrine therapy (hazard ratio, 0.60; 95% CI, 0.43 to 0.83; P = 0.002), with a similar increase in distant relapse–free survival (hazard ratio, 0.58; 95% CI, 0.39 to 0.87; P = 0.009). The relative chemotherapy benefit did not increase as the recurrence score increased. CONCLUSIONS: Among premenopausal women with one to three positive lymph nodes and a recurrence score of 25 or lower, those who received chemoendocrine therapy had longer invasive disease–free survival and distant relapse–free survival than those who received endocrine-only therapy, whereas postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy. (Funded by the National Cancer Institute and others; RxPONDER ClinicalTrials.gov number, NCT01272037.)

BACKGROUND: Beta-2 adrenergic receptor (ß2AR) modulates immune activation and may enhance trastuzumab activity. We assessed the impact of ß2AR gene (ADRB2) expression on the outcomes of patients with HER2-positive early-stage breast cancer enrolled on the NCCTG-N9831 trial. PATIENTS AND METHODS: This is a post-hoc analysis of the NCCTG-N9831 trial, which compared chemotherapy (arm A) versus chemotherapy plus trastuzumab (arms B&C) as adjuvant treatment of patients with HER2-positive early-stage breast cancer, with disease-free survival (DFS) as primary endpoint. Gene expression levels retrieved by DASL assay were used to classify patients as ADRB2-high or ADRB2-low. Hazard ratios (HRs) were calculated by a Cox proportional model adjusted for prognostic variables and ADRB2 expression. Correlations between ADRB2 expression and stromal tumor-infiltrating lymphocyte (TIL) levels were assessed with Pearson coefficient. A multivariable Cox regression model with interaction term was performed to assess the interaction between ADRB2 expression and treatment arm; and ADRB2 expression and a 8-gene signature previously shown to predict trastuzumab benefit. RESULTS: Overall, 1,282 patients were included (ADRB2-high [N = 944] / ADRB2-low [N = 338]). A high expression of ADRB2 was associated with a longer DFS (P = .01) in the overall population. The addition of trastuzumab to chemotherapy improved DFS only in patients with ADRB2-high tumors (P < .01). ADRB2 expression was correlated with TIL levels (r = 0.24, P < .001). No association between ADRB2 expression and the 8-gene trastuzumab benefit signature was observed (P = .32). CONCLUSION: Our findings suggest that a high ADRB2 expression is a favorable prognostic factor and may identify patients with HER2-positive early-stage breast cancer who benefit from adjuvant trastuzumab. TRIAL REGISTRATION: clinicaltrials.gov NCT00005970. ispartof: CLINICAL BREAST CANCER vol:22 issue:4 pages:308-318 ispartof: location:United States status: published

BACKGROUND: The goal of this study was to assess the impact of trastuzumab on locoregional failure. METHODS: The analysis included 2763 patients with HER2-positive (HER2+) breast cancer who were randomly assigned to adjuvant doxorubicin (A), cyclophosphamide (C), paclitaxel (T) and trastuzumab (H) (arm A, AC→T [n = 922]; arm B, AC→T→H [n = 988]; arm C, AC→T+H→H [n = 853]). Radiotherapy was given after AC→T concurrently with H. Radiotherapy was given after lumpectomy (L) or after mastectomy (M) with ≥4 positive lymph nodes but was optional for 1 to 3 positive lymph nodes. Locoregional failures at 10 years (LFR10) as first events were compared using competing risk analysis. RESULTS: The median follow-up was 13.0 years. The first site of failure was local-only in 96 cases, locoregional in 16 cases, regional in 32 cases, and not specified in 2 cases; LFR10 was 4.8% (95% CI 4.1%–5.7%). LFR10 was 5.5% (95% CI 4.3%–7.2%), 4.9% (95% CI 3.7%–6.4%), and 2.8% (95% CI 1.9%–4.1%) in arms A, B, and C (B vs A: hazard ratio [HR] 0.91, P = .62; C vs A: HR 0.72, P = .12). For estrogen receptor–positive patients, LFR10 was 3.7% (95% CI 2.8%–4.8%) and for estrogen receptor–negative patients, it was 6.1% (95% CI 5.0%–7.4%; HR 0.61, P = .004). Local treatment included L+RT (n = 1044 [38%]), M+RT (n = 1025 [37%]), and M (n = 694 [25%]). LFR10 was 6.% (95% CI 5.0%–7.8%), 3.0% (95% CI 2.1%–4.3%), and 5.5% (95% CI 4.0%–7.4%) for L+RT, M+RT, and M, respectively (M+RT vs L+RT: HR 0.43, P < .001; M vs L+RT: HR 0.88, P = .57). For 1 to 3 positive lymph nodes, LFR10 was 6.5% (95% CI 4.8%–8.9%), 4.1% (95% CI 2.4%–7.0%), and 4.3% (95% CI 2.9%–6.5%) in L+RT, M+RT, and M, respectively (M vs L+RT: HR 0.68, P = .14; M vs M+RT: HR 1.2, P = .6). CONCLUSION: Low 10-year LFRs were seen regardless of trastuzumab use. Differences in local therapy in patients with 1 to 3 positive lymph nodes did not appear to improve local control. Local therapy studies for HER2+ and other tumor characteristics are important as the role of local therapies continues to evolve.

Background There are few treatment options for patients with leptomeningeal metastases (LM). Methods We report a case series of patients with breast cancer and LM treated with intra‐CSF topotecan (TOPO). Outcome was assessed by clinical exam and MRI at baseline, at end of induction (4‐5 weeks), then every 3 months; CSF cytology was determined at baseline and with each treatment. Results Thirty‐one women [median age, 58 (37‐81); median KPS 60 (40‐100)] received treatment. At baseline, 68% had positive CSF cytology, and 90%, leptomeningeal enhancement on MRI. 84% of patients also received focal RT (not during TOPO) and 77% received concomitant systemic hormonal or chemotherapy. Median number of TOPO treatments was 14.5 (range, 3‐71); median duration of treatment, 11 weeks (1‐176); and median OS, 6.9 months (range, 0.9‐48.8). Patients remaining progression‐free during 4‐6 weeks of induction (81%) had a median OS of 11.5 months (range, 1.8‐48.8). Overall neurologic PFS at 6, 12, and 24 months was 39%, 26%, and 6%, respectively. Clearing of CSF malignant cells for >3 consecutive samples occurred in 10/21 (48%) patients with positive CSF cytology at baseline, remaining clear for a median duration of 15.9 months (range, 1.4‐34.5). Grade 3 adverse events included headache or vomiting (3pts), T2 hyperintensity surrounding the ventricular catheter (2 pts), and meningitis (2 pts). Conclusions Intra‐CSF TOPO, with focal RT as needed for symptomatic areas of enhancement produced durable clearing of CSF malignant cells in 48% of patients positive at baseline, with promising median PFS and OS., In this case series, intra‐CSF topotecan treatment of women with leptomeningeal metastases and breast cancer was associated with durable CSF clearing of malignant cells in 48% of patients, median OS of 6.9 months, and 11.5 months in those completing 4‐6 weeks induction. Thirty‐two percentage of patients remained free of neurologic progression at 12 months. A method for treatment of patients with VP shunts and programmable valves is also described.

BACKGROUND: The addition of lapatinib (L) to trastuzumab (T) was previously found to be synergistic in preclinical models and in the neoadjuvant setting. Prior to the results of the ALTTO trial, this study assessed the safety and feasibility of adding L to the standard adjuvant docetaxel, carboplatin and trastuzumab (TCH) regimen in early stage HER2-positive breast cancer (HER2+ BC). METHODS: In this single-arm, 2-stage, phase II study, patients with stages I–III HER2+ BC received TCH plus L at 1000 mg daily for a total of 12 months. The primary endpoint was the safety and tolerability, including the rate of diarrhea. Secondary endpoints included adverse event (AE) profile using the NCI CTCAE v3.0 and cardiac safety. RESULTS: Thirty eligible patients were enrolled. Median follow-up is 5.3 years. Diarrhea was the most common AE with 50% Grade (G)1/2 and 43% G3 diarrhea. However, it was responsive to dose reduction of L (750 mg) and institution of anti-diarrheal medications. Cardiovascular AE were infrequent and no patients experienced congestive heart failure while on treatment. CONCLUSION: TCHL was a tolerable regimen at a starting L dose of 750 mg PO daily when given concurrently with chemotherapy.

Introduction: Although HER2+ breast cancer (BC) is considered a moderately immunogenic tumor, several studies have shown a role of pre-existing immunity associated with favorable long-term prognosis and better response to treatment. In this study, we performed exploratory analyses to assess whether the efficacy of HER2 targeted treatment in the MARIANNE trial correlated with immune gene expression. Methods: MARIANNE (NCT01120184) is a phase 3 study in patients (pts) with centrally confirmed HER2+ local advanced/metastatic BC naïve to prior treatments in the advanced disease. Pts were randomized (1:1:1) to trastuzumab+taxane (HT), T-DM1, or T-DM1+Petuzumab (P) and the trial showed noninferior PFS of T-DM1 and T-DM1+P vs HT. Gene expression (RNA) analysis was performed on tumor samples by a custom 800-gene codeset on the nCounter platform. PD-L1, CD8 expressions and immune gene signatures (sign) analyses were assessed by multivariate Cox regression models using median (cut-off) as categorical variable and adjusted by prior HT, presence of visceral disease, world region, baseline ECOG, measureable disease at baseline, therapy setting, HER2 mRNA expression, PIK3CA mutation status. Results: MARIANNE randomized 1095 pts (HT, n=365; T-DM1, n=367; T-DM1+P, n=363). Gene expression results were available for 671 pts (61.3% of the intent-to-treat [ITT] population) which was representative of ITT. In ITT, HR below 1 was observed when comparing pts with high (>median) vs low (≤median) immune gene expression by clinical outcome suggesting a potential association of high immune marker expression with improved PFS (Table 1) and to some extent with OS (data not shown). This association was primarily observed in the T-DM1 arm where the HR suggested a risk reduction of disease progression(PD)/death especially in the high Teff, high PD-L1 and high CD8 subgroups, and to some extent in the HT arm (Table 1). When assessing the predictive impact on PFS by comparing T-DM1 vs HT, HR below 1 was observed especially in pts with high Teff signature, high PD-L1 and high CD8 expressions (HR 0.67 (95% CI (0.47-0.95)), HR 0.68 (95% CI (0.48-0.97), and HR 0.64 (95%CI 0.44-0.93), respectively). When comparing T-DM1+P vs. HT, HR below 1 was observed especially in pts with low Teff signature and low PD-L1 expression (HR 0.70 (95% CI (0.50-0.99), and HR 0.68 (95% CI (0.48-0.96) respectively). No clear differences between immune gene expression subgroups was observed when comparing treatment arms in regards to OS (data not shown). Conclusions: In the exploratory analysis from the MARIANNE study, high immune gene expression, especially in the high PD-L1, CD8 and Teff subgroups, showed an association with improved clinical benefit with HRs reflecting for a risk reduction of PD/death for PFS and partially for OS. This association was less obvious in the T-DM1+P arm. When comparing the treatments effect, the data showed a potential impact of high Teff signature, and high CD8 and PD-L1 expressions on T-DM1 and less on HT. The potential opposite association of low Teff signature and low PD-L1 expression with improved benefit in the T-DM1+P arm was unexpected and needs further investigation. Table 1: Prognostic biomarker effect on PFSBiomarker by categories (>Median vs ≤Median)HR (95% CI) ITT n=671HR (95% CI) HT n=220HR (95% CI) T-DM1 n=227HR (95% CI) T-DM1+P n=224Teff sign0.89 (0.73-1.09)0.97 (0.68-1.38)0.64 (0.45-0.91)1.09 (0.75-1.58)Th1 cytokine sign0.91 (0.74-1.11)0.92 (0.64-1.31)0.78 (0.55-1.11)0.96 (0.67-1.36)Checkpoint inhibitor sign0.95 (0.78-1.15)0.91 (0.64-1.29)0.90 (0.64-1.26)1.02 (0.71-1.47)PD-L10.80 (0.66-0.98)0.79 (0.55-1.13)0.62 (0.44-0.87)1.07 (0.74-1.55)CD80.91 (0.75-1.11)1.10 (0.77-1.57)0.66 (0.46-0.93)0.98 (0.68-1.41) Citation Format: Edith A Perez, Sanne Lysbet de Haas, Carlos H Barrios, Wolfgang Eiermann, Masakazu Toi, Young-Hyuck Im, Pier Franco Conte, Miguel Martin, Tadeusz Pienkowski, Xavier B Pivot, Howard A Burris III, Chiara Lambertini, Silke Hoersch, Monika Patre, Paul Anthony Ellis. Association of immune gene expression with outcome in the MARIANNE phase 3 clinical trial in HER2-positive metastatic breast cancer (MBC) [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 PD5-11.

Sepsis and acute lung injury (ALI) are linked to mitochondrial dysfunction; however, the underlying mechanism remains elusive. We previously reported that c-Jun N-terminal protein kinase 2 (JNK2) promotes stress-induced mitophagy by targeting small mitochondrial alternative reading frame (smARF) for ubiquitin-mediated proteasomal degradation, thereby preventing mitochondrial dysfunction and restraining inflammasome activation. Here we report that loss of JNK2 exacerbates lung inflammation and injury during sepsis and ALI in mice. JNK2 is downregulated in mice with endotoxic shock or ALI, concomitantly correlated inversely with disease severity. Small RNA sequencing revealed that miR-221-5p, which contains seed sequence matching to JNK2 mRNA 3’ untranslated region (3’UTR), is upregulated in response to lipopolysaccharide, with dynamically inverse correlation with JNK2 mRNA levels. miR-221-5p targets the 3’UTR of JNK2 mRNA leading to its downregulation. Accordingly, miR-221-5p exacerbates lung inflammation and injury during sepsis in mice by targeting JNK2. Importantly, in patients with pneumonia in medical intensive care unit, JNK2 mRNA levels in alveolar macrophages flow sorted from non-bronchoscopic broncholaveolar lavage (BAL) fluid were inversely correlated strongly and significantly with the percentage of neutrophils, neutrophil and white blood cell counts in BAL fluid. Our data suggest that miR-221-5p targets JNK2 and thereby aggravates lung inflammation and injury during sepsis.

BackgroundCEA (CEACAM5) is a well-validated cell-surface antigen that is highly expressed in multiple solid tumors. Bolt's immune-stimulating antibody conjugates (ISACs) direct a TLR7/8 agonist into tumors to activate tumor-infiltrating myeloid cells and initiate a broad innate and adaptive anti-tumor immune response.1 The favorable properties of CEA, including robust cell surface expression, low internalization rate, and limited normal tissue expression, suggest that the antigen may be a suitable ISAC target. We are evaluating an anti-CEA ISAC, BDC-2034, as a multi-functional approach to treat CEA-expressing cancers.MethodsAnti-CEA antibodies were tested for binding affinity and specificity, CEA-targeted antibody-dependent cellular phagocytosis (ADCP), and myeloid-mediated tumor cell killing. Selected antibodies were conjugated to proprietary TLR7/8 agonists, and the resulting CEA ISACs were evaluated for in vitro myeloid activation and in vivo efficacy against xenograft tumors.ResultsAntibody CEA1 binds to the CEA protein with high affinity (EC50 = 0.25 nM), binds selectively to CEA-positive tumor cell lines, and mediates ADCP more efficiently than a reference anti-CEA antibody, labetuzumab (figure 1). We generated BDC-2034 by conjugating a potent TLR7/8 agonist to CEA1. BDC-2034 tumor cell binding drives myeloid effector cell ADCP, agonist delivery to TLR7 and TLR8 in endosomes, and secretion of cytokines critical for innate and adaptive immunity (including IL-12p70, CXCL10, and TNFa). In the HPAF II + cDC co-culture model, IL-12p70 is induced with EC50 = 1.2 nM, and the level of induction is at least ten-fold higher than with ISACs using labetuzumab (figure 2). Potent cellular activity is strictly dependent on tumor cell CEA expression; in whole blood, in the absence of CEA-expressing tumor cells, cytokine induction was only observed at approximately 100-fold higher concentrations. BDC-2034 inhibits the growth of HPAF II xenograft tumors in SCID/beige mice with a minimal efficacious dose (MED) of 1 mg/kg, demonstrating anti-tumor activity solely through innate immune activation (figure 3). The TLR7/8 agonist in BDC-2034 has relatively poor activity in mice; a surrogate CEA1 ISAC with a mouse TLR7-activating agonist achieved MED = 0.5 mg/kg in the HPAF II model, with eradication of all tumors at the 5 mg/kg dose.ConclusionsThese pre-clinical data demonstrate the potential of BDC-2034 to treat CEA-expressing human cancers. Most importantly, the antigen-dependent induction of immune-stimulating cytokines promises a robust immune response that combines the activation of innate and adaptive arms.ReferenceAckerman S, Pearson C, Gregorio J. Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity. Nature Cancer 2021;2:18–33. https://doi.org/10.1038/s43018-020-00136-xAbstract 784 Figure 1ADCP. Anti-CEA antibody CEA1 is an efficient inducer of ADCP of Raji/CEA cells by M-CSF differentiated monocyte-derived macrophagesAbstract 784 Figure 2Tumor-dependent dendritic cell activation. BDC-2034 induces IL-12p70 secretion from primary dendritic cells (cDC); native CEA1 antibody and reference anti-CEA ISAC are ineffectiveAbstract 784 Figure 3Efficacy against xenograft tumors. BDC-2034 inhibits the growth of HPAF II tumors in SCID/beige mice; native CEA1 antibody and isotype ISAC are ineffective

Background Racial and ethnic diversity in clinical trials for cancer treatment is essential for the development of treatments that are effective for all patients and for identifying potential differences in toxicity between different demographics. Mining of social media discussions about clinical trials has been used previously to identify patient barriers to enrollment in clinical trials; however, a comprehensive breakdown of sentiments and barriers by various racial and ethnic groups is lacking. Objective The aim of this study is to use an innovative methodology to analyze web-based conversations about cancer clinical trials and to identify and compare conversation topics, barriers, and sentiments between different racial and ethnic populations. Methods We analyzed 372,283 web-based conversations about cancer clinical trials, of which 179,339 (48.17%) of the discussions had identifiable race information about the individual posting the conversations. Using sophisticated machine learning software and analyses, we were able to identify key sentiments and feelings, topics of interest, and barriers to clinical trials across racial groups. The stage of treatment could also be identified in many of the discussions, allowing for a unique insight into how the sentiments and challenges of patients change throughout the treatment process for each racial group. Results We observed that only 4.01% (372,283/9,284,284) of cancer-related discussions referenced clinical trials. Within these discussions, topics of interest and identified clinical trial barriers discussed by all racial and ethnic groups throughout the treatment process included health care professional interactions, cost of care, fear, anxiety and lack of awareness, risks, treatment experiences, and the clinical trial enrollment process. Health care professional interactions, cost of care, and enrollment processes were notably discussed more frequently in minority populations. Other minor variations in the frequency of discussion topics between ethnic and racial groups throughout the treatment process were identified. Conclusions This study demonstrates the power of digital search technology in health care research. The results are also valuable for identifying the ideal content and timing for the delivery of clinical trial information and resources for different racial and ethnic groups.

Treatment of HER2-positive early breast cancer (EBC) continues to evolve with neoadjuvant (pre-operative) and adjuvant (post-operative) HER2-targeted therapies as standard of care. There are two important decision points. The first involves deciding between neoadjuvant therapy or proceeding directly to surgery. Neoadjuvant chemotherapy (NACT) plus pertuzumab–trastuzumab is appropriate for patients with high-risk HER2-positive EBC (tumour diameter ≥2 cm, and/or node-positive disease). Patients with node-negative disease and tumour diameter, SCOPUS: re.j, info:eu-repo/semantics/published

Multiple lines of evidence have demonstrated that cigarette smoke or Chronic Obstructive Pulmonary Disease upregulates angiotensin-converting enzyme 2, the cellular receptor for the entry of the severe acute respiratory syndrome coronavirus 2, which predisposes individuals to develop severe Coronavirus disease 2019. The reason for this observation is unknown. We recently reported that the loss of function of Miz1 in the lung epithelium in mice leads to a spontaneous COPD-like phenotype, associated with upregulation of angiotensin-converting enzyme 2. We also reported that cigarette smoke exposure downregulates Miz1 in lung epithelial cells and in mice, and Miz1 is also downregulated in the lungs of COPD patients. Here, we provide further evidence that Miz1 directly binds to and represses the promoter of angiotensin-converting enzyme 2 in mouse and human lung epithelial cells. Our data provide a potential molecular mechanism for the upregulation of angiotensin-converting enzyme 2 observed in smokers and COPD patients, with implication in severe Coronavirus disease 2019.

Objective The APHINITY trial assessed the effectiveness and the safety of adding pertuzumab to trastuzumab and chemotherapy (THP) compared to trastuzumab and chemotherapy (TH) in the adjuvant management of human epidermal growth factor 2-positive (HER2+) breast cancer. We performed a study to project the potential cost-effectiveness of THP vs. TH. Study Design Trial-based cost-utility modeling analysis. Methods We performed an economic evaluation from a payer perspective using a Markov model with six health states: invasive disease-free survival, non-metastatic recurrence, remission, first-line metastatic, subsequent line metastatic, and death. We parameterized the model using data from both arms in APHINITY extrapolated to a patient’s lifetime horizon. Estimates of health state utilities were based on EQ-5D trial data and the literature, and costs were estimated from government sources and the published literature. The primary outcomes of the model were life-years (LYs), quality-adjusted LYs (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). Uncertainty was addressed via univariate and probabilistic sensitivity analyses. Results For the intention-to-treat population, the model projected improved outcomes (by 0.50 LYs and 0.45 QALYs) and increased costs (by $74 420) for ICERs of $147 774/LY gained and $167 185/QALY gained for PHT vs. HT patients. In the node-positive patient population, the model projected improved outcomes (by 0.86 LYs and 0.76 QALYs) and increased costs (by $66 647) for ICERs of $77 684/LY gained and $87 929/QALY gained. For the hormone-receptor-negative patient population, the model projected health gains, increased costs, and ICERs of $147 022/LY gained and $166 518/QALY gained. The results were sensitive to changes in the model time horizon. Conclusion The addition of pertuzumab to the available regimens for HER2+ early breast cancer is likely to be cost-effective for patients in the U.S. at high risk of recurrence.

Summary Background Although frequently used as a primary endpoint, disease-free survival has not been validated as a surrogate for overall survival in early breast cancer. We investigated this surrogacy in the adjuvant setting of treatment with anti-HER2 antibodies. Methods In a systematic review and meta-analysis, we identified published and non-published randomised controlled trials with completed accrual and available disease-free survival and overall survival results for the intention-to-treat population as of September 2016. Bibliographic databases (MEDLINE, Embase, and Cochrane Central Register of Controlled Trials), clinical trial registries ( Clinicaltrials.gov , EU Clinical Trials Register, WHO International Clinical Trials Registry Platform, and PharmNet.Bund), and trial registries from relevant pharmaceutical companies were searched. Eligibility for treatment of HER2-positive early breast cancer required at least one group to have an anti-HER antibody treatment (ie, trastuzumab, pertuzumab, or trastuzumab emtansine) planned for 12 months, and at least one control arm with chemotherapy without the antibody, a lower total dose or duration of the antibody, or observation alone. Units of analysis were contrasts: two-group trials gave rise to one contrast, whereas trials with more than two groups gave rise to more than one contrast. We excluded trials enrolling patients with recurrent, metastatic, or non-invasive disease, and those testing neoadjuvant therapy exclusively. Our primary objective was to estimate patient-level and trial-level correlations between disease-free survival and overall survival. We measured the association between disease-free survival and overall survival using Spearman's correlation coefficient (rs), and the association between hazard ratios (HRs) for disease-free survival and overall survival using R2. We computed the surrogate threshold effect, the maximum HR for disease-free survival that statistically predicts an HR for overall survival less than 1·00 in a future trial. Findings Eight trials (n=21 480 patients) gave rise to a full set (12 contrasts). Patient-level associations between disease-free and overall survival were strong (rs=0·90 [95% CI 0·89–0·90]). Trial-level associations gave rise to values of R2 of 0·75 (95% CI 0·50–1·00) for the full set. Subgroups defined by nodal status and hormone receptor status yielded qualitatively similar results. Depending on the expected number of deaths in a future trial, the surrogate threshold effects ranged from 0·56 to 0·81, based on the full set. Interpretation These findings suggest that it is appropriate to continue to use disease-free survival as a surrogate for overall survival in trials in HER-2-positive, early breast cancer. The key limitation of this study is the dependence of its results on the trials included and on the existence of an outlying trial. Funding Roche Pharma AG.

Prior studies on the brain bases of arithmetic have not focused on (or even described) their participants' language backgrounds. Yet, unlike monolinguals, early bilinguals have the capacity to solve arithmetic problems in both of their two languages. This raises the question whether this ability, or any other experience that comes with being bilingual, affects brain activity for arithmetic in bilinguals relative to monolinguals. Here, we used functional magnetic resonance imaging to compare brain activity in 44 English monolinguals and 44 Spanish-English early bilinguals, during the solving of arithmetic problems in English. We used a factorial design to test for a main effect of bilingual Language Experience. Based on the known modulating roles of arithmetic operation and age, we used two arithmetic tasks (addition and subtraction) and studied two age groups (adults and children). When collapsing across operations and age, we found broad bilateral activation for arithmetic in both the monolingual group and the bilingual group. However, an analysis of variance revealed that there was no effect of Language Experience, nor an interaction of Language Experience with Operation or Age Group. Bayesian analyses within regions of interest chosen for their role in arithmetic further supported the finding of no effect of Language Experience on brain activity underlying arithmetic. We conclude that early bilingualism does not influence the functional neuroanatomy of simple arithmetic.

Simple Summary Despite the impressive progress in the treatment of triple-negative breast cancer (TNBC), oncologists still face several provocative clinical scenarios in daily practice where clear evidence-based recommendations are lacking, and expert opinion is of utmost importance. In an attempt to seek guidance for these controversial topics in TNBC management, a consensus recommendations session for TNBC was held during the 12th round of the Breast-Gynaecological & Immuno-oncology International Cancer Conference (BGICC) Egypt, 2020. This special session convened a multidisciplinary committee of 35 panellists who specialize in breast cancer care from 13 countries. The consensus covered all the aspects of TNBC management starting from defining TNBC to the management of metastatic disease and highlighted the rapidly evolving landscape in this field. Consensus was reached in 70% of the statements (35/50). In addition, areas of warranted research were identified to guide future prospective clinical trials. Background: The management of patients with triple-negative breast cancer (TNBC) is challenging with several controversies and unmet needs. During the 12th Breast-Gynaecological & Immuno-oncology International Cancer Conference (BGICC) Egypt, 2020, a panel of 35 breast cancer experts from 13 countries voted on consensus guidelines for the clinical management of TNBC. The consensus was subsequently updated based on the most recent data evolved lately. Methods: A consensus conference approach adapted from the American Society of Clinical Oncology (ASCO) was utilized. The panellists voted anonymously on each question, and a consensus was achieved when >= 75% of voters selected an answer. The final consensus was later circulated to the panellists for critical revision of important intellectual content. Results and conclusion: These recommendations represent the available clinical evidence and expert opinion when evidence is scarce. The percentage of the consensus votes, levels of evidence and grades of recommendation are presented for each statement. The consensus covered all the aspects of TNBC management starting from defining TNBC to the management of metastatic disease and highlighted the rapidly evolving landscape in this field. Consensus was reached in 70% of the statements (35/50). In addition, areas of warranted research were identified to guide future prospective clinical trials.

PURPOSE: To compare efficacy and safety of capecitabine and lapatinib with or without IMC-A12 (cituxumumab) in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab. PATIENTS AND METHODS: Following an initial safety run-in cohort, patients were randomized 1:2 to Arm A (capecitabine and lapatinib) or to Arm B (capecitabine, lapatinib, and cituxumumab). Given the frequency of non-hematologic grade ≥3 adverse events in those receiving the three-drug combination in the safety cohort, lapatinib and capecitabine doses were reduced in Arm B only. The primary objective was to determine if the addition of cituxumumab to capecitabine and lapatinib improved progression-free survival (PFS) compared with capecitabine and lapatinib. Secondary objectives included a comparison between arms of other clinical endpoints, safety, change in overall quality of life (QOL) and self-assessed fatigue, rash, diarrhea, and hand-foot syndrome. RESULTS: From July 2008 to March 2012, 68 patients (out of 142 planned) were enrolled and 63 were evaluable, including 8 for the safety run-in and 55 for the randomized cohort. Study enrollment was stopped early due to slow accrual. The addition of cituxumumab to capecitabine and lapatinib did not improve PFS (HR 0.93, 95% CI: 0.52-1.64). Furthermore, no difference in objective response rate or overall survival (OS) was observed. No difference between arms was observed in grade ≥3 adverse events, overall QOL change from baseline after 4 cycles of treatment. CONCLUSION: The addition of cituxumumab to lapatinib and capecitabine did not improve PFS or OS compared with lapatinib and capecitabine in patients with HER2-positive MBC.

Purpose: PAM50-defined breast cancer intrinsic subtypes and risk-of-relapse (ROR) scores are prognostic and predictive of endocrine therapy, and some chemotherapy. We investigated the prognostic and predictive effect of PAM50 classifications by chemotherapy type. Methods: NCIC CTG MA.21 randomized 2104 patients to doxorubicin, cyclophosphamide and paclitaxel (AC/T); dose-intense cyclophosphamide, epirubicin and flurouracil (CEF); or dose-dense, dose-intense epirubicin, cyclophosphamide and paclitaxel (EC/T). Patients were ≤60 years, with node-positive or high-risk node-negative disease, with median 8-year follow-up. Intrinsic subtypes and ROR were determined from RNA extracted from formalin-fixed paraffinembedded sections by the NanoString PAM50 test. Univariate effects on relapse-free survival (RFS) were assessed with stratified log-rank test; multivariate analyses utilized stratified Cox regression. Results: Among 1094 cases completing PAM50 intrinsic subtyping, 27% were classified as luminal A, 23% luminal B, 18% HER2E, and 32% basal-like. CEF and EC/T were superior to AC/T (p=0.01). Higher continuous ROR was multivariately associated with worse RFS (p=0.03), although categorical ROR was neither prognostic nor predictive. Intrinsic subtypes had a significant multivariate prognostic effect on RFS (p=0.002). Compared with luminal A, hazard ratios were: luminal B=1.48 (95% CI= 0.92-2.37); HER2E=2.68 (95% CI=1.60-4.48); basallike=1.97 (95% CI=1.10-3.53). Intrinsic subtypes were not predictive of treatment benefit (AC/T vs EC/T+CEF); however, subgroup analysis indicated subtypes (non-luminal vs. luminal) were predictive of taxane benefit (EC/T vs. CEF; p=0.05). Conclusion: Both NanoString PAM50 subtypes and continuous ROR had significant prognostic effects on RFS for breast cancer patients treated with CEF, EC/T and AC/T. Non-luminal tumors differentially responded to EC/T (with taxane) over CEF.

Triple negative breast cancer (TNBC) comprises 15–20% of all invasive breast cancer and is associated with a poor prognosis. As therapy options are limited for this subtype, there is a significant need to identify new targeted approaches for TNBC patient management. The expression of the folate receptor alpha (FRα) is significantly increased in patients with TNBC and is therefore a potential biomarker and therapeutic target. We optimized and validated a FRα immunohistochemistry method, specific to TNBC, to measure FRα expression in a centrally confirmed cohort of 384 patients with TNBC in order to determine if expression of the protein is associated with invasive disease-free survival (IDFS) and overall survival (OS). The FRα IHC demonstrated exceptional performance characteristics with low intra- and interassay variability as well as minimal lot-to-lot variation. FRα expression, which varied widely from sample to sample, was detected in 274 (71%) of the TNBC lesions. In a multivariable model adjusted for baseline characteristics, FRα expression was associated with improved IDFS (HR = 0.63, p = 0.01) but not with OS. The results demonstrate the potential of targeting the FRα in the majority of TNBC patients and suggest that variable expression may point to a need to stratify on FRα expression in clinical studies.

Background Resected HER2 breast cancer patients treated with adjuvant trastuzumab and chemotherapy have superior survival compared to patients treated with chemotherapy alone. We previously showed that trastuzumab and chemotherapy induce HER2-specific antibodies which correlate with improved survival in HER2 metastatic breast cancer patients. It remains unclear whether the generation of immunity required trastuzumab and whether endogenous antibody immunity is associated with improved disease-free survival in the adjuvant setting. In this study, we addressed this question by analyzing serum anti-HER2 antibodies from a subset of patients enrolled in the NCCTG trial N9831, which includes an arm (Arm A) in which trastuzumab was not used. Arms B and C received trastuzumab sequentially or concurrently to chemotherapy, respectively. Methods Pre-and post-treatment initiation sera were obtained from 50 women enrolled in N9831. Lambda IgG antibodies (to avoid detection of trastuzumab) to HER2 were measured and compared between arms and with disease-free survival. Results Prior to therapy, across all three arms, N9831 patients had similar mean anti-HER2 IgG levels. Following treatment, the mean levels of antibodies increased in the trastuzumab arms but not the chemotherapy-only arm. The proportion of patients who demonstrated antibodies increased by 4% in Arm A and by 43% in the Arms B and C combined (p = 0.003). Cox modeling demonstrated that larger increases in antibodies were associated with improved disease-free survival in all patients (HR = 0.23; p = 0.04). Conclusions These results show that the increased endogenous antibody immunity observed in adjuvant patients treated with combination trastuzumab and chemotherapy is clinically significant, in view of its correlation with improved disease-free survival. The findings may have important implications for predicting treatment outcomes in patients treated with trastuzumab in the adjuvant setting. Trial registration ClinicalTrials.gov, NCT00005970. Registered on July 5, 2000. Electronic supplementary material The online version of this article (10.1186/s13058-018-0989-8) contains supplementary material, which is available to authorized users.

IMPACT: This study examines gray matter volume differences resulting from the bilingual experience in children and adults allowing us to better understand the brains of over half of the world’s population that speaks more than one language. OBJECTIVES/GOALS: Literature is mixed regarding a bilingual advantage in executive control (EC). While it has been shown that young adult bilinguals have greater gray matter volume (GMV) than monolinguals in EC regions, there is behavioral evidence that suggests such difference would be more pronounced in children. METHODS/STUDY POPULATION: Using SPM12 to test this hypothesis, we used a whole-brain t-test to compare GMV in 35 English-speaking monolingual and 20 Spanish-English early (learned both languages before 6 years old) bilingual children. Next, we submitted both groups of children to an ANOVA with 42 English speaking monolingual and 26 Spanish-English bilingual adults to test for an interaction of Language Experience by Age Group at the level of the whole brain. RESULTS/ANTICIPATED RESULTS: e between-group comparison of bilingual and monolingual children, revealed more GMV in bilingual compared to monolingual children in regions associated with EC (right middle and inferior frontal gyri, superior parietal lobule, and precuneus). Our second analysis, an ANOVA comparing bilingual and monolingual children and adults, revealed an interaction in which bilingual>monolingual GMV in children was greater than any bilingual>monolingual GMV (or bilingual=monolingual GMV) in the adult groups in the right superior parietal lobule (BA1). No regions indicated that bilingual>monolingual GMV was more pronounced in adults. DISCUSSION/SIGNIFICANCE OF FINDINGS: These results provide further evidence for GMV differences in early bilinguals in regions associated with EC and indicate that more GMV differences exist between bilingual and monolingual children than adults.

Background: To date, anti-HER2 monoclonal antibodies are the only immune therapies approved for treating pts with HER2-over-expressing cancers. Intratumoral delivery of immunostimulatory adjuncts such as toll-like receptor (TLR) 7/8 agonists can activate tumor resident antigen-presenting cells (APCs) to promote antitumor immunity. To optimize intratumoral delivery while leveraging favorable preclinical biology we developed a novel, systemically delivered ISAC (BDC-1001). BDC-1001 consists of an investigational trastuzumab biosimilar chemically conjugated to a TLR 7/8 agonist (payload) with an intervening non-cleavable linker. BDC-1001 activates human myeloid APCs and retains antibody-mediated effector functions such as antibody-dependent cellular cytotoxicity/phagocytosis. Our trastuzumab-based ISACs seem to elicit potent and durable immune-mediated antitumor efficacy including tumor regression in a TLR- and Fc receptor-dependent manner in xenograft and syngeneic tumor resistant models (Ackerman et al. Nat Cancer 2020). BDC-1001 did not induce interstitial lung disease, cytokine release syndrome, or thrombocytopenia in non-human primate studies. A four-part phase 1/2, first-in-human study was initiated in 2020 to evaluate BDC-1001 with or without (±) pembro in pts with HER2-overexpressing or amplified advanced solid tumors. Methods: This phase 1/2 dose-escalation/expansion study will enroll up to 390 pts with HER2-overexpressing (IHC2+ or 3+) or HER2-amplified (by in situ hybridization or next-generation sequencing) advanced solid tumors. Patients may have received prior anti-HER2 therapies. Primary objectives of dose-escalation are safety and tolerability, and establishing a recommended phase 2 dose of BDC-1001 alone administered IV q3w (Part 1) and combined with pembro (Part 2). Primary endpoints of Parts 1 & 2 include assessment of safety and tolerability; dose-limiting immune-related toxicities in a 3+3 design. The dose-expansion phase 2 portion will evaluate preliminary antitumor activity of BDC-1001 alone (Part 3) and with pembro (Part 4) using RECIST v1.1 and iRECIST. The primary endpoint of the phase 2 is best\ overall response rate; with secondary endpoints of duration of response, disease control rate, and progression-free survival. Exploratory objectives include pharmacokinetic parameters and pharmacodynamic biomarkers associated with drug exposure to help elucidate mechanism of action and identify biomarkers to improve selection of pts most likely to benefit from the single therapy or combination. Recruitment is ongoing (NCT04278144). Citation Format: Manish R. Sharma, Richard D. Carvajal, Daniel Catenacci, Leisha A. Emens, Glenn J. Hanna, Dejan Juric, Yoon-Koo Kang, Jeeyun Lee, Keun-Wook Lee, Bob T. Li, Kathleen Moore, Mark D. Pegram, Paula R. Pohlmann, Drew Rasco, Alexander Spira, Arielle L. Heeke, Ding Wang, Lawrence Garbo, Sudhir Manda, Jasgit Sachdev, Shelley E. Ackerman, Heidi LeBlanc, David Dornan, Marcin Kowanetz, Michael N. Alonso, Amreen Husain, Edith A. Perez, Ecaterina Ileana Dumbrava. Phase 1/2 study of a novel HER2 targeting TLR7/8 immune-stimulating antibody conjugate (ISAC), BDC-1001, alone and in combination with pembrolizumab (pembro) in patients (pts) with HER2-expressing advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT218.

Background: Preclinical evidence indicates that increased insulin-like growth factor receptor-1 (IGF1R) signaling interferes with the action of trastuzumab suggesting a possible mechanism of trastuzumab resistance. Thus, we evaluated IGF1R prevalence, relationship with demographic data, and association with disease-free survival (DFS) of patients randomized to chemotherapy alone (Arm A) or chemotherapy with sequential (Arm B) or concurrent trastuzumab (Arm C) in the prospective phase III HER2+ adjuvant N9831 trial. Experimental Design: IGF1R protein expression was determined in tissue microarray sections (three cores per block; N = 1,197) or in whole tissue sections (WS; N = 537) using IHC (rabbit polyclonal antibody against IGF1R β-subunit). A tumor was considered positive (IGF1R+) if any core or WS had ≥1+ membrane staining in >0% invasive cells. Median follow-up was 8.5 years. Results: Of 1,734 patients, 708 (41%) had IGF1R+ breast tumors. IGF1R+ was associated with younger age (median 48 vs. 51, P = 0.007), estrogen receptor/progesterone receptor positivity (78% vs. 35%, P < 0.001), nodal positivity (89% vs. 83%, P < 0.001), well/intermediate grade (34% vs. 24%, P < 0.001), tumors ≥2 cm (72% vs. 67%, P = 0.02) but not associated with race or tumor histology. IGF1R did not affect DFS within arms. Between Arms A and C, patients with IGF1R+ and IGF1R− tumors had DFS HRs of 0.48 (P ≤ 0.001) and 0.68 (P = 0.009), respectively (Pinteraction = 0.17). Between Arms A and B, patients with IGF1R+ and IGF1R− tumors had DFS HRs of 0.83 (P = 0.25) and 0.69 (P = 0.01), respectively (Pinteraction = 0.42). Conclusions: In contrast to preclinical studies that suggest a decrease in trastuzumab sensitivity in IGF1R+ tumors, our adjuvant data show benefit of adding trastuzumab for patients with either IGF1R+ and IGF1R− breast tumors. Clin Cancer Res; 23(15); 4203–11. ©2016 AACR.

Purpose: Conventional chemotherapy has limited activity in patients with breast cancer and brain metastases (BCBM). Etirinotecan pegol (EP), a novel long-acting topoisomerase-1 inhibitor, was designed using advanced polymer technology to preferentially accumulate in tumor tissue including brain metastases, providing sustained cytotoxic SN38 levels. Methods: The phase 3 BEACON trial enrolled 852 women with heavily pretreated locally recurrent or metastatic breast cancer between 2011 and 2013. BEACON compared EP with treatment of physician’s choice (TPC; eribulin, vinorelbine, gemcitabine, nab-paclitaxel, paclitaxel, ixabepilone, or docetaxel) in patients previously treated with anthracycline, taxane, and capecitabine, including those with treated, stable brain metastases. The primary endpoint, overall survival (OS), was assessed in a pre-defined subgroup of BCBM patients; an exploratory post hoc analysis adjusting for the diagnosis-specific graded prognostic assessment (GPA) index was also conducted. Results: In the trial, 67 BCBM patients were randomized (EP, n = 36; TPC, n = 31). Treatment subgroups were balanced for baseline characteristics and GPA indices. EP was associated with a significant reduction in the risk of death (HR 0.51; P, SCOPUS: ar.j, info:eu-repo/semantics/published

The final efficacy and safety results are reported for the VELVET Cohort 2 trial, which investigated the coinfusion of pertuzumab and trastuzumab in a single infusion bag, followed by vinorelbine., Background. VELVET Cohort 1 demonstrated the applicability of pertuzumab, trastuzumab, and vinorelbine as an alternative first‐line treatment regimen for patients with HER2‐positive locally advanced or metastatic breast cancer (MBC) who cannot receive docetaxel. Co‐infusion of pertuzumab and trastuzumab may reduce clinic time and medical resource utilization. We report results from Cohort 2, in which pertuzumab and trastuzumab were co‐infused, followed by vinorelbine. Patients and Methods. During cycle 1, patients with HER2‐positive locally advanced or MBC received loading doses of pertuzumab (840 mg) and trastuzumab (8 mg/kg) on consecutive days, followed by vinorelbine (25 mg/m2) on days two and nine. From cycle 2 onwards, patients received a co‐infusion of pertuzumab (420 mg) and trastuzumab (6 mg/kg) on day one, followed by vinorelbine (30–35 mg/m2) on days one and eight (or days two and nine). The primary endpoint was objective response rate (ORR) in patients with measurable disease. Secondary endpoints included progression‐free survival (PFS) and safety. Results. Cohort 2 enrolled 107 patients. The ORR was 63.7% (95% confidence interval [CI] 53.0–73.6) in patients with measurable disease (91/107; 85.0%). Median PFS was 11.5 months (95% CI 10.3–15.8). The most common adverse events [AEs] were diarrhea (57.9%), neutropenia (57.0%), and nausea (41.1%). Grade ≥3 AEs occurred in 85 patients (79.4%) and serious AEs in 44 patients (41.1%). Eighteen patients (16.8%) had AEs suggestive of congestive heart failure. Conclusion. These results support the feasibility of pertuzumab and trastuzumab co‐infusion from a safety perspective and support Cohort 1 conclusions that vinorelbine offers an alternative chemotherapy companion for pertuzumab and trastuzumab. The Oncologist 2017;22:1160–1168 Implications for Practice. Combined treatment with pertuzumab, trastuzumab, and docetaxel is the standard of care for first‐line HER2‐positive metastatic breast cancer. However, some patients cannot, or choose not to, receive docetaxel. VELVET Cohort 2 results support the results from Cohort 1 that suggest that pertuzumab plus trastuzumab and vinorelbine is a suitable alternative for these patients. In addition to this, results from Cohort 2 support the feasibility of administering pertuzumab and trastuzumab together in a single infusion bag, which has the potential to offer greater patient convenience and reduce active health care professional time and medical resource utilization compared with administering them separately.

Background: Growing evidence supports the critical role of preexisting immune response in triple negative breast cancer (TNBC). However, there are limitations with current evaluation approaches: inability to functionally assess the type of immune infiltration with traditional pathologic evaluation and loss of spatial distribution in conventional high-plex gene or protein expression analyses from the whole tumor section. Here, we report the initial analysis of immune protein expression as a function of spatial distribution and clinical outcomes in TNBC samples. Methods: NanoString GeoMxTM Digital Spatial Profiling (DSP) was used to quantify 39 immune-related proteins in stromal and tumor segments from 44 TNBC samples from the FinXX trial. Samples were matched for patient characteristics, treatment arm (capecitabine vs. 5-fluorouracil), and outcome based on recurrence-free survival (RFS) with 22 samples from patients who recurred and 22 samples from patients with durable RFS. Regions of interest (ROIs) were selected based on expression of cytokeratin (tumor), CD45 (leukocytes), or CD68 (macrophages). Each ROI was segmented into tumor (pancytokeratin-positive area) and stroma (pancytokeratin-negative/nuclear SYTO13-positive area). The general linear model was used for statistical analysis of differential expression with RFS as a categorical variable (recur yes or no). Results: A total of 950 tumor and stroma segments were included in this initial analysis. In both tumor and stroma segments, over-expression of T cell activation markers (CD137, GITR) was associated with better outcome, whereas T cell markers (CD3, CD4, CD8) were not significantly associated with outcome. In tumor segments alone, improved outcome was significantly associated with increased protein expression [> 2-fold change (FC) at p2.0, p2.0, p Citation Format: Saranya Chumsri, Douglas Hinerfeld, Jennifer M. Kachergus, Yaohua Ma, Heather A Brauer, Sarah Warren, Xue Wang, Torsten O. Nielsen, Karama Asleh, Heikki Joensuu, Edith A. Perez, E. A. Thompson. Digital spatial mapping of the immune landscape of triple negative breast cancer reveals novel features of immune-tumor cell interaction [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 PD5-06.

Biomarker testing, which is now often the standard of care for patients diagnosed with cancer, can be used by physicians to assess cancer risk, diagnose a particular cancer, select treatment, and/or assess treatment response. In this summary of a keynote address, Edith Perez, Professor of Medicine at the Mayo Clinic, discusses basic concepts and issues of biomarker-based precision medicine in clinical trials and oncology practice. She describes the general features of well-designed biomarker-driven clinical trials and offers specific suggestions for designing clinical trials to support FDA approval. Perez predicts that in the near future, tumor sequencing will become standard clinical practice; liquid biopsies will become available to sample circulating tumor DNA (ctDNA); tumor classification will become molecular-based, and tumor-agnostic biomarker strategies may be used to manage patients; and clinical trials in oncology will use sequencing at both enrollment and follow-up. Additionally, she describes some basic concepts and challenges in the use of cancer immunotherapy (CIT) biomarkers, which are revolutionizing oncology. A new Program for Accelerated Cancer Therapies (PACT) was cited as an example of a multidisciplinary collaboration with NIH, NCI, and biopharma that aims to support the development of standardized biomarkers for immunoprofiling and exploratory biomarkers of high relevance to patient care. Finally, Perez explains why bringing biomarker-based trials to patients is challenging and predicts that large collaboratives such as PACT will move precision medicine and oncology forward by linking clinical retrospective and prospective cancer genomic and proteomic data with longitudinal clinical outcomes.

PURPOSE Recent trials have shown potential benefit of extended adjuvant endocrine therapy and relatively high risk of recurrence (RoR) after 5 years in hormone receptor-positive (HR+) human epidermal growth factor receptor 2–negative (HER2−) breast cancer. Although risk of late relapse in HR+ HER2− breast cancer is fairly well defined, the risk in HER2-positive (HER2+) breast cancer treated with adjuvant trastuzumab-based chemotherapy remains largely unknown. METHODS We included 3,177 patients with HER2+ breast cancer treated with adjuvant chemotherapy alone or with trastuzumab from the North Central Cancer Treatment Group N9831 (ClinicalTrials.gov identifier: NCT00005970 ) and National Surgical Adjuvant Breast and Bowel Project B-31 (ClinicalTrials.gov identifier: NCT00004067 ) trials. RESULTS Overall, HR+ breast cancer was significantly associated with improved recurrence-free survival (RFS) during the first 5 years (hazard ratio, 0.65; 95% CI, 0.56 to 0.77; P < .001). Among patients treated with trastuzumab, cumulative hazard for RFS was lower in patients with HR+ HER2+ breast cancer during the first 5 years (10.96% v 17.48%; hazard ratio, 0.60; 95% CI, 0.45 to 0.79; P < .001). However, there was no significant difference in RFS based on HR status during years 5 to 10 (hazard ratio, 1.32; 95% CI, 0.93 to 1.88; P = .12). A comparable degree of trastuzumab benefit was observed in HR+ and HR− breast cancers ( P for interaction = .87). Furthermore, we observed low RoR in years 5 to 10 among patients with HR+ HER2+ breast cancer: 3.23% in patients without lymph node involvement (N0) and 6.39% in patients with involvement of one to three lymph nodes (N1). CONCLUSION The benefit of adjuvant trastuzumab persists for a long time. A distinct pattern of recurrence was observed between HR+ and HR− HER2+ disease but with similar degree of benefit from adjuvant trastuzumab. RoR in years 5 to 10 in HR+ HER2+ breast cancer is low, particularly in patients with N0 or N1 disease.

PURPOSE Older women with breast cancer remain under-represented in clinical trials. The Cancer and Leukemia Group B 49907 trial focused on women age 65 years and older. We previously reported the primary analysis after a median follow-up of 2.4 years. Standard adjuvant chemotherapy showed significant improvements in recurrence-free survival (RFS) and overall survival compared with capecitabine. We now update results at a median follow-up of 11.4 years. PATIENTS AND METHODS Patients age 65 years or older with early breast cancer were randomly assigned to either standard adjuvant chemotherapy (physician’s choice of either cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide and doxorubicin) or capecitabine. An adaptive Bayesian design was used to determine sample size and test noninferiority of capecitabine. The primary end point was RFS. RESULTS The design stopped accrual with 633 patients at its first sample size assessment. RFS remains significantly longer for patients treated with standard chemotherapy. At 10 years, in patients treated with standard chemotherapy versus capecitabine, the RFS rates were 56% and 50%, respectively (hazard ratio [HR], 0.80; P = .03); breast cancer–specific survival rates were 88% and 82%, respectively (HR, 0.62; P = .03); and overall survival rates were 62% and 56%, respectively (HR, 0.84; P = .16). With longer follow-up, standard chemotherapy remains superior to capecitabine among hormone receptor–negative patients (HR, 0.66; P = .02), but not among hormone receptor–positive patients (HR, 0.89; P = .43). Overall, 43.9% of patients have died (13.1% from breast cancer, 16.4% from causes other than breast cancer, and 14.1% from unknown causes). Second nonbreast cancers occurred in 14.1% of patients. CONCLUSION With longer follow-up, RFS remains superior for standard adjuvant chemotherapy versus capecitabine, especially in patients with hormone receptor–negative disease. Competing risks in this older population dilute overall survival benefits.

Following publication of the original article [1], the authors reported the following errors in the article.

Objective: This study aimed to estimate asthma control at specialist treatment centers in four Latin American countries and assess factors influencing poor asthma control.Methods: Patients aged ≥12...

Background In the phase 3 MARIANNE trial, trastuzumab emtansine (T-DM1) with or without pertuzumab showed noninferior progression-free survival and better tolerability than trastuzumab plus a taxane (HT) for the first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. This article reports the final descriptive overall survival (OS) analysis, updated safety data, and additional patient-reported outcomes and biomarker analyses. Methods OS was assessed in 1095 patients with HER2-positive breast cancer and no prior therapy for advanced disease who had been randomized to HT, T-DM1 plus a placebo (hereafter T-DM1), or T-DM1 plus pertuzumab (T-DM1+pertuzumab). A post hoc exploratory landmark analysis of OS, baseline patient and disease characteristics, and tumor biomarkers in patients with and without an objective tumor response (OR) according to the Response Evaluation Criteria in Solid Tumors within 6.5 months of randomization was conducted. Results The median OS was similar across groups (50.9, 53.7, and 51.8 months for the HT, T-DM1, and T-DM1+pertuzumab groups, respectively). Among patients with an OR, the median OS was longer with T-DM1 (64.4 months) and T-DM1+pertuzumab (not reached) versus HT (56.3 months). No baseline characteristics or biomarkers were strongly associated with OR. The incidence of grade 3 or higher adverse events was greater with HT (55.8%) than T-DM1 (47.1%) or T-DM1+pertuzumab (48.6%). The median time to clinically meaningful deterioration (a 3-point or greater change) in neurotoxicity symptoms was shorter with HT (2.1 months) and T-DM1+pertuzumab (4.2 months) than T-DM1 (6.2 months). Fewer patients reported alopecia and diarrhea and were bothered by treatment side effects in the T-DM1 arm. Conclusions These results support T-DM1 as a first-line treatment for patients with HER2-positive metastatic breast cancer who are deemed unsuitable for taxane-based therapy.

535 Background: Invasive lobular carcinoma (ILC) is a rarer form of breast cancer, accounting for 10% of the disease cases. HER2 overexpression in ILC is infrequent and limited data exist regarding clinical characteristics and outcome of HER2-positive (HER2+) ILC patients (pts) treated with adjuvant trastuzumab. Methods: Patient characteristics were compared between ILC and invasive ductal carcinoma (IDC) using Wilcoxon rank sum test for continuous variables and Chi-square test for categorical variables. Kaplan-Meier (KM) method was used to estimate the freedom from mortality and recurrence. Cox regression model was used to evaluate the association between ILC and outcomes adjusted for other characteristics. NanoString technology was used to quantify mRNA to develop immune-related gene signatures. Results: From a total of 3,304 pts, 122 (3.7%) pts had ILC. Pts with ILC were significantly older (median age 54 vs. 49 years), had larger tumors, lower grade, more ER and PR positive tumors, and more lymph node involvement (25.4% had N3 disease compared to 12.7% in IDC). Overall, with KM analysis, pts with ILC had significantly worse overall survival (OS, p = 0.005) and recurrence-free survival (RFS, p = 0.046) compared to IDC. The 15-year freedom from recurrence was merely 57.67% in ILC compared to 72.68% in IDC. A significant number of hormone receptor-positive (HR+) ILC pts developed late recurrence with cumulative event rates increasing from 23% at 5 years to 42% at 15 years. Nevertheless, in multivariate Cox regression analysis adjusting for other clinical characteristics, including age, tumor size, grade, ER/PR, and lymph node status, lobular histology was not significantly associated with worse outcome for OS (HR = 1.19, 95%CI 0.67-2.1, p = 0.55) and RFS (HR = 1.5, 95%CI 0.9-2.5, p = 0.12), as compared with IDC. However, ILC pts appeared to have similar degree of benefit from trastuzumab, with RFS HR = 0.58 compared to HR = 0.67 in the entire population. For immune landscape, there was no significant difference in gene signatures related to CD45, CD8, B cells, or cytotoxic cells. However, ILC had more enrichment in mast cell gene signature and fewer macrophage, NK CD56dim, and regulatory T cell signatures compared to IDC (p < 0.05). Conclusions: HER2+ ILC has distinct clinical characteristics and immune landscape compared to IDC. ILC pts appeared to have worse outcome compared to IDC likely because ILC pts often presented with more locally advanced disease. However, similar benefit of trastuzumab was observed in ILC pts. Due to high risk of late relapse in HR+ HER2+ ILC, extended adjuvant endocrine therapy should be considered in this group of high-risk pts. Clinical trial information: NCT00005970.

2549 Background: BDC-1001 is a novel ISAC consisting of an investigational trastuzumab biosimilar chemically conjugated to a TLR 7/8 agonist with a non-cleavable linker. BDC-1001 was designed to activate the innate immune system, eliciting antibody-mediated effector functions (eg, antibody-dependent cellular phagocytosis) and a durable adaptive immune response. In preclinical tumor models resistant to anti-HER2 treatments, BDC-1001 demonstrated potent and durable immune-mediated antitumor efficacy. Methods: A 4-part, phase 1/2 dose-escalation/expansion study was initiated to evaluate BDC-1001 ± PD1 inhibitor pembrolizumab in pts with HER2-expressing solid tumors who had progressive disease on standard of care (NCT04278144). Preliminary results of the monotherapy dose escalation (Part 1) are reported. Pts with advanced metastatic HER2-expressing (IHC2/3+) or amplified solid tumors received BDC-1001 IV q3w in a 3+3 design w/ 12 pts/cohort backfill allowed. Primary objectives were to evaluate safety, tolerability, dose-limiting toxicities (DLTs) and determine a phase 2 dose; secondary objectives were to assess pharmacokinetics (PK), pharmacodynamics and preliminary anti-tumor activity. Results: As of Jan 29, 2021, 20 pts w/ a median age of 65 (46-85) have enrolled in 4 dose levels (0.15mg/kg to 5 mg/kg). Cancer types include breast, biliary, cervical, colorectal (CRC), lung, gastroesophageal, salivary, urinary tract and endometrial. Pts had received a median of 4 (1-7) prior therapies; 65% received >1 prior anti-HER2 therapy. All pts completed the 21-day DLT period; no DLTs or drug-related serious adverse events (AEs) have been observed. AEs deemed related to BDC-1001 have been mild to moderate including infusion-related reactions. The MTD has not been reached (treatment duration 5-17+wk); enrollment is ongoing. PK evaluations showed Cmax levels consistent with predicted modeling based on non-human primates (NHP). One pt with microsatellite stable (MSS) HER2+ CRC with lung metastases had a confirmed partial response after 4 cycles and remains on study; 2 additional pts with metastatic MSS HER2+ CRC had stable disease (SD) and a pt with heavily pretreated MSS endometrial cancer with lung metastases had confirmed SD and remains on treatment 17+ wk; 3 of these pts had received 2 prior anti-HER2 therapies. Conclusions: In this first-in-human study, BDC-1001 appears to be well-tolerated up to the dose tested to date (5 mg/kg), with Cmax levels achieved as predicted by NHP modeling. Evidence of clinical activity have been observed, including in pts previously treated with anti-HER2 therapy. Dose escalation is ongoing and will be followed by combination dosing with CPI and the phase 2 component in selected tumors. Clinical trial information: NCT04278144.

Background: Growing data established the pivotal role of preexisting immune response in triple negative breast cancer (TNBC). Conventionally, preexisting immune response can be evaluated by quantifying tumor infiltrating lymphocytes mainly in the stroma or gene expression analysis from the whole tumor section. Due to technical challenges with these conventional methods, limited data regarding specific subtypes and spatial distribution of these immune infiltrates are currently available. Methods: NanoString IO360 gene expression analysis and Digital Spatial Profiling (DSP) were used. DSP was used to quantify 29 immune-related proteins in stromal and tumor-enriched segments from 44 TNBC samples from the FinXX trial (NCT00114816) and 335 samples from the Mayo Clinic (MC) cohort of centrally reviewed TNBC (Leon-Ferre BCRT 2018). In FinXX trial, 22 patients with recurrence and 22 patients without recurrence were included. In MC cohort, 217/335 patients received adjuvant chemotherapy while 118 patients had surgery only without adjuvant chemotherapy. Regions were segmented based on pancytokeratin staining. The general linear model was used for statistical analysis of differential expression with recurrence free survival (RFS) as a categorical variable (recur yes or no). Kaplan-Meier (KM) estimates and Cox regression models were also used for analysis. Results: In the FinXX trial, there were 12 out of 29 proteins in tumor epithelial segments (intraepithelial) which were significantly expressed at higher levels among patients who were free of recurrence. These proteins include Beta-2 microglobulin, CD11c, CD20, CD40, CD56, CD8, Granzyme B, HLA-DR, ICOS, PD-L1, PD-L2, and TGFB1. In contrast, merely 5 out of 29 proteins in stromal segments were significantly differentially expressed in these 2 groups of patients. Granzyme B, IDO1, PD-L1, and PD-L2 in stroma were significantly higher and SMA was significantly lower in patients without recurrence. Using Cox regression models, intraepithelial CD56, CD40, and HLA-DR were significantly associated with outcome. When comparing between highest and lowest intraepithelial protein expression by tertile, intraepithelial CD56 (HR 0.12, 95%CI 0.03-0.39, p < 0.001), CD40 (HR 0.13, 95%CI 0.04-0.46, p = 0.002), and HLA-DR (HR 0.24, 95%CI 0.06-0.89, p = 0.032) were significantly associated with improved outcome. However, expression of these same proteins in stroma was not associated with outcome. Using KM estimates, intraepithelial CD56 (p < 0.0001), CD40 (p = 0.0006), and HLA-DR (p = 0.013) were also significantly associated with improved outcome. Nonetheless, RNA expression of these proteins by IO360 from whole tumor sections were not significantly associated with outcome (CD56 p = 0.27, CD40 p = 0.21, HLA-DR p = 0.48). Similar findings with DSP were observed in MC TNBC cohort. Comparing between the highest and lowest quartiles, there were significantly fewer patients who developed recurrence with high protein expression of intraepithelial CD56 (p < 0.001), CD40 (p = 0.002), and HLA-DR (p = 0.006). Conclusions: Using an in-depth analysis with spatially defined context, we identify that there were numerically more intraepithelial immune-related proteins associated with outcome compared to proteins in stroma. Specifically, intraepithelial CD56, CD40, and HLA-DR were significantly associated with improved outcome in both FinXX and MC TNBC cohorts. However, neither expression of these proteins in stroma nor RNA expression from whole tumor were associated with outcome. Our study highlights the impact of spatial biology and the importance of evaluating each potential biomarker in a spatially defined manner. Support: W81XWH-15-1-0292, BCRF 19-161, P50CA116201-9, P50CA015083 Citation Format: Saranya Chumsri, Jodi M. Carter, Yaohua Ma, Douglas Hinerfeld, Heather Ann Brauer, Sarah Warren, Torsten O. Nielsen, Karama Asleh, Heikki Joensuu, Edith A. Perez, Roberto A. Leon-Ferre, David W. Hillman, Judy C. Boughey, Minetta C. Liu, James N. Ingle, Krishna R. Kalari, Fergus J. Couch, Keith L. Knutson, Matthew P. Goetz, E. A. Thompson. Spatially defined immune-related proteins and outcome in triple negative breast cancer in the FinXX trial and Mayo Clinic cohort [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 PS6-02.

Background: Overall, patients with cancer experience a greater risk of adverse outcomes following SARS-CoV-2 infection; however, little is known for those with BC. Methods: CCC19 (NCT04354701) is an international cohort study aimed at investigating the impact of COVID-19 in patients with a history of or active cancer using de-identified data on patient demographics, cancer history, clinical course and outcomes of COVID-19. The current analysis includes patients from U.S. and Canada with invasive BC and laboratory-confirmed SARS-CoV-2 entered between March 17, 2020 and July 2, 2020. Co-primary outcomes were hospitalization during COVID-19 illness and 30-day all-cause mortality. Frequencies for categorical variables and medians (range) for continuous variables were estimated. Final presentation will include bivariable and multivariable Cox proportional hazards regression analysis to identify risk factors (including BC subtypes and therapies, for which data collection is ongoing) associated with 30-day all-cause mortality and severe COVID-19 illness (composite of any hospitalization requiring supplemental oxygen, admission to an intensive care unit [ICU], use of mechanical ventilation, or death). Results: During the study period, a total of 2683 patients with cancer and COVID-19 were accrued in the CCC19 registry including 529 (20%) with invasive BC. Among patients with BC, 352 (67%) were 60 years or older; 518 (98%) were women; 275 (52%) non-Hispanic White, 116 (22%) non-Hispanic Black, 70 (13%) Hispanic, 56 (11%) in other categorizations; 178 (34%) had a smoking history; 75 (14%) ECOG performance status ≥2; 191 (36%) with >2 active comorbidities; 64 (12%) with AJCC stage IV disease at BC diagnosis; and 267 (50%) were on anti-cancer treatment including systemic therapy, radiation, or surgery within 3 months of COVID-19 diagnosis. At least 323 (61%) patients with BC had 30-day follow-up after COVID-19 diagnosis, and 35 (7%) had 90-day follow-up. COVID-19 illness at initial diagnosis required outpatient care in 288 (54%), inpatient care in 193 (36%), and ICU care in 40 (8%). Overall, 247 (47%) were hospitalized and 30-day all-cause mortality was 9%. 30-day all-cause mortality rates by receipt of major BC treatment modalities (within past 3 months) were: 10% for those on cytotoxic systemic therapy vs 5% and 12% for noncytotoxic systemic therapy and local therapy, respectively. The table shows hospitalization and mortality outcomes by major demographic and BC treatment strata. The final presentation will incorporate the latest patient accrual and evaluate independent clinical risk factors associated with serious COVID-19 outcomes in patients with BC. Conclusions: This represents the largest study to date of COVID-19 outcomes in patients with invasive BC. Nearly half of the patients with BC required hospitalization during their COVID-19 disease course and we observed a 9% 30-day all-cause mortality. Submitted on behalf of the COVID-19 and Cancer Consortium (ccc19us.org) Table 1. COVID-19 related hospitalization and 30-day all-cause mortality for all patients with invasive BCNAny Hospitalization30-day all-cause MortalityN% [95% CI]N% [95% CI]Total population52924747 [42-51]499 [7-12]Age219112968 [60-74]2915 [10-21]Treatment IntentCurative1866434 [28-42]95 [2-9]Palliative743953 [41-64]1216 [9-27]Cancer StatusRemission/NED33115447 [41-52]247 [5-11]Active disease, stable or responding to treatment1194840 [31-50]76 [2-12]Active disease, progressing372773 [56-86]1130 [16-47]Treatment Modality (within 3 months)Cytotoxic chemotherapy833542 [31-54]810 [4-18]Noncytotoxic therapy1856435 [28-42]105 [3-10]Local therapy (surgery or radiation)341750 [32-68]412 [3-27] Citation Format: Ali Raza Khaki, Dimpy P Shah, Maryam B Lustberg, Melissa K Accordino, Daniel G Stover, Gayathri Nagaraj, Donna R Rivera, Edith A Perez, Sara M Tolaney, Jeffrey Peppercorn, Petros Grivas, Jeremy L Warner, Corrie A Painter, Gilberto de Lima Lopes, Jr, Solange Peters, Michael A Thompson, Toni K Choueiri, Brian I Rini, Gary H Lyman, Nicole M Kuderer, Shaveta Vinayak. Characteristics and outcomes of SARS-CoV-2 infection in patients with invasive breast cancer (BC) from the COVID-19 and cancer consortium (CCC19) cohort study [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 PS7-01.

Funding: Supported by National Cancer Institute grants U10CA180888, U10CA180819, U10CA180820, U10CA180821, U10CA180868, U10CA180863; and in part by Susan G. Komen for the Cure® Research Program, The Hope Foundation for Cancer Research, Breast Cancer Research Foundation, and Genomic Health, Inc. Acknowledgement: The authors wish to thank Dr. Ana M. Gonzalez-Angulo, MD, for her invaluable contributions to the design and implementation of this study. Background: The clinical utility of the RS to determine CT benefit is well established in pts with HR+, HER2-, axillary lymph node (LN)-negative BC. Retrospective analyses from SWOG S8814 support the potential prognostic and predictive role of RS for CT benefit in postmenopausal pts with LN+ BC. SWOG S1007 is a prospective, randomized trial of endocrine therapy (ET) vs. chemoendocrine therapy (CET) in women with 1-3 +LN and a RS < 25 (NCT01272037). Methods: Eligibility criteria included women > 18 years of age with HR+, HER2- BC and 1-3 +LN and no contraindications to taxane and/or anthracycline based CT. Women with a RS < 25 were randomized to receive ET or CET in 1:1 randomization using 3 stratification factors: (1) RS (0-13 vs.14-25); (2) menopausal status; and (3) axillary nodal dissection vs. sentinel node biopsy. The primary objective was to determine the effect of CT on invasive disease-free survival (IDFS) and whether the effect depended on the RS. The primary analysis was to test for a significant interaction of the treatment arm and continuous RS using a Cox regression model for IDFS, adjusting for treatment, RS, and menopausal status. A total of 832 IDFS events were expected for the final analysis. Secondary objectives included overall survival (OS). The protocol specified that interaction between treatment and the stratification variables was to be tested and, if significant, separate analyses performed by stratum. Annual interim analyses were planned starting at 24% of events. At the third interim analysis with 410 IDFS events, the Data and Safety Monitoring Committee recommended reporting results, with a decision by the NCI’s Cancer Therapy Evaluation Program, the study sponsor. Results: Of the 9,383 women screened from 2/28/11-9/29/17, 5,083 pts (54.2%) were randomized. With a median follow-up of 5.1 years, 447 IDFS events have been observed. For the primary analysis, the interaction test for CT benefit and continuous RS was not statistically significant, p=0.30. In a model with CT, RS, and menopausal status (no interaction term), higher continuous RS was associated with worse IDFS [HR 1.06, 2-sided p Citation Format: Kevin Kalinsky, William E Barlow, Funda Meric-Bernstam, Julie R Gralow, Kathy S Albain, Daniel Hayes, Nancy Lin, Edith A Perez, Lori J Goldstein, Stephen Chia, Subkhbinder Dhesy-Thind, Priya Rastogi, Emilio Alba, Suzette Delaloge, Miguel Martín, Miguel Gil Gil, Claudia Arce-Salinas, Etienne Brain, In Hae Park, Jean-Yves Pierga, Ana Hernandez Lluch, Manuel Ramos Vasquez, Manuel Ruiz Borrego, Kyung Hae Jung, Jean-Marc Ferrero, Anne Schott, Steve Shak, Priyanka Sharma, Danika L Lew, Jieling Miao, Debu Tripathy, Gabriel Hortobagyi, Lajos Pusztai. First results from a phase III randomized clinical trial of standard adjuvant endocrine therapy (ET) +/- chemotherapy (CT) in patients (pts) with 1-3 positive nodes, hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer (BC) with recurrence score (RS) < 25: SWOG S1007 (RxPonder) [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 GS3-00.

Background: Although risk of late relapse in hormone receptor-positive (HR+) breast cancer is well established, most existing data pertain to the HR+ HER2-negative (HER2-) subgroup. CTS5 is one of the models for predicting risk of late relapse in HR+ HER2- breast cancer. However, the value of this model in HR+ HER2+ disease is less known, particularly in the context of adjuvant trastuzumab. Here, we evaluated CTS5 in patients with early stage HR+ HER2+ breast cancer treated in the NCCTG N9831 (Alliance for Clinical Trials in Oncology) and NSABP B-31 (NRG) trials. Methods: Stage I-III HR+ (ER+ and/or PR+) HER2+ breast cancer patients who were free of recurrence after 5 years in N9831 and B-31 trials were included. The online CTS5 calculator was used to determine CTS5 score and risk group (low, intermediate, and high) based on age, tumor size, grade, and number of involved nodes. Kaplan-Meier (KM) estimates, Cox regression models, and C index were used for analysis. N9831 and B-31 trials were analyzed separately. Results: 1,204 patients in N9831 and 658 patients in B-31 met the entry criteria. Baseline characteristics were similar between both trials, including median age, tumor size, and follow up. Similar distribution within CTS5 risk group was observed in both trials; 68.2% and 70.1% patients were high risk, 24% and 21.9% as intermediate risk, as well as 7.8% and 8.1% as low risk classified in N9831 and B-31, respectively. Using univariate Cox regression analysis, CTS5 score as a continuous variable was associated with recurrence-free survival (RFS) in the entire study cohort, including patients who received chemotherapy alone or in combination with trastuzumab, (HR 1.37, 95%CI 1.03-1.81, p=0.03, C index 0.57 in N9831 and HR 1.36, 95%CI 1.06-1.76, p=0.02, C index 0.54 in B-31), but not in patients who received concurrent trastuzumab (HR 1.19, 95%CI 0.73-1.2, p=0.49, C index 0.54 in N9831 and HR 1.35, 95%CI 0.96-1.9, p=0.08, C index 0.54 in B-31). As categorical variable in the entire study cohort, CTS5 risk group was not significantly associated with RFS among patients with intermediate vs. low (HR 0.47, 95%CI 0.18-1.22, p=0.12 and HR 1.61, 95%CI 0.66-3.92, p=0.29) and high vs. low (HR 1.23, 95%CI 0.57-2.67, p=0.6 and HR 1.93, 95%CI 0.85-4.41, p=0.12) with the C index of 0.58 and 0.53 in N9831 and B-31 respectively. There was also no significant difference in RFS among 3 CTS5 risk groups with Kaplan-Meier estimates. Among patients who received concurrent trastuzumab, similar trends were observed with no statistical difference in RFS between high vs. low (HR 0.68, 95%CI 0.24-1.97, p=0.48 and HR 1.44, 95%CI 0.52-3.96, 0.49) with the C index of 0.55 and 0.51 in N9831 and B-31, respectively. Paradoxically, patients with intermediate risk had better RFS than low risk (HR 0.18, 95%CI 0.03-0.97, p=0.05) in N9831 but no significant difference in B-31 (HR 1.31, 95%CI 0.44-3.95, p=0.63). Conclusions: While CTS5 score as a continuous variable was associated with outcome in overall HR+ HER2+ population, this model was not prognostic in patients receiving adjuvant trastuzumab in both N9831 and B-31 trials. Furthermore, the correlation (C index) was modest and CTS5 risk group as a categorical variable could not stratify outcome in this group of patients. This study underlines the need to develop a new prognostic model to better delineate the risk of late relapse in HR+ HER2+ breast cancer patients receiving trastuzumab as this model can facilitate clinical decision for extended adjuvant endocrine therapy. Support: BCRF-19-161, U10CA180821, U10CA180868 and U10CA180822 (NRG), Genentech. https://acknowledgments.alliancefound.org Citation Format: Tanyami Pai, Angelica Gil, Yaohua Ma, Zhuo Li, Pooja Advani, Moreno Moreno-Aspitia, Gerardo Colon-Otero, Edith A. Perez, Yan Asmann, Katherine Pogue-Geile, E. A. Thompson, Saranya Chumsri. Prognostic value of clinical treatment score post-5 years (CTS5) and late relapse risk in hormone receptor-positive HER2-positive breast cancer in the North Central Cancer Treatment Group (NCCTG) N9831 (Alliance) and NSABP B-31 (NRG) trials [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 PS6-03.

Purpose In 1998, the US Food and Drug Administration (FDA) approved human epidermal growth factor receptor 2 (HER2) testing guidelines to determine eligibility for HER2-directed therapy (HDT) in breast cancer. ASCO and the College of American Pathologists published immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) HER2 testing guidelines in 2007 (AC2007) and updated these guidelines in 2013 (AC2013). We compared the HER2 FISH amplification frequency using these three guidelines. Methods Patient samples that were sent to the Mayo Clinic cytogenetics laboratory for FISH testing (n = 2,851; from November 2013 to October 2014) were analyzed. Frequency of HER2 FISH amplification was examined and impact of AC2013 assessed. Results IHC results were available for 1,922 patient samples (67.4%), 137 of which were from Mayo Clinic. Distribution was 2.4% IHC 0, 7.9% IHC 1+, 84.8% IHC 2+, and 2.5% IHC 3+. Among IHC 2+ patients, HER2 FISH positivity was 11.8% (FDA), 9.4% (AC2007), and 24.1% (AC2013). Overall, 11.8% (n = 339) were positive with a FISH ratio ≥ 2.0, 1.3% (n = 35) with a FISH ratio ≥ 2.0 despite a HER2 signal < 4.0, and 3.0% (n = 86) with HER2 signal ≥ 6.0 despite FISH ratio < 2.0. Among 405 patients (14.2%) who were initially considered FISH-equivocal (ratio < 2.0 with HER2 signal ≥ 4.0, but < 6.0; AC2013), use of an alternative chromosome 17 probe reassigned 212 (7.4% overall) patients to FISH-positive and 36 (1.3% overall) patients to FISH-negative, whereas 157 (5.5% overall) patients remained equivocal. Final HER2 positivity with AC2013 (23.6%) was increased (P < .001) compared with FDA (13.1%) and AC2007 (11%) guidelines. Conclusion In a reference laboratory cohort that was highly enriched for IHC 2+ patient samples, AC2013 guidelines led to a larger number of FISH-equivocal patients. Approximately one half of these FISH-equivocal patients (7.4% overall) became HER2-positive upon alternative FISH probe testing. However, these patients would not have participated in the pivotal HDT trials. Clinical utility data on HDT benefit in these patients and other special subsets are needed.

Background Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2–positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain. Methods In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2–positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T→L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T. Results Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P ≤ .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4% reduction was observed with T→L compared with T (HR, 0.96; 97.5% CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms. Conclusion Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care.

Introduction Histone deacetylase inhibitors have been found to restore sensitivity to the estrogen receptor in endocrine-resistant and triple-negative breast cancer cell lines. We decided to test panobinostat, a pan-histone deacetylase inhibitor, because of preclinical data, combined with letrozole in a phase I study. Patients and Methods We enrolled patients with metastatic breast cancer to determine the safety and tumor response using Response Evaluation Criteria In Solid Tumors. Dose level 1 was panobinostat 20 mg orally 3 times weekly with oral letrozole 2.5 mg daily. Dose level 2 was panobinostat 30 mg orally 3 times weekly, with the same dose of letrozole. Results A total of 12 patients (6 at each dose level) were enrolled, and 43 cycles of treatment were given. Of the 6 patients at dose level 1, 1 experienced dose-limiting toxicity (20-mg dose level; an increase in creatinine). At the 30-mg dose level, 3 of 6 patients experienced dose-limiting toxicity, 1 each of grade 3 thrombocytopenia with bleeding, grade 4 thrombocytopenia, and grade 3 diarrhea. The maximum tolerated dose was 20 mg. Of the 12 patients, 2 experienced a partial response, and 5 had stable disease. The most common severe adverse event was thrombocytopenia, occurring in 4 of 12 patients. Conclusion The recommended phase II starting dose is panobinostat 20 mg orally 3 times weekly (eg, Monday, Wednesday, Friday) and oral letrozole 2.5 mg daily. This dose should be escalated to 30 mg orally 3 times weekly if no grade 3 toxicity has developed, because the partial responses occurred in patients receiving the 30-mg dose.

Purpose Significant improvement in survival outcomes has been established with the addition of trastuzumab to adjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2) –positive early breast cancer treatment. However, trastuzumab may increase the risk of cardiac toxicity, and long-term evaluation of its incidence and risk factors are warranted. Methods NCCTG (Alliance) N9831 trial compared adjuvant doxorubicin and cyclophosphamide (AC) followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or paclitaxel plus trastuzumab followed by trastuzumab alone (arm C) in patients with HER2-positive breast cancer. Cumulative incidence of cardiac events (CE) and left ventricular ejection fraction (LVEF) were evaluated in 1,944 women who proceeded to post-AC therapy. Risk factors for trastuzumab-induced cardiac toxicity were identified by Cox regression models. Results The 6-year cumulative incidence of CE was 0.6% in arm A, 2.8% in arm B, and 3.4% in arm C. At a median follow-up of 9.2 years, only two additional CHF diagnoses (of 1,046 patients) occurred beyond our previously reported follow-up time of 3.75 years. LVEF recovered in the majority of the patients who developed CHF. There were two cardiac deaths in arm A and one each in arms B and C. Age of 60 years or older, registration LVEF less than 65%, and use of antihypertensive medications were associated with an increased risk of CE in arms B and C. Conclusion The cumulative incidence of CE at 6 years was slightly higher with the addition of trastuzumab; however, the late development of CE is infrequent. Trastuzumab (in the context of anthracycline- and taxane-based therapy) continues to have a favorable benefit-risk ratio.

Background: The intrinsic immune response in triple negative breast cancer (TNBC) has both prognostic and predictive utility, and immune-related biomarkers are now actionable targets in TNBC. Current modalities for immune profiling are limited by lack of spatial context and precise quantitation. We used quantitative digital spatial profiling (DSP) to 1) characterize the immune architecture of tumoral and stromal regions in TNBC and 2) identify prognostic immune signatures. Methods: From the FinXX trial of adjuvant capecitabine therapy, tumor sections (FFPE) matched for patient characteristics, treatment arm and RFS-based outcome (N=44) were assessed with Nanostring GeoMxTM DSP. Briefly, with 3-plex immunofluorescence (pan-cytokeratin, CD45, CD68 with SYTO-13 dye for nuclei), spatially-defined CD45-enriched or CD68-enriched stromal segments and adjacent tumor segments (N=950) were selected for digital quantitation (NanoString nCounter) of 39 immune proteins (e.g. immune cell profiling proteins: CD3, CD4, CD8, CD11c, CD20, CD56, CD68, HLA-DR, PD-1, PD-L1, Granzyme B), immune drug targets (e.g. VISTA, STING, IDO1), and activation status-related proteins (e.g. ICOS, PD-L2, CD40, CD40L, CD44). Normalized, differentially-expressed (DE) proteins were evaluated, and weighted gene co-expression network analysis (WGCNA) was performed to identify modules of highly co-expressing immune proteins, and association with RFS as a categorical variable was determined. Results: 20 DE proteins in tumor segments were associated with RFS. Among them, those with the highest RFS-associated fold changes (FC) included CD20, CD40, CD56, HLA-DR, Granzyme B, and PD-L2 (FC): 2.1-4.4) (p < 0.05). In contrast, only 4 DE proteins were associated with RFS in stromal segments (Granzyme B, IDO-1, PD-L1, and PD-L2 (FC: 1.5-3.3) (p < 0.05). By WGCNA, 2 tumor-based immune modules [IM1 (lymphocyte infiltration) and IM2 (lymphocyte activation)] were identified based on their co-expression. The top three co-expressed proteins in IM1 were CD4, CD40, and CD45 (r >0.9). The three top co-expressed proteins in IM2 were PD-L1, PD-L2, and Granzyme B (r > 0.85). Together with CD56 expression, IM1 and IM2 comprised a set of 3 intratumoral immune features that associated with RFS. For recurring tumors, all 3 immune features clustered with low scores . Among non-recurrent tumors, two distinct, non-overlapping clusters with inverse characteristics were identified: high IM2, low IM1, low CD56 vs. low IM2, high IM1, and high CD56. Overall, across all 3 immune features, PDL2, CD40 and CD56 expression most strongly associated with RFS. Conclusion: With spatially-defined, precise quantification of immune proteins, we identified 3 immune features, including two distinct immune modules, IM1 and IM2 that correlate with durable RFS. These immune modules of highly co-expressing proteins were associated with RFS only when present in the tumor compartment but not tumor-adjacent, immune cell-rich stroma. Citation Format: Jodi M. Carter, Saranya Chumsri, Yaohua Ma, Xue Wang, Jennifer M. Kachergus, Douglas Hinerfeld, Heather Ann Brauer, Sarah Warren, Heikki Joensuu, Edith A. Perez, Aubrey Thompson. Quantitative digital spatial profiling reveals novel prognostic intratumoral immune signatures in triple-negative breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1004.