Rocío Urbano Cubero

An early diagnosis of cancer is fundamental not only in regard to reducing its mortality rate but also in terms of counteracting the progression of the tumor in the initial stages. Breast cancer (BC) is the most common tumor pathology in women and the second deathliest cancer worldwide, although its survival rate is increasing thanks to improvements in screening programs. However, the most common techniques to detect a breast tumor tend to be time-consuming, unspecific or invasive. Herein, the use of untargeted hydrophilic interaction liquid chromatography-mass spectrometry analysis appears as an analytical technique with potential use for the early detection of biomarkers in liquid biopsies from BC patients. In this research, plasma samples from 134 BC patients were compared with 136 from healthy controls (HC), and multivariate statistical analyses showed a clear separation between four BC phenotypes (LA, LB, HER2, and TN) and the HC group. As a result, we identified two candidate biomarkers that discriminated between the groups under study with a VIP > 1 and an AUC of 0.958. Thus, targeting the specific aberrant metabolic pathways in future studies may allow for better molecular stratification or early detection of the disease.

PURPOSE: HER2-targeted therapies have dramatically improved outcomes of patients with HER2-positive breast cancer (BC), as demonstrated in neoadjuvant trials. This study aims to provide real-world evidence on the use and effectiveness of combined pertuzumab, trastuzumab and chemotherapy (CT) in early-stage HER2-positive BC. METHODS: A retrospective, multicentre study was conducted on patients diagnosed with HER2-positive early BC treated with neoadjuvant pertuzumab and trastuzumab plus CT at 13 Spanish sites. The primary endpoint was pathological complete response (pCR). RESULTS: A total of 310 patients were included. Pertuzumab and trastuzumab were combined with anthracyclines and taxanes, carboplatin and docetaxel, and taxane-based CT in 77.1%, 16.5%, and 6.5% of patients, respectively. Overall, the pCR rate was 62.2%. The pCR was higher amongst patients with hormone receptor-negative tumours and with tumours expressing higher levels of Ki-67 (> 20%). After postoperative adjuvant treatment, 13.9% of patients relapsed. Those patients who did not achieve pCR, with tumours at advanced stages (III), and with node-positive disease were more likely to experience distant relapse. Median overall survival (OS) and distant disease-free survival (D-DFS) were not reached at the study end. The estimated mean OS and D-DFS times were 7.5 (95% CI 7.3-7.7) and 7.3 (95% CI 7.1-7.5) years, respectively (both were significantly longer amongst patients who achieved pCR). Grade 3-4 anti-HER2 related toxicities were reported in six (1.9%) patients. CONCLUSION: Neoadjuvant pertuzumab and trastuzumab plus CT achieve high pCR rates in real-life patients with HER2-positive early BC, showing an acceptable safety profile. Innovative adjuvant strategies are essential in patients at high risk of distant disease recurrence.

Abstract Background: Pertuzumab (P) has been aproved in neoadjuvant setting for HER2 positive early breasta cancer patients in association with Trastuzumab (T) and chemotherapy. Diverse studies support this combination as NeoSphere, Tryphaena, GeparSepto or Berenice trial. Some of these studies combine P - T with taxanes and sequencing anthracyclines, and other use antraciclines-free regimen as Carboplatine-Docetaxel-P-T. The patologic complete response (pCR) showed achieve percentages from 45.8 % to 66.6% depending on chemotherapy combination. In Spain, the approval of new drugs is a national issue, but sometimes regional regulatory agencies could modify some indications. We have carry out this study in routine patients as our daily clinical practice. Aims: This is a retrospective and multicentric study that has investigated the clinical characteristics, treatment patterns, safety and clinical outcomes for patient with HER-2 positive early breast cancer patients. Methods: We have collected all HER2 positive early breast cancer patients treated with P in neoadjuvant setting in our hospitals. The effect of adding Pertuzumab on pCR was analyzed, as well as other predictive factors of response using logistic regression analyses. Results: A total of 298 patients met the selection criteria. The median age was 50 years (range 24-88 years), 54,2% were premenopausic. 4 patients were stage I, 194 patients stage II, 95 patients were stage III and one patient was stage IV. 76,3% of the patient had a ki67 >20%. The majority of the patient received anthracyclines and taxanes with P and T regimen (80,7%), 13,2% received carboplatin-docetaxel-P-T combination and only 6,1% received taxane-P-T. 292 patients were analysed for response. pCR was seen in 61,7 % of the patients, dividing by hormonal receptor (HR) status, pCR was 53,29% in HR-positive and 72,14% in HR-negative. 63,4% of the patients received breast conservative surgery. Grade 3-4 chemo-related toxicity was presented in 14,2% of patients, 3 patients presented cardiac toxicity. Different treatments patterns were seen between hospitals: only 15 patients (5,1%) complete adjuvant Pertuzumab, 4 patients (1,4%) received adjuvant Neratinib and 2 patients (0,7%) received adjuvant TDM1. Only 12 patients (4,1%) has presented a distant recurrence, 6 of them (50%) had achieved a previous pCR. Conclusion: In our knowledge, this is the biggest real-world-data presented until this year, for Pertuzumab in the neoadjuvant setting of HER2 positive breast cancer patients. Our results are consistent with those published in previous clinical trial. pCR by subtypepCR NOpCR YESTotalLuminal B HER2+7181152HER2+39101140Total110182292 Citation Format: Alejandro Falcón González, Rocío Álvarez Ambite, Elisenda Llabrés Valenti, Rocío Urbano Cubero, Maria del Carmen Álamo de la Gala, Antonia Martínez Guisado, Carlos José Rodríguez González, Marta Amérigo Góngora, Encarnación González Flores, Salvador Gámez Casado, María Valero Arbizu, Alicia Quilez Cutillas, Josefina Cruz Jurado, Pedro Sánchez Rovira, Fernando Henao Carrasco, Javier Salvador Bofill, Manuel Ruiz Borrego. Neopersur: Neoadjuvant pertuzumab in a real world data population in the south of Spain [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 P1-18-29.

Pertuzumab (P) has been approved in neoadjuvant setting for HER2-positive early breast cancer patients (pts) in association with Trastuzumab (T) and chemotherapy. Diverse studies support this treatment. The pathologic complete response (pCR) showed achieve percentages from 45.8 % to 66.6% depending on chemotherapy combination. This is a retrospective and multicentric study. We have collected all HER2-positive early breast cancer pts treated with P in neoadjuvant setting in our hospitals between 2015 and 2018. The effect of adding P on pCR was analyzed, as well as other predictive factors of response using logistic regression analyses. Kaplan Meier analysis has been used for survival analysis. A total of 310 pts met the selection criteria. The median age was 51 years (22-88 years), 54,5% were premenopausal. 4 pts were stage I, 204 pts stage II, 101 pts were stage III. The majority of the patient received anthracyclines and taxanes with P and T regimen (77,1%), 16,5% received carboplatin-docetaxel-P-T combination and 6,5% received taxane-P-T. 307 pts were analysed for response. pCR was seen in 62,2 % of the pts, dividing by hormonal receptor (HR) status, pCR was 53,8% in HR-positive and 71,1% in HR-negative. Treatment was well tolerated with only 14.8 % G3-4 adverse events related to chemotherapy and 1.9% related to antiHER2 therapy. Different adjuvant treatments patterns were seen between hospitals. After a follow-up of 7,5 years, 43 pts (13,9%) had a distant relapse, 16 of them (37,2%) had achieved a previous pCR. 38,5% had CNS recurrence and 61,5% non-CNS recurrence. In multivariate analysis non-pCR pts have 3.9 relative risk of experience disease relapse event (p 0.0001; 1.84-8.88), and patients with stage III at diagnosis have 4.3 relative risk (p 0.00004; 2.15-8.75). Disease free-survival (DFS) rates at 7.5 years is 86.4 %. After separating between pCR outcomes, results were statistical significative (p < 0.0001) with DFS rates of 89.4% in pCR pts and 70.6% in non-pCR pts. In our knowledge, this is the first real-world study that shows survival results for adding Pertuzumab in the neoadjuvant setting of HER2-positive breast cancer patients. Our results are consistent with those previously published.

Activation of the phosphatidylinositol-3-kinase (PI3K) pathway is responsible of activating the phosphorylation cascade that regulates cell survival and metabolism. Mutations in this pathway may occur in 28-46% of HR+/HER2- advanced breast cancers. It is known that the presence of this mutation confers a worse prognosis. We set out to analyze if PI3K mutations in different exons confer resistance to treatments directed against this target and to cyclin inhibitors (inh-CDK4/6). We have analyzed 96 patients with advanced breast cancer HR+/HER2- subsidiaries of treatment with PI3K-targeted therapy in the hospital of Jaén from February/20 to January/23. To detect PIK3CA mutations we used the cobas ® diagnostic kit that detects: exons 1 (R88Q), 4, 7 (C420R), 9 (E542K, E545K/A/D/G, Q546E/R) and 20 (H1047R/Y/L). We obtained 26% mutations in PI3K (5% exon 1, 40% exon 9, 55% exon 20). All in women with a mean age at diagnosis of 48 years and 56 at diagnosis of metastases, located at bone 65%, lung 35%, liver 23% and CNS 4% All patients have been treated with inh-CDK4/6. The median progression-free survival (mSLP) is 17 months (1-60). In patients with exon 1 mutation, mSLP is 25 months, in exon 9, 13 (2-43) and in exon 20, 19 (1-60) 60% of the patients have progressed to inh-CDK4/6 and as next treatment we used alpelisib. In 58% corresponds to 2 line in metastatic disease. The mSLP is 5 months (1-22) with a median follow-up of 14 months (1-34) and 69% of events. In patients with mutation in exon 1 the mSLP is 2 months, in exon 9, 5 (1-13) and in exon 20, 9 (2-22). Treatment was associated with an antiestrogen (77%) with a mSLP 7 months (1-22) or an aromatase inhibitor with a mSLP 3 months (2-10). 53% suffered grade 3 adverse effects (G3 AE): hyperglycemia (80% exon 9, 16% exon 20), diarrhea (20% exon 9) and skin rash (16% exon 20). 14% discontinued treatment due to toxicity. The PFS with alpelisib is lower than reported in the SOLAR1 study and is similar to Bylieve study, whose population is most similar to our sample. Exon 20 carriers are those who obtain a higher PFS, as well as those who receive it with an antiestrogen. Exon 9 carriers have a higher rate of G3 AE With respect to inh-CDK4/6, the PFS corresponds to the literature, with exon 20 carriers obtaining a higher PFS.