Optimal [18F]FDG PET/CT Cutoff for Pathologic Complete Response in HER2-Positive Early Breast Cancer Patients Treated with Neoadjuvant Trastuzumab and Pertuzumab in the PHERGain Trial.

The PHERGain trial investigated the potential of metabolic imaging to identify candidates for chemotherapy deescalation in human epidermal growth factor receptor 2 (HER2)-positive, invasive, operable breast cancer with at least 1 breast lesion evaluable by [18F]FDG PET/CT. [18F]FDG PET/CT responders were defined as patients with an SUVmax reduction (ΔSUVmax) of at least 40% in all of their target lesions after 2 cycles of trastuzumab and pertuzumab (HP) (with or without endocrine therapy). In total, 227 of 285 patients (80%) included in the HP arm showed a predefined metabolic response and received a total of 8 cycles of HP (with or without endocrine therapy). Pathologic complete response (pCR), defined as ypT0/isN0, was achieved in 37.9% of the patients. Here, we describe the secondary preplanned analysis of the best cutoff of ΔSUVmax for pCR prediction. Methods: Receiver-operating-characteristic analysis was applied to look for the most appropriate ΔSUVmax cutoff in HER2-positive early breast cancer patients treated exclusively with neoadjuvant HP (with or without endocrine therapy). Results: The ΔSUVmax capability of predicting pCR in terms of the area under the receiver-operating-characteristic curve was 72.1% (95% CI, 65.1-79.2%). The optimal ΔSUVmax cutoff was found to be 77.0%, with a 51.2% sensitivity and a 78.7% specificity. With this cutoff, 74 of 285 patients (26%) would be classified as metabolic responders, increasing the pCR rate from 37.9% (cutoff ≥ 40%) to 59.5% (44/74 patients) (P < 0.01). With this optimized cutoff, 44 of 285 patients (15.4%) would avoid chemotherapy in either the neoadjuvant or the adjuvant setting compared with 86 of 285 patients (30.2%) using the original cutoff (P < 0.001). Conclusion: In the PHERGain trial, an increased SUVmax cutoff (≥77%) after 2 cycles of exclusive HP (with or without endocrine therapy) achieves a pCR in the range of the control arm with chemotherapy plus HP (59.5% vs. 57.7%, respectively), further identifying a subgroup of patients with HER2-addicted tumors. However, the original cutoff (≥40%) maximizes the number of patients who could avoid chemotherapy.

Maintained complete response to talazoparib in a BRCA-2 mutated metastatic luminal breast cancer: case report and review of literature.

PARP inhibitors are progressively becoming a part of our therapeutic arsenal against BRCA-defective tumors, because of their capacity to induce synthetic lethality in cells with a deficiency in the homologous recombination repair system. Olaparib and talazoparib have been approved for metastatic breast cancer in carriers of germline BRCA mutations, which are found in approximately 6% of patients with breast cancer. We report the case of a patient with metastatic breast cancer, carrier of a germline mutation in BRCA2, with a complete response to first-line treatment with talazoparib, maintained after 6 years. To the best of our knowledge, this is the longest response reported with a PARP inhibitor in a BRCA-mutated tumor. We have made a review of literature, regarding the rationale for PARP inhibitors in carriers of BRCA mutations and their clinical relevance in the management of advanced breast cancer, as well as their emerging role in early stage disease, alone and in combination with other systemic therapies.

Trastuzumab deruxtecan in patients with central nervous system involvement from HER2-positive breast cancer: The DEBBRAH trial.

BACKGROUND: Trastuzumab deruxtecan (T-DXd) has shown durable antitumor activity in pretreated patients with HER2-positive advanced breast cancer (ABC), but its efficacy has not yet been evaluated in patients with active brain metastases (BMs). DEBBRAH aims to assess T-DXd in patients with HER2-positive or HER2-low ABC and central nervous system involvement. METHODS: This ongoing, five-cohort, phase II study (NCT04420598) enrolled patients with pretreated HER2-positive or HER2-low ABC with stable, untreated, or progressing BMs, and/or leptomeningeal carcinomatosis. Here, we report findings from HER2-positive ABC patients with non-progressing BMs after local therapy (n = 8; cohort 1), asymptomatic untreated BMs (n = 4; cohort 2), or progressing BMs after local therapy (n = 9; cohort 3). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days. The primary endpoint was 16-week progression-free survival (PFS) for cohort 1 and intracranial objective response rate (ORR-IC) for cohorts 2 and 3. RESULTS: As of October 20, 2021, 21 patients received T-DXd. In cohort 1, 16-week PFS rate was 87.5% (95%CI, 47.3-99.7; P < .001). ORR-IC was 50.0% (95%CI, 6.7-93.2) in cohort 2 and 44.4% (95%CI, 13.7-78.8; P < .001) in cohort 3. Overall, the ORR-IC in patients with active BMs was 46.2% (95%CI, 19.2-74.9). Among patients with measurable intracranial or extracranial lesions at baseline, the ORR was 66.7% (12 out of 18 patients; 95%CI, 41.0-86.7), 80.0% (95%CI, 28.4-99.5) in cohort 1, 50.0% (95%CI, 6.7-93.2) in cohort 2, and 66.7% (95%CI, 29.9-92.5) in cohort 3. All responders had partial responses. The most common adverse events included fatigue (52.4%; 4.8% grade ≥3), nausea (42.9%; 0% grade ≥3), neutropenia (28.6%; 19% grade ≥3), and constipation (28.6%; 0% grade ≥3). Two (9.5%) patients suffered grade 1 interstitial lung disease/pneumonitis. CONCLUSIONS: T-DXd showed intracranial activity with manageable toxicity and maintained the quality of life in pretreated HER2-positive ABC patients with stable, untreated, or progressing BMs. Further studies are needed to validate these results in larger cohorts.

Prolonged Responses With Trastuzumab Emtasine Treatment of Human Epidermal Growth Factor Receptor 2-positive Metastatic Breast Cancer Refractory to Trastuzumab and Pertuzumab: Systematic Review of Evidence.

Amplification of human epidermal growth factor receptor 2 (HER2) occurs in around 25% of breast cancers and has been associated with aggressive disease. Here, we summarize published evidence on efficacy and prolonged responses with trastuzumab emtansine (T-DM1) after first-line trastuzumab plus pertuzumab and provide possible factors related to prolonged responses to T-DM1. We conducted a literature search using PubMed, and articles that were published in English between July 1, 2012 and December 31, 2019 were included. A review of the bibliography included in the articles found was made. Nine articles were eligible; 2 were case reports, and the remaining 7 were nonexperimental studies, all retrospective. Five were multi-center works. The total number of patients was 796 (276 received pertuzumab). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used for this systematic review. The population included was heterogeneous among studies according to hormone receptor status, de novo metastatic disease, number of metastatic sites, visceral involvement, brain metastasis, previous neoadjuvant or adjuvant trastuzumab, and line of therapy in which T-DM1 was administered. Less efficacy in terms of responses (overall response rate, 18%-33%) and progression-free survival (4-6 months) with second-line T-DM1, in patients pretreated with pertuzumab, was shown (if compared with the EMILIA trial). The results are more similar to those of the TH3RESA trial (very pretreated population). Prolonged treatments (6 months or more) were observed in at least 17% of cases. The efficacy of T-DM1 after a previous pertuzumab treatment is lower than if pertuzumab is not given, although prolonged responses are observed in this setting.

Myocarditis and carotidynia caused by Granulocyte-Colony stimulating factor administration.

A 59 year-old woman was treated with adjuvant chemotherapy for triple negative breast cancer (TNBC) stage IB. She received pegfilgrastrim as secondary prophylaxis of neutropenia. After administration of pegfilgrastrim on day 11, she was hospitalised because of carotidynia and myocarditis that improved with antibiotics and steroids as an infection was suspected. Once she was recovered, another cycle of chemotherapy with pegfilgrastrim was administrated. At this time, the patient presented to our hospital with fever, odynophagia and chest pain, with diagnosis of myocarditis coupled with cardiogenic shock. She received antibiotics and steroids, advanced life support and also a pericardial window was done, with recovery of her condition. After a complete evaluation and exclusion of other possible aetiologies, we concluded that pegfilgrastrim was responsible for inducing carotidynia and myocarditis. Few cases have been published about Granulocyte-Colony stimulating factor (G-CSF) induced carotidynia and aortitis. However, this is the first reported case about G-CSF induced myocarditis and carotidynia.

Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR+/HER2- Breast Cancer.

PURPOSE: neoMONARCH assessed the biological effects of abemaciclib in combination with anastrozole in the neoadjuvant setting. PATIENTS AND METHODS: Postmenopausal women with stage I-IIIB HR+/HER2- breast cancer were randomized to a 2-week lead-in of abemaciclib, anastrozole, or abemaciclib plus anastrozole followed by 14 weeks of the combination. The primary objective evaluated change in Ki67 from baseline to 2 weeks of treatment. Additional objectives included clinical, radiologic, and pathologic responses, safety, as well as gene expression changes related to cell proliferation and immune response. RESULTS: Abemaciclib, alone or in combination with anastrozole, achieved a significant decrease in Ki67 expression and led to potent cell-cycle arrest after 2 weeks of treatment compared with anastrozole alone. More patients in the abemaciclib-containing arms versus anastrozole alone achieved complete cell-cycle arrest (58%/68% vs. 14%, P < 0.001). At the end of treatment, following 2 weeks lead-in and 14 weeks of combination therapy, 46% of intent-to-treat patients achieved a radiologic response, with pathologic complete response observed in 4%. The most common all-grade adverse events were diarrhea (62%), constipation (44%), and nausea (42%). Abemaciclib, anastrozole, and the combination inhibited cell-cycle processes and estrogen signaling; however, combination therapy resulted in increased cytokine signaling and adaptive immune response indicative of enhanced antigen presentation and activated T-cell phenotypes. CONCLUSIONS: Abemaciclib plus anastrozole demonstrated biological and clinical activity with generally manageable toxicities in patients with HR+/HER2- early breast cancer. Abemaciclib led to potent cell-cycle arrest, and in combination with anastrozole, enhanced immune activation.

Molecular effects of lapatinib in patients with HER2 positive ductal carcinoma in situ.

INTRODUCTION: Human epidermal growth factor receptor 2 (HER2) amplification is frequent in ductal carcinoma in situ (DCIS) of the breast and is associated with poorly differentiated tumors and adverse prognosis features. This study aimed to determine the molecular effects of the HER2 inhibitor lapatinib in patients with HER2 positive DCIS. METHODS: Patients with HER2 positive DCIS received 1,500 mg daily of lapatinib for four consecutive weeks prior to surgical resection. Magnetic resonance imaging (MRI) was used to determine changes in tumor volume. The molecular effects of lapatinib on HER2 signaling (PI3K/AKT and RAS/MAPK pathways), cell proliferation (Ki67 and p27) and apoptosis (TUNEL) were determined in pre and post-lapatinib treatment samples. RESULTS: A total of 20 patients were included. Lapatinib was well tolerated with only minor and transient side effects. The agent effectively modulated HER2 signaling decreasing significantly pHER2 and pERK1 expression, together with a decrease in tumor size evaluated by MRI. There was no evidence of changes in Ki67. CONCLUSIONS: Four weeks of neoadjuvant lapatinib in patients with HER2-positive DCIS resulted in inhibition of HER2 and RAS/MAPK signaling pathway. TRIAL REGISTRATION: 2008-004492-21 (Registered June 25th 2008).

Revisión de la teoría de la recuperación de la información: ¿qué convierte a la información en dependiente del contexto? / Revision of Retrieval Theory of forgetting: what does make information context-specific?

Este artículo explora el papel del contexto en la recuperación de la información, centrándose en los efectos diferenciales que el cambio de contexto tiene sobre la adquisición y la información interferente. Proponemos una modificación de la teoría de la recuperación de la información basada en resultados recientes de nuestro laboratorio que sugieren que la dependencia contextual de la información no depende de sus características específicas, sino de las características concretas de la situación que llevan a los participantes a prestar atención al contexto. Una vez aparece algo en la situación que lleva a los participantes a prestar atención al contexto, toda la información aprendida parece convertirse en específica del contexto, independientemente de si es el primer o segundo significado de la clave. Se proponen las bases de esta teoría atencional del procesamiento contextual

The role of context in retrieval of the information is explored, focusing in the differentiae effects of context change on acquisition and interfering information. Retrieval theory has proposed that context changes affect a specific type of information, either inhibitory or second-learned, interfering information. We propose a modification of retrieval theory based on recent results in our laboratory that suggests that context-specificity does not depend on specific features of the information, but on specific features of the situation that lead participants to pay attention to the context. Once there is something in the situation that leads participants to pay attention to the context, all the information learned seems to become context specific, regardless of whether it is the first or the second meaning of the cue. The outlines of this attentional theory of context processing are proposed