HER2-positive Breast Cancer Pts Research Articles

Randomized, open-label, phase II, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with locally advanced, inflammatory, or early HER2-positive breast cancer—Immun-HER trial (GOIRC-01-2016)

BackgroundIt is possible to induce immunomodulation in HER2-positive breast cancer (BC) by modifying the route of administration of trastuzumab.MethodsIn this multicenter randomized phase II trial, all enrolled patients (pts) with...

FS-1502 in HER2-positive advanced breast cancer: Results from an open-label, phase 1 study.

3044 Background: FS-1502 is an anti-HER2 antibody-drug conjugate that was well tolerated and showed good antitumor activity in patients (pts) with advanced HER2 -expressing solid tumors in the dose-escalation stage of the current Phase 1 study. The results were presented at SABCS 2022. The recommend Phase 2 dose (RP2D) was 2.3 mg/kg IV once every 3 weeks. Here, we report the efficacy and safety of HER2-positive breast cancer (BC) pts treated with FS-1502 at the RP2D. Methods: This open-label Phase 1 trial was conducted at 9 hospitals in China. Heavily pretreated HER2-positive (IHC 3+ or 2+/FISH+) BC pts who had failed prior anti-HER2 therapy were recruited in the dose-expansion stage. All HER2-positive BC pts treated at the RP2D were pooled for analysis. Efficacy endpoints included objective response rate (ORR) and disease control rate (DCR) per RECIST v1.1. Safety endpoints included treatment-emergent adverse events (TEAEs) and the laboratory data. Results: As of cutoff date, December 24, 2022, the median study follow-up duration was 5.2 months. A total of 70 female HER2-positive BC pts, with a median age of 51.8 (range: 31-76) years, were enrolled and received at least one dose of FS-1502. The median prior therapy line was 3 (range: 1-16), and 91.4% (64/70) of pts had previously received at least 2 therapy lines. The most common metastasis organs were lung 55.7% (39/70), lymph node 54.3% (38/70) and bone 50% (35/70). 81.4% (57/70) of pts had at least 3 metastatic lesions. All pts had previously received anti-HER2 therapy, among which trastuzumab ± pertuzumab (n = 67, 96%) and pyrotinib (n = 52, 74%) were the most common. Among 68 efficacy-evaluable pts, the best ORR of 52.9% (36/68) (95% CI, 40.45-65.17) was achieved with 2 complete responses and 34 partial responses. DCR was 88.2% (60/68), median progression-free survival was 15.5 months (95% CI, 4.57,-), and median duration of response was 12.9 months (95% CI, 5.72,-). FS-1502 was well tolerated. No related interstitial lung disease occurred in any grade. Eye toxicity was mostly Grade 1 or 2 of dry eye and keratitis. Grade ≥ 3 study-related TEAEs were reported in 27 (38.6%) pts, in which the most common events (≥ 5%) were hypokalemia (18.6%), platelet count decreased (7.1%), and neutrophil count decreased (5.7%). One (1.4%) patient experienced adverse events leading to drug discontinuation (hemoptysis). Adverse events leading to death were reported in 2 (2.9%) pts (bacterial pneumonia and hemoptysis, respectively). Bacterial pneumonia was not related to FS-1502, while hemoptysis was possibly related to the drug. Conclusions: FS-1502 demonstrated very promising antitumor activity and was well tolerated in heavily pretreated HER2-positive BC, with mild eye toxicity and no related interstitial lung disease reported. A Phase 3 clinical trial is under planning to further confirm efficacy and safety of FS-1502 in pts with advanced HER2-positive BC. Clinical trial information: NCT03944499 .

Effect of adjuvant trastuzumab for HER2 positive breast cancer combined with radiation therapy and anthracyclines on left ventricular function

Abstract Funding Acknowledgements Type of funding sources: None. Background Although trastuzumab has benefits in treatment of HER2 positive breast cancer, its use is associated with an increased risk of cardiotoxicity. Purpose To assess the effect of adjuvant trastuzumab in HER2 positive breast cancer pts, in addition to prior radiation and antracyclines therapy, on left ventricular function. Methods Fifty HER2 positive female breast cancer patients (mean age, 59.57±9.6 years) were enrolled in the study. In all patients (pts) left ventricular left ventricular ejection fraction-LVEF(%) and left ventricular mass – LVM (g) were assesed at the beginning and after the therapy with trastuzumab. All pts were on sequential therapy with anthracyclines (IV cycles) within the FAC regimen (fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2) on day 21, and after that followed with trastuzumab (6 mg/kg of body weight on day 21) for the period of one year. The pts are divided in two groups: the group of patients (N=32 pts) who had prior radiation therapy (25 daily sessions of 2 Gy dose each, up to the total dose of 50 Gy) and group without radiation therapy (N=18). Results After completion of trastuzumab therapy pts who underwent radiation therapy, reduced LVEF by 2.24 % (from 66.58 ± 5.36 % to 64.34±7.34 %; p=0.048) and increased LVM by 17.95 g (from 160.38 ± 46.21 g to 178.33 ± 53.14 g; p=0.018) . The group of pts without radiation therapy, reduced LVEF by 0,72 % (from 63.33±7.60 % to 62.61±6.92 %; p=0.979) and increased LVM 23.34 g (from 141.98±35.82 g to 165.32±47.45 g; p=0.062). Conclusion The results of the study showed that the decline of LVEF and increase of LVM after completion of adjuvant trastuzumab therapy for HER2 positive breast cancer iz related with previous prior radiation administration. The pts with radiation had greater reduction of LVEF and increase of LVM than those without radiation.

281MO Quality of life and neurocognitive function in patients with active brain metastases of HER2-positive breast cancer treated with trastuzumab-deruxtecan: Secondary endpoint analysis of the prospective single-arm phase II TUXEDO-1 trial

Maintaining quality-of-life (QoL) and neurocognitive function is a main goal in the setting of brain metastases (BM) in HER2-positive breast cancer (BC) patients (pts). TUXEDO-1 investigated QoL and neurocognitive function during trastuzumab-deruxtecan (T-DXd) therapy in HER2-positive BC BM pts. TUXEDO-1 is a prospective, open-label, single-arm phase II trial and enrolled adult HER2-positive BC pts with newly diagnosed BM or progressive BM with no immediate need for local therapy. T-DXd was administered every three weeks at standard dose until disease progression, unacceptable side-effects or consent withdrawal. A secondary endpoint of the trial was QoL and pts completed the EORTC QLQ-C30 questionnaire at cycle 1, 3, 5 and every 9 weeks thereafter. A final assessment was performed at first survival follow-up three months after end-of-treatment. Linear mixed-effect models were used to analyze changes in QoL scores (sub-domains global QoL score, cognitive/emotional/physical function scores; scores range from 0-100) over time (slope). TUXEDO-1 is registered with EU Clinical Trials Register (EudraCT 2020-000981-41) and ClinicalTrials.gov (NCT04752059) and enrollment is closed. Fifteen pts (14 females, 1 male; 12/15 luminal B) were enrolled and received at least one dose of T-DXd. Median age at inclusion was 69 (range 30-76) years. Pts received a median of two (range 1-5) prior systemic therapies for metastatic BC and 9/15 (60%) pts received prior local therapy (whole brain radiotherapy, stereotactic radiotherapy or neurosurgery) for BM. Neurologic symptoms at inclusion were present in 6/15 (40%) of pts. Median follow-up time was 11 months. The QLQ-C30 global QoL (slope -0.13 per follow-up visit, p=0.953), the physical (0.52, p=0.363), emotional (-0.24, p=0.835) as well as the cognitive functioning scores (-0.79, p=0.429) were all maintained over the duration of T-DXd therapy. TUXEDO-1 showed maintained QoL and neurocognitive function during T-DXd therapy in HER2-positive BC BM pts. Our data support first-line systemic therapy with T-DXd in pts with active BM.

165MO Trastuzumab-deruxtecan (T-DXd) in HER2-positive breast cancer patients (pts) with active brain metastases: Primary outcome analysis from the TUXEDO-1 trial

Brain metastases (BM) are a frequent and devastating complication of HER2-positive breast cancer (BC). T-DXd is an antibody-drug conjugate with high activity in pretreated pts but information regarding activity in active BM is limited. Therefore, the prospective, single-arm, phase II TUXEDO-1 trial investigated T-DXd in HER2-positive BC pts with active BM.

Abstract P2-13-26: Trastuzumab deruxtecan in previously treated HER2-positive metastatic or unresectable breast cancer (BC): First real-life data from the cohort temporary authorization for use (cATU) program in France

Abstract Background Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) composed of an HER2-directed antibody and a topoisomerase I inhibitor covalently linked via a tetrapeptide-based cleavable linker. In DESTINY-Breast01, tolerability and efficacy of T-DXd including overall response rate, progression-free survival, duration of response and overall survival have been demonstrated for HER2-positive metastatic and/or unresectable BC in patients (pts) relapsing after 2 or more anti-HER2-based regimens. In France, rapid and fair access to innovative drugs outside clinical trials, prior to their marketing authorization in a given indication, is granted by the French Health Agency, ANSM (Agence Nationale de Sécurité du Médicament et des Produits de Santé), through cATU program. Here we report first real world evidence data from cATU program in HER2+ BC pts treated with T-DXd. Methods T-DXd 5.4mg/kg was given intravenously in monotherapy every 3 weeks in HER2-positive metastatic and/or unresectable BC pts who had previously received at least 2 lines of anti-HER2 regimens in the metastatic setting. Eligible pts needed to have normal neutrophil count and no left ventricular dysfunction. Pts with active or history of interstitial lung disease (ILD), pneumonitis, severe pulmonary disease were excluded. Clinical, biological and safety data were collected until the end of cATU, as well as treatment response according to RECIST 1.1., dose modification, treatment interruption and discontinuation. Analysis was performed on March 31th, 2021 on the basis of available collected data. Results From September 30th, 2020 to March 31th, 2021, 155 centers requested at least one ATU for a total of 539 adult pts; 468 requests were accepted and 71 were refused as they did not meet eligibility criteria. T-DXd was received by 459 pts with the following characteristics: 99.1% were women, median age was 58 years, 90.4% had a ECOG score of 0-1, 98.9% had initial HER2-positive BC (IHC 3+ or IHC 2+/ISH+), 67% were hormone receptor positive. The main sites of metastases were bones (57.3%), lymph nodes (51.6%), lungs (36.2%), liver (33.1%), brain (28.1%) and cutaneous/subcutaneous (13.9%). Median time between initial diagnosis of primary BC and inclusion was 6.6 years (range: 6.6 months - 33.9 years). 81.7% of pts had previously received radiotherapy and 76.5% underwent surgery. The median number of prior cancer regimens in the metastatic setting was 4 (range: 2-22). 21.1% received 2 prior lines of metastatic treatments, 19.6% received 3 lines and 59.3% received 4 lines or more. 94.8% pts received prior trastuzumab emtansine, and 79.3% had prior pertuzumab. During follow-up, data on tumor assessment were available for 160 pts. Of these, 56.7% had complete or partial response and 12.1% had progression. Of the 459 treated pts, 97 pts (21.1%) experienced ≥ 1 Adverse Drug Reaction (ADR) including 41 pts (8.9%) with ≥ 1 serious ADR. Most frequent ADRs were related to gastrointestinal toxicity (35.4%). During cATU, 17 cases (3.7%) with ILD or considered as ILD were reported but no cases had a fatal outcome (only grade 1 or 2 when reported by physicians). 13 fatal cases were reported (no drug-related deaths, attributed by physician). ADRs leading to T-DXd discontinuation were reported in 4 pts (0.9%). Dose reductions were reported in 17 pts (3.7%) and 21 pts (4.6%) had temporary interruptions. Conclusions We report here the first real world data from the French cATU in HER2-positive BC pts treated by T-DXd. The enrolment of 468 pts in 6 months illustrated the unmet medical need for this population. T-DXd had antitumor activity with a similar response rate to that reported in previous clinical studies. T-DXd was well tolerated and no new safety signals were observed. Citation Format: Thierry Petit, Nawale Hajjaji, Eric-Charles Antoine, Marc-Antoine Benderra, Michel Gozy, Cyril Foa, Jean-Loup Mouysset, Julien Grenier, Mireille Mousseau, Audrey Mailliez, Mahasti Saghatchian, Emma Lachaier, Isabelle Desmoulins, Audrey Hennequin, Patricia Maes, Delphine Loirat, Francesco Ricci, Véronique Diéras, Dominique Berton, Florence Lai Tiong, Luis Teixeira, Nadine Dohollou, Christelle Lévy, Thomas Bachelot, Jean-Yves Pierga. Trastuzumab deruxtecan in previously treated HER2-positive metastatic or unresectable breast cancer (BC): First real-life data from the cohort temporary authorization for use (cATU) program in France [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-26.

Abstract P2-13-07: Zanidatamab (ZW25), a HER2-targeted bispecific antibody, in combination with chemotherapy (chemo) for HER2-positive breast cancer (BC): Results from a phase 1 study

Abstract Background: Despite the availability of multiple HER2-targeted therapies, most patients (pts) with advanced HER2-positive BC experience disease progression, and an unmet medical need remains. Zanidatamab (zani) binds to HER2 across a range of expression levels and induces formation of receptor clusters, resulting in receptor internalization and downregulation that affect signal transduction. Zani potently activates antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity. In this ongoing phase 1 study (NCT02892123), data from BC pts treated with zani monotherapy have been previously reported. Here, we evaluated the safety and antitumor activity of zani in combination with chemo in HER2-positive BC pts. Methods: Pts with locally advanced and/or metastatic HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+/fluorescence in situ hybridization+) BC who received prior trastuzumab (tras), pertuzumab (pert), and T-DM1 were enrolled. Eligibility criteria included Eastern Cooperative Oncology Group performance status ≤1 and adequate organ function. Prior history of treated stable brain metastases was allowed. Zani (20 mg/kg Q2W or 30 mg/kg Q3W) was administered in combination with paclitaxel (pac), capecitabine (cap), or vinorelbine (vin). Zani + chemo was continued until disease progression or toxicity; if chemo was discontinued due to toxicity, zani treatment could be continued. Primary endpoints were safety and tolerability assessments; secondary efficacy endpoints included objective response rate (ORR) and disease control rate (DCR; complete response [CR] + partial response [PR] + stable disease [SD]) per RECIST v1.1, and progression-free survival (PFS). Clinical benefit rate (CBR) was defined as SD ≥24 weeks or best overall response of CR or PR. Results: As of 3 May 2021, 20 HER2-positive BC pts had enrolled (zani + pac, n=4; zani + cap, n=9; zani + vin, n=7). Ten pts were hormone receptor positive (data available for 19 pts), and 7 pts had a prior history of brain metastases. Median age was 53 years (range, 38-72), with median prior systemic therapies of 4.5 (range, 2-7) and median of 2 regimens in the metastatic setting. Pts received a median of 3 prior HER2 regimens; all pts received tras and T-DM1, 17 received pert, and 6 received tyrosine kinase inhibitors. In the 16 response evaluable (measurable disease and either post-baseline assessments or earlier death/progression) pts, confirmed ORR was 37.5% (with 1 additional response pending confirmation), CBR was 50%, and DCR was 81.3%. Median duration of response was not reached (range, 1.8+ to 16.8+ mo), with 4 of 6 confirmed responses ongoing. Among all pts (n=20), the most common (≥30% of pts) zani- and/or chemo-related adverse events (AEs) were diarrhea (65%), nausea (45%), peripheral neuropathy (35%), and fatigue (30%). One pt experienced grade 3 diarrhea leading to dose reduction of zani, and 1 pt discontinued zani due to AEs (abdominal pain and nausea, both grade ≤2). Four grade 4 AEs were observed in 4 (20%) pts: neutrophil count decreased (2 pts) and neutropenia (1 pt), all related to chemo, and hyponatremia (1 pt, not related to study treatment). Serious AEs were observed in 2 (10%) pts (pleural effusion, 1 pt; pneumonitis and upper respiratory tract infection, 1 pt), none related to zani. No grade 5 AEs were reported. Conclusions: Zani in combination with chemo is well tolerated, with encouraging and durable antitumor activity in heavily pretreated (including prior tras, pert, and T-DM1) pts with HER2-positive BC. These data support further investigation of zani as a novel therapeutic for these pts. The cap and vin cohorts continue to enroll, and additional cohorts are evaluating zani ± chemo in combination with tucatinib. Citation Format: Philippe L Bedard, Seock-Ah Im, Elena Elimova, Sun Young Rha, Rachel Goodwin, Cristiano Ferrario, Keun-Wook Lee, Diana Hanna, Funda Meric-Bernstam, Jose Mayordomo, Murali Beeram, Erika Hamilton, Jorge Chaves, Melody Cobleigh, Tony Mwatha, Joseph Woolery, Do-Youn Oh. Zanidatamab (ZW25), a HER2-targeted bispecific antibody, in combination with chemotherapy (chemo) for HER2-positive breast cancer (BC): Results from a phase 1 study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-07.

Clinical outcomes in HER2-positive and triple-negative breast cancer: Assessing racial disparities.

e18624 Background: Triple negative breast cancer (TNBC) & HER2 positive breast cancer (Her2BC), are aggressive breast cancer subtypes. Both are associated with higher mortality in Non-Hispanic Black (NHB) compared to Non-Hispanic White women (NHW). Factors attributed to this racial disparity include socioeconomic status, insurance status, diagnosis(dx)/ treatment delays & comorbidities. We examined the association between race & clinical outcomes (pathological complete response, pCR; recurrence free survival, RFS & overall survival, OS) in patients (pts) dxed with TNBC/Her2BC treated with neoadjuvant chemotherapy (NAC) at Roswell Park Comprehensive Cancer Center. Methods: Pts dxed with Stage I-III TNBC/Her2BC who received NAC from 2000-2018 were included. pCR was defined as absence of residual invasive cancer in the breast & lymph nodes after NAC. Association of race with pCR & survival outcomes was evaluated using logistic & Cox regression models, respectively. Multivariate (MV) models were used to evaluate the association between race & pCR or survival while controlling for relevant confounders including age, BMI, insurance, comorbidities, clinical stage, grade & time from dx to chemotherapy(chemo)/surgery. Analysis was conducted using SAS v9.4 at a significance level of 0.05. Results: 174 TNBC (49 NHB, 125 NHW) & 80 Her2BC (13 NHB, 67 NHW) pts were analyzed. Among TNBC pts, NHB pts had higher baseline BMI(34.3 vs 28.6 kg/m2; p<0.001), higher incidence of hypertension (HTN) (45% vs. 24%; p<0.01), diabetes mellitus (20% vs 8%; p<0.05) & higher Medicare/Medicaid use (M/M) (55% vs. 28%; p<0.01). Among Her2BC pts, NHB pts had higher incidence of HTN (54% vs 25%; p<0.05). There was no statistically significant difference in mean chemo relative dose intensity by race. Among TNBC pts, those with pCR were younger (47 vs 53 yrs; p=0.002) & had more grade 3 tumors (96% vs 80.5%; p<0.05) at dx compared to pts without pCR. Similarly, among Her2BC pts, those with pCR had more grade 3 tumors (64% vs 36%; p<0.05) at dx compared to pts without pCR. Among TNBC pts, advanced age, higher clinical stage & longer time from dx to surgery were associated with worse RFS & OS (p<0.05). Among Her2BC pts, M/M use & advanced clinical stage were associated with worse RFS & OS (p<0.05). There were no significant associations between race & pCR/RFS/OS on MV analysis (table below). Conclusions: Similar outcomes were noted between races for TNBC/Her2BC pts treated at a single academic center in Buffalo, NY. Given the known genetic diversity of African American ancestry in the US, further studies investigating the interplay between race, geography & clinical outcomes are warranted.[Table: see text]

Phase I study of A166 in patients with HER2-expressing locally advanced or metastatic solid tumors.

1024 Background: A166 is an antibody-drug conjugate composed of a novel cytotoxic drug (Duo-5, anti-microtubule agent) site-specifically conjugated to an anti-HER2 antibody (transtuzumab) via a stable protease-cleavable valine citrulline linker. In a phase I trial in US patients (pts) with relapsed or refractory advanced solid tumor, A166 had an acceptable toxicity profile and best objective response rate (ORR) of 36% at efficacious dose levels (Yongheng Liu et al. ASCO 2020). Here we report a phase I study of A166 in Chinese pts with locally advanced or metastatic solid tumors (CTR20181301). Methods: KL166-I-01-CTP is a single arm, open-label, dose-escalation and dose-expansion phase I study evaluating A166 in pts with HER2-expressing locally advanced or metastatic solid tumors. Pts received A166 at doses of 0.1, 0.3, 0.6, 1.2, 2.4, 3.6, 4.8, 6.0 mg/kg IV Q3W. Dose cohorts were expanded at 4.8 and 6.0 mg/kg Q3W. The objectives were to determine the safety and tolerability, pharmacokinetics and antitumor activity of A166. Results: 57 pts (median age 53 [range 26-74], 50 female, 7 male) enrolled from Aug 1, 2018 to Nov 30, 2020. HER2 expression was available for all 57 pts: 51 HER2-positive (3+ or 2+/ISH+), 6 HER2-low (1+ or 2+/ISH-). 61.4% (35/57) had received ≥5 prior lines of therapy. No DLTs were observed in all dose groups. Any grade treatment-related AEs (TRAEs) were documented in 96.5% (55/57) of pts, with 31.6% (18/57) being grade 3 or higher. Common TRAEs were corneal epitheliopathy (73.7%), vision blurred (59.6%), peripheral sensory neuropathy (26.3%), dry eye (21.1%), anemia (19.3%), hyponatremia (19.3%). Most common grade ≥3 TRAEs were corneal epitheliopathy (17.5%), hypophosphatemia (5.3%), and dry eye (5.3%). Four pts had serious AEs, two of which were possibly related to the study drug, including thrombosis and fatigue. TRAEs led to 5.3% (3/57) dose reduction and 5.3% (3/57) treatment discontinuation. One death occurred during the treatment due to progressive disease. At the doses of 0.3-6.0 mg/kg, the exposure of ADC in serum were dose dependent and the mean half-life was found to be 1.17-11.04 days. Serum free toxins was about 0.1% and 0.2% of total A166 (ADC) on a molar basis with the Cycle 1 Cmax and AUC, respectively. At efficacious dose, 36 HER2-positive breast cancer pts with measurable disease were assessed for efficacy, best ORR were 59.1% (13/22) and 71.4% (10/14) in 4.8 and 6.0 mg/kg cohort, respectively. Median progression-free survival (PFS) was not reached, and one patient in 4.8 mg/kg cohort has undergone the treatment for more than 19 months. Conclusions: A166 had a manageable safety profile and high stability in the circulation with much lower acute hematological and gastrointestinal toxicities in terms of incidence rate and grade. It demonstrated promising antitumor activity with clinically meaningful responses in heavily pretreated subjects with HER2-positive breast cancer. Clinical trial information: CTR20181301 .

Cardiac safety of dual anti-HER2 blockade with pertuzumab plus trastuzumab (P+T) in the APHINITY trial.

510 Background: Trastuzumab (T) increases the incidence of cardiac events (CEs) in patients (pts) with early breast cancer (BC). Dual blockade with P+T improves BC outcomes and is the standard of care for high-risk HER2-positive BC pts following the phase 3 APHINITY trial that evaluated the addition of P or placebo (Pla) to T and chemotherapy (CT). We analyzed the cardiac safety of P+T in APHINITY. Methods: APHINITY eligibility required a left ventricular ejection fraction (LVEF) ≥55% at study entry. LVEF assessment was performed every 3 months (mos) during treatment, every 6 mos up to month 36, and yearly thereafter. Primary CE was defined as heart failure (HF) class III/IV and a significant decrease in LVEF of at least 10 percentage points from baseline and to <50%, or cardiac death. Secondary CE was defined as a confirmed significant decrease in LVEF or CEs confirmed by the cardiac advisory board. Results: The safety analysis population consists of 4,769 pts. With 74 mos median follow-up (FU), CEs were observed in 159 pts (3.3%): 83 (3.5%) in the P+T and 76 (3.2%) in Pla+T arms, respectively. Most CEs occurred during anti-HER2 therapy: 123/159 (77.4%) and were asymptomatic or mildly symptomatic LVEF decrease (133/159; 83.6%) (Table 1). There were 2 cardiac deaths in each arm (0.1%). More CEs occurred in pts receiving an anthracycline-based CT compared to those receiving non-anthracycline CT (139 vs. 20 CEs, respectively). Acute recovery from a CE based on subsequent LVEF values was observed in 127/155 pts (81.9%). Conclusions: Dual blockade with P+T does not increase the risk of CE compared to Pla+T alone. The use of anthracycline-based CT increases the risk of a CE; hence non-anthracycline CT may be considered particularly in pts with other cardiovascular risk factors. Clinical trial information: NCT01358877. [Table: see text]

Abstract P4-10-09: Association between pertuzumab (P) induced diarrhea and skin rash and survival outcomes in patients (pts) with HER2-positive metastatic breast cancer enrolled in the CLEOPATRA trial

Abstract Introduction: P and trastuzumab (T) are approved for the treatment of early and advanced breast cancer (BC) pts. Skin rash and diarrhea are frequent adverse events (AE) with P. With the use of lapatinib, we demonstrated that early development of rash correlates with pathologic complete response in the NeoALTTO trial and is both a prognostic and predictive marker in the ALTTO trial. In this subanalysis of the CLEOPATRA trial, we investigated if incidence of rash and diarrhea associates with progression free survival (PFS) or overall survival (OS) and if it can predict the benefit of P+T. Methods: In the CLEOPATRA phase III trial, advanced HER2-positive BC pts where randomized between first-line T vs P+T with at least 6 cycles of docetaxel. We evaluated whether rash (any grade) and/or diarrhea (any grade or grade ≥3) were prognostic in pts receiving P+T and/or predictive of benefit from P+T vs T. To deal with immortal-time bias, we performed a landmark analysis removing pts progressing/dying before a minimum of 46 days (median time to rash/diarrhea occurrence) after treatment initiation (cohort 1), and after end of docetaxel treatment (cohort 2). Survival endpoints were PFS and OS according to study definition. We also investigated if age (<50 or ≥50 years) influences the incidence of diarrhea or rash and if the 2 AEs are associated with one another. For both AEs, the earliest event was considered for analysis. Results: Of the 808 patients in the CLEOPATRA study, cohort 1 included 777 pts (T: 379; P+T: 398) and cohort 2 included 518 pts (T: 232; P+T: 286). The table summarizes the incidence and impact of rash and diarrhea by treatment arm and their effect on outcomes after a median PFS and OS follow-up of 43.6 (IQR 22.9-50.5) and 48.4 (IQR 43.5-55.0) months, respectively, in cohort 1. It shows that rash is prognostic for both PFS and OS (P+T treated) but not predictive of P+T benefit vs T; while diarrhea is not prognostic but predicts P+T PFS benefit. In cohort 2, diarrhea and rash were prognostic for PFS (rash, HR 0.42 [95% CI 0.29-0.60], p<0.001; diarrhea 0.48 [0.35-0.65], p<0.001) and only rash for OS (rash, 0.50 [0.29-0.86], p=0.013; diarrhea, 0.64 [0.39-1.03], p=0.064), but neither were predictive of P+T benefit for PFS (rash, p for interaction of any grade x treatment [pint]=0.695; diarrhea, pint=0.194) nor OS (rash, pint=0.841; diarrhea, pint=0.155). Younger age (<50 years) was not associated with diarrhea (OR 1.01 [95% CI 0.76-1.35], p=0.932), rash (1.07 [0.79-1.45], p=0.69) or both (0.92 [0.67-1.27], p=0.635). Having diarrhea (any grade) was associated with having rash (any grade; p<0.001, Cramér’s V 0.24).Conclusion: Rash is prognostic both for PFS and OS, but not predictive of pertuzumab benefit. Conversely, diarrhea predicts PFS benefit of P when occurring during docetaxel administration but is prognostic only after docetaxel withdrawal. These results may be used to reassure pts experiencing these AEs during treatment. Incidence and Impact of Diarrhea and/or Rash on PFS and OS in cohort 1Patients, n (%)PFS, % at 2 yrsOS, % at 2 yrsPrognostic role (pertuzumab treated)RashYes, any grade169 (42.5)48.587.3No, any grade229 (57.5)37.478.0HR (95% CI), p-value (any grade vs. no)NA0.71 (0.56-0.91), p<0.0060.66 (0.48-0.91), p<0.001DiarrheaYes, any grade238 (59.8)42.683.5No, any grade160 (40.2)41.679.6Yes, grade ≥337 (9.3)50.480.8No, grade ≥3361 (90.7)41.482.1HR (95% CI), p-value (any grade vs. no)NA0.97 (0.77-1.24), p<0.8340.93 (0.68-1.28), p=0.677Predictive role (overall cohort 1)RashYes, any grade271 (34.9)45.584.6No, any grade506 (65.1)28.872.0pintNAp=0.477p=0.711DiarrheaYes, any grade406 (52.2)39.479.3No, any grade371 (47.8)29.673.4Yes, grade ≥357 (7.3)40.574.8No, grade ≥3720 (92.7)34.376.7pint (any grade vs. no)NAp=0.049p=0.564 Citation Format: Arlindo R. Ferreira, Noam Pondé, Matteo Lambertini, Christian Maurer, Samuel Martel, Luis Costa, Evandro De Azambuja. Association between pertuzumab (P) induced diarrhea and skin rash and survival outcomes in patients (pts) with HER2-positive metastatic breast cancer enrolled in the CLEOPATRA trial [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 P4-10-09.

Abstract P1-13-13: The treatment patterns and clinical outcomes of trastuzumab in early human epidermal growth factor receptor 2 (HER2) positive breast cancer in the real-world setting in China

Abstract Background:Several prospective interventional studies have proved the efficacy and safety of trastuzumab in adjuvant treatment in HER2positive breast cancer,while limited data existed to address the treatment patterns and real-world performance of trastuzumab in early HER2 positive breast cancer in China. Methods:We retrospectively analyzed all the pts who were diagnosed with HER2-positive breast cancer,underwent surgery and received adjuvant treatment in National Cancer Center from 2000 to 2012.The treatment patterns and disease free survival (DFS),overall survival (OS) were analyzed respectively. Results:A total of 1398 HER2 positive breast cancer pts were identified.The median follow-up time was 79.1 months.68.5% pts received chemotherapy alone,3.4% pts only received mono trastuzumab,28.2% pts received trastuzumab plus chemotherapy.Among 433 trastuzumab treated pts,64.7% received concurrent trastuzumab with chemotherpy,and 35.3% pts received sequential trastuzumab with chemotherapy Baseline characteristics by Chemotherapy alone and Chemotherapy + Trastuzumab.No(%) of patients characteristicTrastuzumab- (N=957)Trastuzumab+ (N=441)Total (N=1398)Age (years) <=3596 ( 10.0)44 ( 10.0)140 ( 10.0)36 - 50434 ( 45.4)244 ( 55.3)678 ( 48.5)>50427 ( 44.6)153 ( 34.7)580 ( 41.5)Histologic grade I15 ( 1.6)7 ( 1.6)22 ( 1.6)I-II,II480 ( 50.2)224 ( 50.8)704 ( 50.4)II-III,III285 ( 29.8)166 ( 37.6)451 ( 32.3)IDC148 ( 15.5)29 ( 6.6)177 ( 12.7)Other29 ( 3.0)15 ( 3.4)44 ( 3.1)Clinical stage 026 ( 2.7)16 ( 3.6)42 ( 3.0)I259 ( 27.1)108 ( 24.5)367 ( 26.3)II434 ( 45.4)196 ( 44.4)630 ( 45.1)III238 ( 24.9)121 ( 27.4)359 ( 25.7)Hormone receptor status Positive635 ( 66.4)256 ( 58.0)891 ( 63.7)Negative322 ( 33.6)185 ( 42.0)507 ( 36.3) .Trastuzumab plus chemo had significantly longer DFS compared with chemo alone.(85.03%vs72.15%,hazard ratios,HR=0.531,95% confidence interval,95%CI:0.406-0.696, p<0.001).In addition,the concurrent trasuzumab showed the trend with longer DFS compared to the sequential regimen(86.07%vs82.35%,HR=0.843,95%CI:0.515-1.378, p=0.495).Age,tumor size, lymph node status,clinical stage were associated with DFS Results of Cox regression hazard model with treatment groups and patient characteristics on DFSGroupHR95% CIP valueTreatment group Concurrent Trastuzumab0.8430.515-1.3780.495Sequential Trastuzumab Chemotherapy+Trastuzumab0.5310.406-0.696<0.001Chemotherapy alone Age group (years) 0.001<=351.6501.198-2.2730.00236 - 500.8880.702-1.1220.319>50 Histologic grade <0.001I0.5200.210-1.2880.158I-II,II0.5040.379-0.671<0.001II-III,III0.5320.390-0.725<0.001Other0.5140.264-0.9970.049IDC Clinical stage <0.00100.2610.107-0.6370.003I0.2860.207-0.395<0.001II0.4800.379-0.607<0.001III Hormone receptor status 0.022Positive0.7730.621-0.9620.021Negative .OS was also prolonged in trastuzumab plus chemotherapy compared with chemotherapy alone.(93.20%vs85.45%,HR=0.561,95%CI:0.377-0.835, p=0.004). Conclusions:Our study revealed that,there were still more than half of HER2-positive breast cancer pts couldn't reach anti-HER2 therapy in China,the early stage HER2-positive breast cancer pts could significantly benefit from trastuzumab adjuvant therapy in real-world setting. Citation Format: Guo J, Xu B, Li Q, Zhang P, Yuan P, Wang J, Ma F, Fan Y, Cai R, Luo Y, Li Q. The treatment patterns and clinical outcomes of trastuzumab in early human epidermal growth factor receptor 2 (HER2) positive breast cancer in the real-world setting in China [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-13-13.

Abstract P6-03-06: Assessing occult brain metastasis with CT scan or MRI in HER2-positive breast cancer patients at initial diagnosis

Abstract Patients (pts) with HER2-positive breast cancer (BC) have a high risk of developing brain metastases (BM) that might be due to longer survival, low diffusion of Trastuzumab (T) in the CNS or an unknown incidence of occult BM at diagnosis. In a series of metastatic BC, occult metastasis was found in 15 % of the patients and Her2 over expression was an independent risk factor 1.In a series of early BC treated with T the cumulative incidence of BM at 12 and 24 months was 0.6 and 2 % respectively 2. Time to BM was 13.7 months in retrospective study 3 . Systematic cranial magnetic resonance imaging (MRI) in the staging of HER2-positive BC pts detected BM in 22 % of asymptomatic, metastatic pts versus 3.6 % in asymptomatic, non-metastatic pts 4. Early detection of BM decreases the cerebral death rate, but do not prolong survival in metastatic pts 4 . Therefore brain imaging is not recommended at diagnosis. However, retrospective trials assessing the incidence of BM in HER2-positive BC were mainly performed during follow up and not at the initial diagnosis. Pts treated for HER2-positive locally BC with adjuvant sequential chemotherapy including anthracycline and taxane associated with T, classified according to classical prognosis factor as histological subtype, TNM, SBR and hormonal receptor (HR), were systematically assessed for occult BM at initial diagnosis with CT scan or MRI. Retrospectively analyzed for the occurrence of BM was performed. Disease free metastatic survival (DFMS) and overall survival (OS) was estimated by Kaplan Meier estimation. Between March 2006 and July 2013 84 pts were included. The median follow up is 4.7 years. The characteristics pts were median age 57 years [30-86], ductal carcinoma 67 pts (93 %), lobular carcinoma 5 pts (7%), pT1 to 4 respectively 38 (48 %), 28 (36 %), 3 (4%), 9 pts (12%), pN 0 to 3 respectively 44 (54%), 27 (33%), 5 (6%), 5 pts (6%), SBR 1 to 3 respectively 1 (1%), 35 (43%), 43 pts (54%), RO positive 47 pts (59 %), RP positive 27 pts (63%). Thirty eight pts (45 %) had brain imaging at diagnosis or within 5 months of diagnosis. Only one pt with a pT4, pN2, ductal carcinoma, RO+, RP-, SBR 2 presented with BM (2.6 %) at initial diagnosis, with simultaneous lung, liver, bone and nodes metastasis. Four pts (4.8 %) presented BM during follow up, among those two symptomatic pts (2.4 %) as the only site of recurrence at 21 and 28 months. Median DFMS was 8.5 years and median OS was 16.7 years. This is the first report of systemic imaging at initial diagnosis of HER2 positive locally BC pts. The results did not support initial brain imaging in this subset of pts. Only pts with symptoms seems to benefit from brain imaging. Further prospective study should be launched to confirm this observation. Citation Format: Delbaldo C, Sarrade T, Brieau B, Billemont B, Denis J, Cojean-Zelek I, Bornier C, Vincens E. Assessing occult brain metastasis with CT scan or MRI in HER2-positive breast cancer patients at initial diagnosis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-03-06.

Abstract P2-09-11: PAM50 intrinsic subtyping as a predictor of pathological complete response to neoadjuvant trastuzumab-based chemotherapy in early HER2-positive breast cancer

Abstract Background: HER2-positive breast cancer (BC) is a heterogeneous disease from a clinical and biological perspective. Intrinsic subtype defined by gene expression has an important role in determining response to treatment, as seen in several neoadjuvant trials (e.g. CALGB40601, CherLOB, NeoALTTO and PAMELA). However, limited data exist in an off-trial setting. The objective of this study was to evaluate the association of intrinsic subtypes with pathological completed response (pCR) and survival outcomes of a series of HER2-positive patients (pts) homogeneously treated with trastuzumab-based primary chemotherapy (PC) in a single comprehensive cancer center. Methods: Clinical-pathological data were evaluated in a series of 150 consecutive stage II-IIIC (T4d included) HER2-positive BC pts treated in ICO-Hospitalet (Spain) from August-2009 to December-2012 with weekly paclitaxel x12 followed by FEC/3w x 4 and concurrent trastuzumab for a total of 24w. HER2-positivity was considered according to ASCO-CAP 2007 guidelines. pCR was defined as ypT0/isypN0. The expression of 105 BC-related genes, including the PAM50 genes, was determined in baseline and residual formalin-fixed paraffin-embedded tumor samples using the nCounter platform. Intrinsic subtypes were determined by the research-based PAM50 gene expression predictor. Association of variables with pCR or disease-free survival (DFS) was evaluated using logistic regression analyses and cox proportional hazard models.All statistical tests were two-sided and considered significant when p≤0.05. Results: Most pts had T2 (64%) and T4 (20%) tumors and clinically node-positive disease (77%). 53% had hormonal receptor (HR)+ disease. 84 of the 150pts (56%) achieved a pCR; HR-neg was associated with higher pCR rates (72.5%vs 42% in HR+ P<0.001). 90 of the 150 (60%) baseline samples were evaluated. Baseline subtype distribution: HER2-enriched (HER2-E) 63%, Luminal A 11%, Basal-like 8.9%, Normal-like 8.9% and Luminal B 7.8%. Although HER2-E predominated in HR-neg tumors (74%), 53% of HR+ tumors were HER2-E. pCR rates varied according to intrinsic subtype (P<0.001). HER2-E tumors were associated with higher pCR rates compared to non-HER2-E (68.4% vs 33.3%, P<0.001) regardless HR-status. Five of the 8 PAM50 signatures (HER2E, ROR-S, ROR-P, Basal-like and Proliferation score) were associated with pCR, whereas Luminal A was associated with no-pCR (P<0.001). With a median follow-up of 6.6 years, HER2-E subtype was associated with a better DFS compared to non-HER2-E (5-year DFS 92.4% vs 75.9%; HR= 0.27; 95% CI 0.08-0.91; P=0.034). Finally, 28 of the 66 (42.4%) surgical specimens with residual disease were studied. Residual subtype distribution was: Normal-like (50.0%), Luminal A (32.1%), HER2-E (14.3%) and Luminal B (3.5%). Conclusions: In this consecutive series of HER2-positive BCtreated homogeneously with neoadjuvant trastuzumab-based PC, all of the main intrinsic molecular subtypes were identified with a predominance of HER2-E. HER2-E was significantly associated with pCR and survival outcome. Distribution of the intrinsic subtypes in residual disease differed from untreated tumors. Citation Format: Pernas S, Petit A, Climent F, Pare L, Perez-Martin J, Ventura L, Galvan P, Falo C, Morilla I, Fernandez-Ortega A, Stradella A, Pascual T, Gil-Gil M, Prat A. PAM50 intrinsic subtyping as a predictor of pathological complete response to neoadjuvant trastuzumab-based chemotherapy in early HER2-positive breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-11.

Trastuzumab-related subclinical cardiotoxicity in patients with early stage HER2-positive breast cancer: A retrospective single-center cohort study.

10123 Background: Trastuzumab-based therapy (TT) is standard treatment for HER2-positive breast cancer (HBC). Subclinical cardiotoxicity (SCTx), defined as asymptomatic decline in left ventricular ejection fraction (LVEF) > 10% to < 50%, has been reported in up to 30 % of HBC patients (pts) receiving TT. Objectives included: determine prevalence of SCTx; associated risk factors (RF); and completion rates of TT in pts with HBC referred to a cardio-oncology clinic (COC). Methods: HBC patients receiving TT referred to the Ottawa Hospital COC were included. Demographics, TNM staging, performance status, stage, cardio-vascular (CV) RF (history of heart disease, hypertension, smoking, dyslipidemia, and diabetes), cardiac medications (CM) (ACE-inhibitors, beta-blockers), baseline LVEF, previous cancer therapy, baseline anthracycline exposure, previous radiation therapy (RT) (including mediastinal RT) were collected. LVEF was evaluated by ECHO or MUGA. Rate of successful completion of TT among pts with SCTx was determined. Risk ratio (RR) and logistic regression analysis was performed. Results: 240/408 BC pts referred to the COC (2008-2016) had HBC and 163/240 (68%) were referred with SCTx while on TT. 139/163 (85 %) pts with SCTx recovered after COC assessment: 77/163 (47%) pts were prescribed CMs. A significantly higher proportion of recovery was observed in pts who did not require CM (0.92 vs 0.78, p = 0.012; RR = 0.85, 95%CI:0.74-0.91). A total of 129/163 (79%) pts who experienced SCTx finished a full course of TT. Regression analysis found baseline LVEF, diabetes, and diastolic blood pressure as significant RFs for SCTx. There were no independent predictors for recovery after asymptomatic drop in LVEF while on TT. Diabetes (OR:2.97, 95%CI:1.3-6.8) and left chest wall RT (OR:2.4, 95%CI:1.1-5.6) significantly increased risk of permanent TT interruption in pts with asymptomatic drop in LVEF. Conclusions: The majority of HBC pts who experience SCTx can safely complete a full course of TT; many without use of CMs. While CV RFs were associated with increased risk of SCTx, this did not impact CV recovery after asymptomatic drops in LVEF.

HER2-amplification level and tumor-infiltrating lymphocytes in breast cancer patients treated with neoadjuvant trastuzumab.

596 Background: Trastuzumab-based neoadjuvant treatment (TNT) has shown clinical benefit in terms of both overall response and pathologic complete response (pCR). In particular, TNT is indicated for women with HER2-positive locally advanced breast cancer and allows for breast-conserving surgery. In addition, some evidences show that TIL may play a role in the response to anti-HER2 therapy. This study aims to investigate the possibility that HER2-amplification level and high level of TIL are predictive factors of response to TNT in locally advanced breast cancer. Methods: 75 HER2-positive breast cancer pts treated from 2009 to 2014 with TNT were included in this retrospective study. Preoperative biopsies or cytological samples were collected and analyzed by dual-color fluorescence in situ hybridization (FISH) to determine HER2-amplification. We used the cut-off recommended by ASCO/CAP 2013. TIL were evaluated in both pre- and post-treatment specimen; TIL score was assessed on hematossilin-eosin slides based on Salgado et al. recommendations. Clinical-pathological characteristics were recorded. Statistical analyses were performed using IBM-SPSS (V21.0). A p-value < 0.05 was considered statistically significant. Results: Among the 75 cases, HER2-amplification level was low (LA) in 14 cases (19%), intermediate (IA) in 17 cases (23%) and high (HA = gene copy number > 10 or clusters of signals) in 44 cases (59%). TNT achieved pCR in 19 of 75 tumors and correlated with HER2-amplification level (36% HA vs 6% IA vs 14% LA, p-value = 0.01). TILs levels were evaluated in 58 biopsies and surgical specimens: only 6 pts were classified as lymphocyte-predominant breast cancer (TILs ≥ 50%). The probability of developing pCR increased with TILs levels, although a statistically significant correlation was not achieved. No correlation was found between TIL and HER2-amplification levels. Age, stage, tumor grade and hormone receptor status were not significantly correlated to pCR. Conclusions: We show that while HER2-amplification level correlates positively with pCR to TNT, high level of TIL is not predictive of better response to trastuzumab in locally advanced HER2-positive disease.

Abstract P1-14-09: Long term survival of locally advanced breast cancers (LABC) treated with neoadjuvant treatment, results of a multicenter randomised phase II study (Remagus 02 trial)

Abstract Backgound : The primary analysis of the REMAGUS-02 multicenter randomized phase II trial demonstrated that celecoxib did not improve pCR rates in pts with HER2-negative localized invasive breast cancer (BC), whereas trastuzumab increased pCR rates in HER2-positive ones [Pierga BCRT 2010]. We report here the long-term follow-up results of this trial for disease free survival (DFS) and overall survival (OS). Patients and methods: From May 2004 to October 2007, 340 stage II-III BC patients were randomly assigned to receive 4 cycles (c) of epirubicin–cyclophosphamide q 3 w followed by 4 c of docetaxel q 3 w +/- trastuzumab in HER2 positive pts (120 pts) or +/- celecoxib in HER2 negative pts (n=220). From September 2005, all pts with HER2 positive BC received adjuvant T for a total of 18 c (n=106). Patients with hormone receptors (HR) positive tumor received adjuvant endocrine treatment according to menopausal status Results: With a median follow up of nearly 8 years (94.4 months, 20-127m), 112 relapses and 75 deaths have been observed (median DFS and OS not reached). Eight years DFS and OS were respectively 63 % [57%-71%] and 75 % [70%-81%] in HER2 negative group; and 75% [67%-83%] and 82 % [74%-90%] in HER2 positive group. DFS was significantly higher in HER+ pts than in HER2-(HR: 0.64 [0.42-0.99], p=0.042), whereas OS did not differ significantly (HR: 0.67, [0.41-1.11], p=0.123). In the overall population, progesterone receptor (PgR) positivity was associated with a better DFS (p=0.012) and OS (p&amp;lt;0.001) as compared to ER+/PgR- (DFS: HR=2.07 [1.27-3.39]; OS: HR=2.53 [1.3-4.92]) and ER-/PR-; DFS: HR=1.56 [0.98-2.46]; OS: HR: 3.34 [1.87 – 5.97]. In the ER-/PR- group, DFS reached a "plateau" after three years follow-up, while the annual risk of relapse remained constant in the ER+/PR- subgroup. In the HER2- subgroup, no effect of neoadjuvant celocoxib was observed on survival, neither in intention to treat (ITT) nor in per protocol analyses. In the multivariate analysis clinical stage (T3/T4 versus T2, HR: 1.92 [1.209 - 3.05], p=0.006), PgR status (positive versus negative HR : 0.52, [0.32-0.84], p=0.007) and pCR (yes vs no, HR : 0.213 [0.066-0.687], p=0.01) were significant predictors of DFS. In the HER2+ subgroup, neoadjuvant versus adjuvant trastuzumab was not significantly associated with DFS, neither in the ITT, nor in the per protocol analysis. Conclusion: Celecoxib was not associated with pCR or survival benefit when added to conventional neoadjuvant CT in Her2-negative BC pts. Lack of PgR expression is a major prognostic factor for survival. Neoadjuvant versus adjuvant trastuzumab increased pCR rates but did not change significantly DFS and OS of HER2 positive BC pts. Citation Format: Giacchetti S, Hamy-Petit A-S, Delaloge S, Brain E, Berger F, Mathieu M-C, de Cremoux P, Bertheau P, Guinebretière J-M, Saghatchian M, Tembo O, Marty M, Pierga J-Y. Long term survival of locally advanced breast cancers (LABC) treated with neoadjuvant treatment, results of a multicenter randomised phase II study (Remagus 02 trial). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-09.

Abstract P4-12-21: Trastuzumab cardiac toxicity and HER2 polymorphism: A case-control study

Abstract Background: Gene polymorphisms of HER2 have been identified. Their impact on the risk of breast cancer, the response and the toxicity of anti HER2 treatments have been studied. According to a small report of Beauclair (2007), the polymorphism at codon 655 of the HER2 gene may represent a risk factor for cardiotoxicity induced by Trastuzumab (T). In this study, we evaluated the incidence of the Val655Ile polymorphism in (neo)adjuvant breast cancer patients (pts) with cardiac toxicity and in matched patients without cardiac toxicity. Methods: 40 HER2 positive breast cancer pts treated between 2008 and 2011 by (neo)adjuvant sequential chemotherapy plus T developed a cardiac toxicity. Definition of cardiac toxicity was a 10% absolute decrease in LVEF (Left Ventricular Ejection Fraction) or a decrease in LVEF to a threshold value of &amp;lt;50%. 84 pts without cardiac toxicity were matched according to age, received dose of anthracyclin and T, BMI and cardiac risk factors. Polymorphism of Her2 gene in codon 655 was searched by PCR on lymphocyte DNA from blood samples in this population and in the control group. Genomic DNA was extracted from EDTA blood samples (300ml) on the MagNa Pure Compact instrument. The HER2 Ile655Val (rs1163201) polymorphism was detected by sequencing using a 3730 DNA Analyser. Results: In the cardiac toxicity group 2,5% (1 patient) presented a genotype Val/Val at HER2 codon 655, 40% (16) were heterozygous (Ile) and 57,5% (23) had the wild type. In the control population, the incidence was respectively 3,6% (3 pts), 36,9% (31) and 59,5% (50). No differences were found between the both groups (p = 0,91). Conclusions: The incidence of mutated, heterogeneous and wild type genotype was similar to the literature. We could not confirm the Val allele at HER2 codon 655 as a risk factor of cardiotoxicity. HER2 polymorphism cannot be used in clinical practice to predict the risk of cardiac toxicity of T. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-21.

Abstract P2-16-02: Bevacizumab, etoposide, and cisplatin (BEEP) is highly effective in brain metastases of HER2 positive breast cancer progressing from whole brain radiotherapy - Subgroup analysis of a multi-center phase II study

Abstract Background: We have recently reported that starting bevacizumab (BE) 1 day before chemotherapy could further induce tumor vascular normalization, thereby significantly enhanced the activity of etoposide (E) and cisplatin (P) in breast cancer patients (pts) with progressing brain metastases after whole brain radiotherapy (WBRT) (ESMO 2013). Lapatinib plus capecitabine is the only proven active regimen for the treatment of brain metastases of HER2 positive breast cancer, with a central nerve system (CNS) objective response rate (ORR) of 18-38% and median time to progression (TTP) of 3.6-5.1 months (mo) in those who had had prior WBRT. Material and methods: Twenty-three HER2 positive breast cancer pts with progressing brain metastases after WBRT were enrolled from Jan 2011 to Jan 2013. Protocol treatment was given in 21 day cycles: BE 15 mg/kg on day 1, E 70 mg/m2/day from day 2 to day 4, and P 70 mg/m2 on day 2 (BEEP regimen), for a maximum of 6 cycles. The primary endpoint was a centrally assessed CNS ORR. A CNS objective response was defined as a ≥50% reduction in the volumetric sum of all measurable CNS lesions in the absence of increasing steroid use, development of new CNS lesion, or progressive neurologic symptoms. This trial is registered with ClinicalTrials.gov (NCT01281696). Results: Median age was 55.1 (range 33-75); 9 pts were ER+, 14 pts were ER-; 15 pts were ECOG 0-2 (65.2%), and 8 pts were ECOG 3 (34.8%). All of them had previous exposure to trastuzumab, and 20 (87.0%) of them had received trastuzumab containing regimen for the treatment of metastatic disease. Eleven pts (47.8%) received lapatinib treatment before enrollment into this trial. The median lines of chemotherapy for the treatment of metastatic disease were 3 (range 1-8). The median BEEP treatment cycles were 6 (range 1-6). Sixteen of 23 pts (69.6%; 95%CI 47.1-86.8) achieved CNS objective response, including 6 pts (26.1%) with ≥80% and 10 pts (43.5%) with 50-80% CNS volumetric reduction, respectively. Five pts (21.7%) had 20-50% CNS volumetric reduction. Seven of 11 (63.6%) who were refractory to lapatinib treatment had CNS tumor response, and 9 of 12 (75.0%) who were lapatinib naive had CNS ORR. With median follow-up of 12.1 months (mo), the median time to progression was 7.7 mo (95% CI 6.6-8.8), and overall survival was 11.8 mo (95% CI 7.0-16.6) among the 23 pts. Only 3 pts (13.0%) had disease progression during protocol treatment. Grade 3/4 toxicities (≥1%) included neutropenia, leukopenia, thrombocytopenia, infection, anemia, and in 32.7%, 14.0%, 8.4%, 8.4%, and 5.6% per cycles, respectively. Ten pts (43.5%) needed dose reduction of E to 60 mg/m2 and P to 60 mg/m2, and 2 pts discontinued from treatment due to toxicity. Conclusions: BEEP regimen has a significant anti-tumor effect for HER2 positive breast cancer with brain metastasis which progresses after WBRT. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-02.

Abstract 2389: Positive or negative clinical implications of PI3K/Akt/mTOR pathway activation for predicting patient response to targeted therapy using multiplexed protein imaging of tumor tissue.

Abstract Background: In this ongoing clinical exploratory study, FFPE tissue sections are probed for protein biomarkers along the PI3K/Akt/mTOR pathway. A panel of assays was developed using Layered Immunohistochemistry (L-IHC). L-IHC allows for concurrent measurement of 6-8 proteins (total and/or phosphorylation sites) using a single tissue section. The goal was to discover applications of the technique based on complementary rationales about the implications of pathway activation. Those were: 1) in a scenario where the test indicates drug target activation, analysis for a positive response to an mTOR-targeted tyrosine kinase inhibitor (everolimus and/or temsirolimus) in kidney cancer; or 2) analysis for predicting no response to a HER2-targeted drug (trastuzumab) in breast cancer, assuming a scenario where the test would indicate activation of a functional by-pass pathway. Methods: FFPE pre-treatment tissue samples from patients (pts) with advanced renal cell carcinoma (aRCC) treated with temsirolimus and/or everolimus, and trastuzumab treated HER2-positive breast cancer pts were studied. In L-IHC tissue-transfer layers, the intensity of specific protein biomarker signals in the cancer regions is visually scored. The expression levels are then summed and correlated with the patient's clinical outcome status. Results: In the trastuzumab study, four biomarkers were determined to correlate with patient response. A total of 32 responders and 13 non-responders have been analyzed to date. The sum score for a 4-biomarker panel discriminated between responders and non-responders. The test correctly identified 28/32 responders and 10/13 non-responders for a sensitivity of 87%, specificity of 76%, and an accuracy of 81%. In the mTOR inhibitor study, 35 RCC cases were analyzed, and a composite score based on 6 biomarkers was found to correlate to patient response. 11/14 OR/SD pts (sensitivity 79%) and 18/21 PD pts (specificity 86%). Conclusions: These results indicate that multiplexed protein analysis of tumor tissue is capable of providing scenario-specific information, which could help guide targeted therapy with either a positive or a negative clinical significance. Funding source: Supported in part by NCI Grant 5R44CA123994-06 and by 20/20 GeneSystems. Citation Format: Alexandrine Derrien-Colemyn, Soon Park, John Gillespie, Michael Lebowitz, Peter Tunon. Positive or negative clinical implications of PI3K/Akt/mTOR pathway activation for predicting patient response to targeted therapy using multiplexed protein imaging of tumor tissue. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2389. doi:10.1158/1538-7445.AM2013-2389