Azambuja, Evandro de

Background: The association between obesity and prognosis in HER2-positive early breast cancer remains unclear, with limited data available. This study aimed to determine the impact of body mass index (BMI) at baseline and weight change after 2 years on outcomes of patients with HER2-positive early breast cancer. Methods: ALTTO was a randomized phase III trial in patients with HER2-positive early breast cancer. BMI was collected at randomization and 2 years after. WHO BMI categories were used: underweight, <18.5 kg/m2; normal weight, 18.5 to <25 kg/m2; overweight, ≥25 to <30 kg/m2; and obese ≥30 kg/m2. A weight change from baseline of ≥5.0% and ≤5.0% was categorized as weight gain and weight loss. The impact of BMI at randomization and of weight change on disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) were investigated with multivariate analyses, adjusting for baseline patients and tumor characteristics. Results: A total of 8,381 patients were included: 187 (2.2%), 3,797 (45.3%), 2,690 (32.1%), and 1,707 (20.4%) were underweight, normal weight, overweight, and obese at baseline, respectively. Compared with normal weight, being obese at randomization was associated with a significantly worse DDFS (adjusted hazard ratio [aHR], 1.25; 95% CI, 1.04–1.50) and OS (aHR, 1.27; 95% CI, 1.01–1.60), but no significant difference in DFS (aHR, 1.14; 95% CI, 0.97–1.32). Weight loss ≥5.0% at 2 years after randomization was associated with significantly poorer DFS (aHR, 1.34; 95% CI, 1.05–1.71), DDFS (aHR, 1.46; 95% CI, 1.07–1.98), and OS (aHR, 1.83; 95% CI, 1.18–2.84). Hormone receptor and menopausal status but not anti-HER2 treatment type influenced outcomes. Toxicities were more frequent in obese patients. Conclusions: In patients with HER2-positive early breast cancer, obesity at baseline is a poor prognostic factor. Weight loss during treatment and follow-up negatively impacts clinical outcomes. Dietary counseling should be part of survivorship care programs.

AbstractThe JAK/STAT3 signaling pathway may be aberrantly activated and have various and conflicting roles in breast cancer. The current study explored prognostic implications of activated STAT3 in human epidermal growth factor receptor 2 (HER2)‐positive primary breast cancers in the context of a large prospective study (ALTTO). Activated STAT3 was determined by immunohistochemical analysis of STAT3 phosphorylation (Y705) performed on the primary tumors. This analysis evaluated whether patients with activated STAT3 had disease‐free survival (DFS) and overall survival (OS) different from patients without activated STAT3. A total of 5694 patients out of the 8381 patients enrolled in ALTTO were included in this analysis (67.9%), and 2634 of them (46%) had evidence of STAT3 activation (minimum tumor Allred score ≥2). The median follow‐up was 6.93 years (6.85‐6.97 years), at the end of which 1035 (18.18%) and 520 (9.13%) patients experienced DFS and OS events, respectively. Patients with STAT3 activation experienced improved DFS compared to those without it (multivariable hazard ratio [HR], 0.84; 95% confidence interval [CI] 0.74‐0.95; P = .006). There were no group differences in OS (multivariable HR, 0.92; 95% CI 0.78‐1.10; P = .37). This effect was limited to ER‐positive tumors. In conclusion, these findings support the role of STAT3 activation as a marker of favorable outcome in ER‐positive/HER2‐positive breast cancer patients.

11553 Background: Little is known about the toxicity of trastuzumab (T) or of trastuzumab + lapatinib (T + L), approved in the advanced setting, in older pts. We have performed a sub-analysis of the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial focused on treatment completion and toxicity of T and T+L in older pts (aged ≥65 years (yr)). Methods: The ALTTO trial (NCT00490139, NCCTG N063D) randomised 8381 pts with early HER2+ BC into 4 arms and we included the T and T+L arms in our analysis. Eligible pts for our study were those having received at least one dose of assigned treatment. Treatment completion was evaluated through the rate of temporary treatment interruptions (TTI), permanent treatment discontinuations (PTD) and lapatinib dose reductions (LDR). Toxicity was evaluated via a selected set of adverse events of interest (AEIs). Risk factors for TTI, PTD, LDR and AEIs were assessed, including comorbidities and polypharmacy at baseline (defined as use 5 or more co-medications) and AEIs during treatment. Results: A total of 430 pts≥65-year-old were identified for this sub-analysis, out of a total of 4190 pts with a median age of 68 yrs (range 65-80). Older pts were more likely to have comorbidities (70% vs 38%). Treatment completion was worse among older pts in the T+L arm but not in the T arm (Table). AEIs were more common in the T+L arm in all patients, with older patients having higher AEI rates (78.04% in older vs 63.38% in younger), particularly diarrhea (60.75% vs 38.0%). Identified risk factors (multivariate) for worse treatment completion in the T and T+ L arms included concomitant use of chemotherapy and the occurrence of grade 3 adverse events, among others. Conclusions: T + L has worse treatment completion and is more toxic in older patients, while T was well tolerated. Identifiable risk factors at baseline and during the course of treatment could be used to aid in regimen selection and management for both T and T + L in their respective indications. Support: UG1CA189823, Novartis;https://acknowledgments.alliancefound.org. [Table: see text]

Abstract Background: The level of immune suppression in an individual breast cancer (BC) patient is relevant for having a major benefit from treatments that act via or are directed to the immune response, such as anti-HER2 agents and immune checkpoint molecules, respectively. The link(s) between the tumor immune microenvironment and treatment responses has been investigated in HER2-positive BC. This study analyzed the association between baseline expression of genes regulating T cell activities (PD1, CTLA4, LAG3, TIM3, PDL1, PDL2, FOXP3, IL10, TGFβ (1-3), FOXP1 and other related genes) and pathologic complete response (pCR) rates in the NeoALTTO trial. Methods: NeoALTTO randomized early-stage HER2-positive BC patients to neoadjuvant trastuzumab (T), lapatinib (L) or T+L for 6 weeks followed by 12 weeks of concurrent paclitaxel. Anthracyclines were given after surgery (FEC). Patients with RNA sequencing data from their baseline tumor samples (N=254 patients out of 455 from the original cohort) were included in the current study. The primary endpoint, pCR, was defined as ypT0/is ypN0. Logistic regression was used for analysis of pCR. Cox regression univariate and multivariate (adjusted for clinicopathological parameters and treatment arms) analyses were performed. Results: In the total cohort analyzed, high PD1 (odds ratio, OR: 1.4, P=0.03), PDL2 (OR: 1.4, P=0.04), CTLA4 (OR: 1.4, P=0.03) and TGFβ3 (OR: 1.4, P=0.02) expression was associated with an increased probability of achieving pCR at the multivariate analysis. ERBB2 (HER2) expression was associated with pCR in the three arms (T: OR: 2.7, P=0.02; L: OR: 2.3, P=0.01; T+L: OR: 5, P&lt;0.001). Additionally in the T+L arm, PAM50 HER2-enriched subtype (OR: 2.9, P=0.03), as well as immune genes PD1 (OR: 2.1, P=0.01), PDL1 (OR: 1.8, P=0.03) and CTLA4 (OR: 2; P=0.01), were also associated with pCR. Conclusions: In the NeoALTTO population examined, PD1, PDL2, CTLA-4 and TGFβ3 expression at diagnosis were all associated with improved pCR rates after anti-HER2 treatment. The effect of these treatments seemed to be dependent on HER2 expression levels, which was particularly relevant in the T+L arm. These observations confirm previous findings that link immune infiltrates to higher pCR rates, demonstrate the clinical significance of the PD-1 pathway and additionally show that CTLA-4 and TGFβ3 could also be important in early stage HER2-positive BC. The association of tumors linked with immune regulatory gene expression with positive responses to neoadjuvant anti-HER2 agents suggests that they act in a way that reinvigorates the antitumor immunity in the face of tumor-mediated suppression. Patients whose tumors highly express these genes may be good candidates for immunotherapy before the start or after the neoadjuvant treatment when residual disease is detected at surgery, although these hypotheses require further confirmation. Citation Format: Cinzia Solinas, Pushpamali De Silva, David Venet, Soizic Garaud, Chunyan Gu-Trantien, Florentine Hilbers, Evandro de Azambuja, Olena Werner, Lorena De la Peña, Amylou Dueck, Serena Di Cosimo, Istvan Lang, Jens Huober, Sherko Küemmel, Carsten Denkert, Roberto Salgado, Christos Sotiriou, Martine Piccart-Gebhart, Debora Fumagalli, Karen Willard-Gallo. Immune regulatory gene expression and clinical outcome in the NeoALTTO trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3132.

Abstract Background We investigated the clinical outcomes and behavior of HER2+ EBC according to centrally tested HR status in pts treated with modern chemotherapy (CT) and trastuzumab (T)-based regimens. Patients and methods ALTTO is an international phase 3 trial in HER2+ EBC pts randomized to 4 adjuvant anti-HER2 treatment arms: T alone, lapatinib (L) alone, their sequence (T-&gt;L) or their combination (T+L). Pts in the L alone arm were excluded from the present analysis. HER2 and HR status were centrally tested for all patients. HER2 status was defined based on the 2007 ASCO/CAP guidelines. HR-positive (HR+) was defined as ≥1% tumor cells with expression of estrogen (ER) and/or progesterone receptors.We investigated the prognosis of pts with HR+ or negative (HR-) HER2+ EBC, the risk of developing early (years 0-5) and late (years 6-8) recurrences, the factors impacting this risk, and the patterns of relapse according to HR status. Univariate and multivariate Cox proportional hazard models were used to compare hazard rates within the HR subgroups; a conditional landmark analysis was conducted to investigate late recurrences. For the hazard ratios for HR status, an interaction between log(time) and HR status was included as proportional hazard assumption was not satisfied. Results This analysis included 6,271 HER2+ pts of whom 3,601 (57%) had HR+ and 2,670(43%) HR- EBC. Median follow-up was 6.93 years (range 6.81-6.96). 5-year disease-free survival (DFS) was 86% (85-87) in HR+ and 83% (82-85) in HR- pts; 8-year DFS was 80% (78-81) in HR+ and 79% (77-81) in HR- pts. The mean annual hazards of recurrence in years 0-5 were 3% in HR+ and 4% in HR- pts, while in years 6-8 they were 3% in HR+ and 2% in HR- pts. The hazard ratios for HR status (ref=HR-) were 0.60 (0.51-0.72) overall, 0.74 (0.65-0.85) for years 0-5 and 1.61 (1.17-2.24) for years 6-8. In HR+ pts, risk factors for recurrence overall were age ≥65 (p=0.01), tumor size pT3-4 (p&lt;0.001), nodal status pN1-3 (p&lt;0.001), tumor grade 2 or 3 (p&lt;0.001), anthracycline-only CT (p&lt;0.001), no use of aromatase inhibitors (p&lt;0.001), and ER&lt;10% (p=0.01). Main risk factors for recurrence in both years 0-5 and years 6-8 were pN2-3 (p=0.04 for both) and high (≥5) HER2 FISH ratio (p=0.02 for both). In HR- pts, risk factors for recurrence overall were BMI (obesity or underweight; p=0.01), pT3-4 (p&lt;0.001), pN1-3 (p&lt;0.001) and anthracycline-only CT (p&lt;0.001). No significant risk factors for recurrence in years 0-5 were identified. Main risk factor for recurrence in years 6-8 was BMI (obesity; p=0.002). HR+ pts had lower incidence of visceral disease (58.8% vs. 69.6%; p=0.005) and lung metastasis (18.5% vs. 27.8%; p=0.006); bone was the most common site of first recurrence (30%). Conclusions This large analysis of centrally tested HR+ and HR- HER2+ EBC provides strong evidence on the existence of two different diseases within the HER2+ population based on HR expression. These up-to-date estimates of pts outcomes after modern CT and T-based regimens may be used as “historical control” for the design of future de-escalation or escalation trials separately in HR+ and HR- HER2+ EBC pts. Citation Format: Lambertini M, Campbell C, Gelber RD, Viale G, McCullough A, Tonghua L, Hilbers F, Korde LA, Werner O, Chumsri S, Jackisch C, Wolff AC, Vaz-Luis I, Ferreira AR, Prat A, Moreno Aspitia A, Piccart M, Loi S, de Azambuja E. Dissecting the effect of hormone receptor (HR) status expression in patients (pts) with HER2-positive (HER2+) early breast cancer (EBC): Exploratory analysis from the ALTTO (BIG 2-06) trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-14.

Background Limited data exist on the safety of using anti–human epidermal growth factor receptor 2 (HER2) targeted agents during pregnancy. To date, only retrospective studies have assessed the prognosis of patients with a pregnancy after prior early breast cancer, with no data in HER2‐positive patients. Methods The Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO) trial and the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) trial were randomized phase 3 trials for patients with HER2‐positive early breast cancer. In both trials, pregnancy information was prospectively collected. Pregnancy outcomes were compared between patients unintentionally exposed to trastuzumab and/or lapatinib during gestation (the exposed group) and those who became pregnant after trastuzumab and/or lapatinib completion (the unexposed group). In the ALTTO trial, disease‐free survival (DFS) was compared between pregnant patients and those aged 40 years or younger without a subsequent pregnancy via an extended Cox model with time‐varying covariates to account for a guarantee‐time bias. Results Ninety‐two patients (12 in the exposed group and 80 in the unexposed group) had a pregnancy: 7 in the NeoALTTO trial and 85 in the ALTTO trial. Seven patients (58.3%) in the exposed group and 10 patients (12.5%) in the unexposed group opted for an induced abortion; in the unexposed group, 10 patients (12.5%) had a spontaneous abortion. No pregnancy/delivery complications were reported for the remaining cases, who successfully completed their pregnancy, with the exception of 1 fetus with trisomy 21 (Down syndrome). No significant difference in DFS (adjusted hazard ratio, 1.12; 95% confidence interval, 0.52‐2.42) was observed between young patients with a pregnancy (n = 85) and young patients without a pregnancy (n = 1307). Conclusions For patients with HER2‐positive early breast cancer, having a pregnancy after treatment completion appears to be safe without compromising fetal outcome or maternal prognosis.