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Background: Olaparib (O) is approved for the treatment of HER2[-] patients (pts) with early or metastatic breast cancer and a germline BRCA mutation. Nevertheless, there is no evidence that HER2[+] tumors are resistant to PARPi. Preclinical data support that HER2[+] cells are sensitive to PARPi and strongly suggest that PARP inhibition augments the efficacy of trastuzumab (T). To test whether PARPi is synergistic with anti-HER2 therapy, the OPHELIA study has assessed the efficacy and safety of O in combination with T in pts with HER2[+] germinal BRCA-mutated advanced breast cancer (ABC). Methods: OPHELIA (NCT03931551) is an open-label, multicenter, single-arm, phase II trial. The study enrolled pts aged ≥18 years diagnosed of HER2[+] ABC with germinal deleterious mutations in BRCA1 or BRCA2 who had received at least one prior systemic regimen for advanced disease (including a pertuzumab- or trastuzumab emtansine based regimen). Pts received O (300 mg oral, twice daily) plus T (either loading dose of 8 mg/kg IV infusion, and subsequent 3-weekly doses of 6 mg/kg IV infusion; or 600 mg SC injection, on day 1 of every 21-day cycle) until disease progression, unacceptable toxicity, or consent withdrawal. Primary endpoint was investigator-assessed clinical benefit rate (CBR) for at least 24 weeks as per RECIST v.1.1. Secondary endpoints included overall response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS); and safety and tolerability as per NCI-CTCAE v.5.0. The primary analysis evaluated CBR (H0: ≤5%; H1: ≥30%) based on exact binomial test. Sample size was designed to attain a 90% power at 10% one-sided alpha level. Results: From Mar 25, 2019, through Mar 2, 2022, 5 pts (from a total of 42 pts evaluated) were enrolled at 17 sites in Spain. Median age was 37.0 (range 32–54) years, 1 (20.0%) patient was male, 4 (80.0%) pts carried germinal BRCA2 mutations, 4 (80.0%) pts had received ≥ 3 advanced disease treatments lines, and 4 (80.0%) pts presented ≥ 2 metastatic sites. At data cutoff (Mar 2, 2022), with a median follow-up of 18.7 months (min: 11.7; max: 22.1), 40.0% of pts remained on therapy. CBR at 24 weeks was 80.0% meeting the primary endpoint (4 of 5 pts; 95% CI, 28.4% to 99.5%, p< 0.001). ORR (1 complete and 2 partial responses) was 60.0% (95% CI, 17.4% to 94.7%), and median DoR was 3.8 months (95% CI, 2.5 to 8.3 months). Two (40.0%) pts had PFS events due to disease progression at 5.2 and 1.2 months, respectively. Rest of pts were treated for 5.5, 11.2, and 19.0 months. There were 2 (40.0%) deaths at 14.0 and 18.5 months. The most common non-hematological treatment emergent adverse events (TEAEs) of any grade (G) were fatigue (60.0%; 0% G≥3), nausea (60.0%; 0% G≥3), vomiting (40.0%; 0% G≥3), and back pain (40.0%; 0% G≥3). Anemia (40.0%; 20.0% G≥3) and lymphopenia (40.0%; 20.0% G≥3) were the most frequent hematological TEAEs. One (20.0%) patient discontinued treatment because of a drug-related TEAE (leukopenia). A dose reduction of O was reported in 1 (20.0%) patient. No treatment-related deaths were reported. Conclusions: HER2 overexpression in germline BRCA-mutated ABC is infrequent. The activity observed in these 5 pts indicates that O+T combination might be of help in this group of pts. We strongly believe that randomized data are not needed, and RWE studies might help us to understand the real activity of this combination. Toxicity was as expected. Citation Format: José E. Alés-Martínez, Judith Balmaña, Pedro Sánchez-Rovira, Francisco Javier Salvador Bofill, José Ángel García-Sáenz, Isabel Pimentel, Serafin Morales Murillo, Adela Fernández, Ainhara Lahuerta Martínez, Neus Ferrer, Pilar Zamora, Begoña Bermejo, Tamara Díaz-Redondo, María Helena Lopez-Ceballos, María Galán, Andrea Malfettone, Laura Calabuig, Miguel Sampayo-Cordero, José Manuel Pérez-García, Javier Cortés, Antonio Llombart-Cussac. Olaparib plus Trastuzumab in HER2[+] BRCA-Mutated Advanced Breast Cancer Patients: The OPHELIA Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-29.

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.

Supplementary Table S1. Selection Criteria; Supplementary Table S2. Recruiting Sites, Principal Investigators, and Patient Numbers; Supplementary Table S3. Study Members; Supplementary Table S4. List of antibodies used for immunohistochemistry analysis; Supplementary Table S5. Cutoff values for the quantitative assessment of biomarkers by immunohistochemistry; Supplementary Table S6. The 77-gene panel by the AVENIO ctDNA Expanded Kit used for targeted NGS on plasma samples; Supplementary Table S7. Representativeness of study participants; Supplementary Table S8. Association of baseline clinical and pathologic characteristics of trial participants included in the efficacy analysis with clinical benefit; Supplementary Table S9. Relative dose intensity and drug discontinuation; Supplementary Table S10. All causality AEs according to NCI-CTCAE version 4.0.3 occurring in at least 5% of the patients; Supplementary Table S11. Adverse events of special interest according to NCI-CTCAE version 4.0.3; Supplementary Table S12. Baseline clinical and pathologic characteristics of trial participants included in the retinoblastoma and signature subsets; Supplementary Table S13. Tumor best response according to RECIST version 1.1 of trial participants included in the retinoblastoma and signature subsets; Supplementary Table S14. Association of biomarkers and composite signatures with clinical benefit.

Summary of all adverse events according to NCI-CTCAE version 4.0.3.

Purpose:To assess the efficacy and exploratory biomarkers of continuing palbociclib plus endocrine therapy (ET) beyond progression on prior palbociclib-based regimen in patients with hormone receptor–positive/HER2-negative (HR+/HER2−) advanced breast cancer (ABC).Patients and Methods:The multicenter, open-label, phase II BioPER trial included women who had experienced a progressive disease (PD) after having achieved clinical benefit on the immediately prior palbociclib plus ET regimen. Palbociclib (125 mg, 100 mg, or 75 mg daily orally for 3 weeks and 1 week off as per prior palbociclib-based regimen) plus ET of physician's choice were administered in 4-week cycles until PD or unacceptable toxicity. Coprimary endpoints were clinical benefit rate (CBR) and percentage of tumors with baseline loss of retinoblastoma (Rb) protein expression. Additional endpoints included safety and biomarker analysis.Results:Among 33 patients enrolled, CBR was 34.4% [95% confidence interval (CI), 18.6–53.2; P < 0.001] and 13.0% of tumors (95% CI, 5.2–27.5) showed loss of Rb protein expression, meeting both coprimary endpoints. Median progression-free survival was 2.6 months (95% CI, 1.8–6.7). No new safety signals were reported. A signature that included baseline mediators of therapeutic resistance to palbociclib and ET (low Rb score, high cyclin E1 score, ESR1 mutation) was independently associated with shorter median progression-free survival (HR, 22.0; 95% CI, 1.71–282.9; P = 0.018).Conclusions:Maintaining palbociclib after progression on prior palbociclib-based regimen seems to be a reasonable, investigational approach for selected patients. A composite biomarker signature predicts a subset of patients who may not derive a greater benefit from palbociclib rechallenge, warranting further validation in larger randomized controlled trials.

Background: Cyclin-dependent kinases 4 and 6 inhibitors in combination with endocrine therapy frequently lead to a complete cell-cycle arrest (CCCA) in luminal EBC. However, the rates of pathological complete response (pCR) or Residual Cancer Burden (RCB) 0-I are modest. The effect of this treatment in terms of molecular downstaging as assessed by a genomic signature more refined than Ki67 remains undetermined. We aimed to assess the biological and clinical activity of letrozole plus palbociclib as neoadjuvant treatment in HR-positive/HER2-negative EBC pts with an Oncotype DX RS ≥18. Methods: DxCARTES was a multicenter, open-label, non-comparative, phase 2 trial across 16 hospitals in Spain. Participants were pre- and post-menopausal women aged ≥18 years with centrally confirmed HR-positive/HER2-negative, Ki67≥20%, stage II-IIIB EBC with a RS ≥18. Eligible pts with baseline RS 18-25 (cohort A) and RS 26-100 (cohort B) received six 28-days cycles of letrozole (2.5 mg QD), ± goserelin if premenopausal, plus palbociclib (125 mg QD, 3/1 schedule) before surgery. Tumor samples were prospectively collected at baseline and surgery for Ki67 and RS assessments. The coprimary endpoint was the proportion of pts in either cohort who achieved RS ≤25 or a pCR (ypT0/is ypN0) at surgery. Secondary endpoints included analysis of RCB, preoperative endocrine prognostic index (PEPI), CCCA (Ki67 Citation Format: Antonio Llombart-Cussac, Ángel Guerrero-Zotano, Manuel Ruiz, Begoña Bermejo, Miguel Gil-Gil, Juan de la Haba, Emilio Alba, Vanesa Quiroga, Vicente Carañana, Ander Urruticoechea, Serafín Morales, Meritxell Bellet, Antonio Antón, José Manuel Pérez-García, María Fernández-Abad, Sonia Servitja, Pedro Sánchez-Rovira, Sofia Braga, Miguel Sampayo-Cordero, Andrea Malfettone, Javier Cortes. Neoadjuvant letrozole plus palbociclib in patients (pts) with hormone receptor (HR)-positive/HER2-negative early breast cancer (EBC) with baseline Ki67 ≥20% and an Oncotype DX Breast Recurrence Score® result (RS) ≥18: DxCARTES [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 P5-16-12.

Background: The presence of stromal tumor-infiltrating lymphocytes (TILs) represents an independent prognostic factor in HER2-positive early-stage breast cancer (EBC) treated with trastuzumab/pertuzumab-containing regimens. Among distinct subsets of TILs, conventional CD8+ αβ T cells require TCR signaling as a part of adaptive immunity, while γδ T cells display also innate-like activity via the NKG2D receptor contributing to a very rapid tumor immunosurveillance. Specific γδ T cell subsets were associated with remission and improved overall survival of patients with triple-negative breast cancer. However, very little is known about circulating αβ and γδ T cells and their immunological status in HER2-positive breast cancer. In this substudy, we aimed to characterize the αβ and γδ T cell subsets and the association with clinical outcome in peripheral blood of patients with HER2-positive EBC enrolled in the PHERGain trial, which assessed the possibility of chemotherapy de-escalation with neoadjuvant dual HER2 blockade with trastuzumab and pertuzumab using an 18F-fluorodeoxyglucose-PET and pathological response-adapted strategy. Methods: Peripheral blood was obtained from 24 consecutive patients who were assigned to the trastuzumab and pertuzumab group (+/- endocrine therapy as per hormone receptor status) before randomization (baseline) and after 2 treatment cycles (6 weeks). Blood samples were also collected from 48 age-matched healthy donors who represented the control group. Absolute numbers of CD3+, CD3+/CD4+, CD3+/CD8+, and CD3+/CD56+ according to the TCR expression, and annexin V apoptotic rate on αβ and γδ T cells were evaluated by flow cytometry. Subset distribution of T cell differentiation within naïve, central memory, effector memory, and terminally differentiated effector memory cells was also determined. The changes in the frequency of peripheral T cells and rate of apoptotic subsets between timepoints, patients, and healthy donors were compared with Wilcoxon test. The analyses were set at two-sided 0.05 level of significance. Results: Among 24 patients with evaluable blood samples at both timepoints, median age was 50.5 years (IQR 45.8-61), 45.8% had node-positive disease, 79.2% had hormone receptor-positive status, 79.2% had tumors with HER2 IHC 3+ status, and 54.2% achieved a pathological complete response (ypT0/is ypN0) after treatment. At baseline, levels of αβ and γδ T cells in EBC patients were significantly lower than levels in healthy subjects (P ≤0.05). After 6 weeks of study treatment, these levels in EBC patients did not significantly differ from those at baseline. Baseline rates of apoptotic subsets were higher in EBC patients than rates in healthy subjects (P Citation Format: Juan Carlos Andreu-Ballester, José Manuel Pérez-García, Begoña Bermejo, Vicente Carañana, Vega Iranzo, Joaquín Gavilà, Ana Santaballa, María Carmen Gómez-Soler, Miguel Sampayo-Cordero, Andrea Malfettone, Javier Cortes, Antonio Llombart-Cussac. Analysis of αβ and γδ circulating T cells in the PHERGain randomized phase 2 trial for patients with HER2-positive early breast cancer receiving neoadjuvant trastuzumab and pertuzumab without chemotherapy: LINGain [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 P5-13-30.

Background: The introduction of trastuzumab (H) and pertuzumab (P) and ado-trastuzumab emtansine (T-DM1) has drastically improved clinical outcomes in patients (pts) with HER2-positive early breast cancer, allowing to explore chemotherapy-sparing approaches in this population. PHERGain trial is evaluating the efficacy of dual HER2-blockade with HP as both neoadjuvant and adjuvant treatment using an 18F-fluorodeoxyglucose-PET-based and a pathological response-adapted strategy [Pérez-García JM et al., Lancet Oncol. 2021;22:858-871]. PHERGain-2 study is an additional step forward and aims to assess the feasibility of chemotherapy de-escalation with neoadjuvant HP followed by adjuvant HP or T-DM1 using a pathological response-adapted strategy in low-risk HER2-positive early breast cancer pts. Trial Design: PHERGain-2 is a multicenter, open-label, non-comparative, phase 2 trial. Eligible participants are patients aged ≥18 years with previously untreated, centrally confirmed, HER2-positive (immunohistochemical score 3+), invasive, node-negative breast cancer (>0.5 and Citation Format: José Manuel Pérez-García, Ángel Guerrero-Zotano, Jacques Medioni, Andreas Schneeweiss, Marco Colleoni, Miguel Sampayo-Cordero, Andrea Malfettone, Javier Cortés, Antonio Llombart-Cussac. A phase 2 study of chemotherapy de-escalation using a pathological response-guided strategy in patients with HER2-positive, low-risk early breast cancer: PHERGain-2 [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 OT1-12-07.

Background Palbociclib has gained a central role in the treatment of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC). Despite its manageable toxicity profile, venous thromboembolism (VTE) or interstitial lung disease (ILD)/pneumonitis may infrequently occur. Therefore, we provide a comprehensive summary of the safety and tolerability of the combination of endocrine therapy and palbociclib among patients included in the randomized phase 2 PARSIFAL study. Materials and Methods Patients with endocrine-sensitive HR+/HER2- ABC and no prior therapy in an advanced setting (n = 486) were randomly assigned 1:1 to receive fulvestrant–palbociclib (FP) or letrozole–palbociclib (LP). Laboratory tests and the incidence of adverse events (AEs) were recorded at baseline and day 1 of each cycle. Progression-free survival (PFS) was estimated for patients with and without VTE. Results A total of 483 patients were analyzed. Neutropenia, leukopenia, anemia, asthenia, arthralgia, fatigue, and diarrhea were the most frequent AEs in both groups. Febrile neutropenia occurred in 3 (1.2%) patients of the FP group and in 1 (0.4%) patient in the LP group. Six (2.5%; 0.4% grade 3) patients in the FP group and 6 patients (2.5%; 0.4% grade 3) in the LP group experienced ILD/pneumonitis. Pulmonary embolism was reported in 12 (5.0%) patients in the FP group and 6 (2.5%) patients in the LP group. Advanced age at baseline was the only factor significantly associated with an increased risk of pulmonary embolism (P Conclusion The PARSIFAL data confirmed the favorable safety profile of both palbociclib regimens. VTE and ILD/pneumonitis were occasionally reported, and their early detection allowed patients to continue treatment effectively without detriment to efficacy. ClinicalTrials.gov Identifier NCT02491983; https://clinicaltrials.gov/ct2/show/NCT02491983).

Hormone receptor; Advanced breast cancer Càncer de mama avançat; Receptor hormonal Cáncer de mama avanzado; Receptor hormonal Purpose: To assess the efficacy and exploratory biomarkers of continuing palbociclib plus endocrine therapy (ET) beyond progression on prior palbociclib-based regimen in patients with hormone receptor–positive/HER2-negative (HR+/HER2−) advanced breast cancer (ABC). Patients and Methods: The multicenter, open-label, phase II BioPER trial included women who had experienced a progressive disease (PD) after having achieved clinical benefit on the immediately prior palbociclib plus ET regimen. Palbociclib (125 mg, 100 mg, or 75 mg daily orally for 3 weeks and 1 week off as per prior palbociclib-based regimen) plus ET of physician's choice were administered in 4-week cycles until PD or unacceptable toxicity. Coprimary endpoints were clinical benefit rate (CBR) and percentage of tumors with baseline loss of retinoblastoma (Rb) protein expression. Additional endpoints included safety and biomarker analysis. Results: Among 33 patients enrolled, CBR was 34.4% [95% confidence interval (CI), 18.6–53.2; P < 0.001] and 13.0% of tumors (95% CI, 5.2–27.5) showed loss of Rb protein expression, meeting both coprimary endpoints. Median progression-free survival was 2.6 months (95% CI, 1.8–6.7). No new safety signals were reported. A signature that included baseline mediators of therapeutic resistance to palbociclib and ET (low Rb score, high cyclin E1 score, ESR1 mutation) was independently associated with shorter median progression-free survival (HR, 22.0; 95% CI, 1.71–282.9; P = 0.018). Conclusions: Maintaining palbociclib after progression on prior palbociclib-based regimen seems to be a reasonable, investigational approach for selected patients. A composite biomarker signature predicts a subset of patients who may not derive a greater benefit from palbociclib rechallenge, warranting further validation in larger randomized controlled trials. This work was supported by Pfizer. The authors would like to thank the patients, their caregivers, and their families for participating in this study and all investigators and site personnel. The BioPER study was conceived and designed by Medica Scientia Innovation Research (MEDSIR) in collaboration with Pfizer Inc., which funded the study and provided palbociclib. J. Albanell acknowledges CIBERONC CB16/12/00241, PI21/00002, funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union, Generalitat de Catalunya (2017 SGR 507).

IntroductionSevere coronavirus disease 2019 (COVID-19) is associated with immune dysregulation and hyperinflammation (lymphocyte exhaustion and elevated IL-6). Pembrolizumab (P; immune-activating anti-PD-1 antibody) plus tocilizumab (TCZ; anti-IL6 receptor antibody) might interrupt the hyperinflammation and restore the cellular immunocompetence. We assessed the efficacy and safety of P + TCZ + standard of care [SOC] in high-risk, hospitalized, COVID-19 pneumonia patients without mechanical ventilation.MethodsRandomized, controlled, open-label, phase 2 trial in patients with severe SARS-CoV-2-infection to assess the hospitalization period to discharge.ResultsTwelve patients were randomized (P + TCZ + SOC, n = 7; SOC, n = 5). Nine (75%) were males, with a median age of 68 (41–79) years. Median time to discharge with P + TCZ + SOC and SOC was 10 and 47.5 days (p = 0.03), with 0 (n = 1 patient had P–related grade 5 myositis) and 2 COVID-19-related deaths, respectively.ConclusionsThe addition of P and TCZ to SOC reduced the hospitalization period, with higher and faster discharges without sequelae than SOC alone.

Background: The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) significantly improved survival outcomes of HER2-low advanced breast cancer (ABC) patients (pts) compared to standard chemotherapy in the DESTINY-Breast04 trial. DEBBRAH is assessing the efficacy and safety of T-DXd in HER2[+] and HER2-low ABC pts with a history of brain metastases (BM) and/or leptomeningeal carcinomatosis (LMC); here, we report results of HER-low ABC pts. Methods: DEBBRAH (NCT04420598) is a multicenter, open-label, five-cohort, non-comparative, phase 2 study across 18 hospitals in 2 countries. A total of 39 pts aged ≥18 years with pretreated HER2[+] or HER2-low ABC with stable, progressing, or untreated BM and/or LMC, were enrolled in 5 cohorts: (1) HER2[+] ABC with non-progressing BM after radiotherapy and/or surgery; (2) HER2[+] or HER2-low ABC with asymptomatic untreated BM; (3) HER2[+] ABC with progressing BM after local treatment; (4) HER2-low ABC with progressing BM after local treatment; (5) HER2[+] or HER2-low ABC with LMC. Pts received 5.4 mg/kg T-DXd intravenously once every 21 days until disease progression, unacceptable toxicity, or consent withdrawal. Primary endpoint for cohorts 2 and 4 was intracranial overall response rate (ORR-IC) according to RANO-BM. Secondary endpoints included overall response (ORR) according to RECIST v1.1, progression-free survival (PFS), duration of response (DoR), clinical benefit rate (CBR); and safety and tolerability as per NCI-CTCAE v.5.0. Primary analysis is the estimation of ORR-IC (H0: ORR-IC ≤5%; H1: ORR-IC ≥40%) based on the one-sided binomial exact test. Sample size was planned to attain an 80% power at a nominal α level of 0.05 in each cohort. Results from cohort 2 should be considered descriptive since formal testing has to be performed in the whole cohort of pts with HER2[+] or HER2-low ABC and asymptomatic untreated BM. Results: From Oct 23, 2020, through Feb 15, 2022, 6 pts and 7 pts were allocated into cohorts 2 and 4, respectively. One patient with LMC included in cohort 4 was excluded from analysis. Median age was 54 (range 40–73) years. Median number of previous lines of therapy for advanced disease was 7 (range, 4-8) and 3 (range, 2-4) for cohorts 2 and 4, respectively. Median follow-up was 9.5 months (range, 1.6-15.7). At data cutoff (Apr 29, 2022), no patient of cohort 2 and 3 (50.0%) pts of cohort 4 remained on therapy. In cohort 2, ORR-IC was 66.7% (4 of 6 pts had intracranial partial response [PR]; 95% CI, 22.3–95.7). In cohort 4, ORR-IC was 33.3% meeting the primary endpoint (2 of 6 pts had intracranial PR; 95% CI, 4.3–77.7; P = .033). Overall, ORR-IC in all pts was 50% (6 of 12 pts; 95% CI, 21.1-78.9) and CBR was 66.7% (8 of 12 pts; 95% CI, 34.9-90.1). Combining pts with measurable intracranial or extracranial disease from cohorts 2 and 4, ORR, CBR and median DoR were 41.7% (5 of 12 pts; 95% CI, 15.2–72.3), 50.0% (6 of 12 pts; 95% CI, 21.1–78.9), and 7.2 months (95% CI, 2.5-16.4), respectively. Median PFS was 5.7 months (95% CI, 4.7-NA) among these pts. The most common treatment emergent adverse events (TEAEs) of any grade (G) were fatigue (58.3%; 8.3% G≥3) and nausea (50.0%; 0% G≥3). Two (16.7%; 0% G≥3) cases of interstitial lung disease/pneumonitis were reported. Serious unrelated TEAEs occurred in 2 (16.7%) of 12 pts; 1 case of general pain (G3) and 1 case of venous embolism (G5) that led to death. There were no drug-related deaths due to TEAEs. Conclusions: T-DXd showed a preliminary antitumor activity in pretreated HER2-low ABC pts with asymptomatic untreated or progressing BM after local treatment. The substantial response of BM to T-DXd in this setting is promising and warrants further investigation. Citation Format: José Manuel Pérez-García, Marta Vaz Batista, Patricia Cortez-Castedo, Manuel Ruiz Borrego, Juan Miguel Cejalvo, Juan de la Haba-Rodríguez, Laia Garrigós, Fabriccio Racca, Sonia Servitja, Salvador Blanch, Maria Gión, Mónica Nave, Adela Fernández, Alejandro Martínez-Bueno, Antonio Llombart-Cussac, Miguel Sampayo-Cordero, Andrea Malfettone, Javier Cortés, Sofía Braga. Trastuzumab Deruxtecan in patients with Unstable Central Nervous System Involvement from HER2-Low Advanced Breast Cancer: The DEBBRAH Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD7-02.

Background: HG is an on-target AE of PI3K inhibition, reported in 63.7% (36.6% G≥3) of HR[+]/HER2[-] ABC patients (pts) treated with ALP plus fulvestrant in SOLAR-1. HG was the most frequent adverse event (AE) leading to ALP discontinuation (6.3%). MET reduces systemic insulin resistance and suppress PI3K and Ras signaling. METALLICA is assessing the prophylactic use of MET for prevention of ALP-induced G3-4 HG in PIK3CA-mutated, HR[+]/HER2[-] ABC pts with normal fasting glycemia or prediabetic criteria. Methods: This is an open-label, single-arm, two-cohort, phase 2 trial. Pts aged ≥18 years, ECOG PS of 0–1, and PIK3CA-mutated, HR[+]/HER2[-] ABC, progressing to an aromatase inhibitor (AI)-containing regimen, ≤2 previous endocrine therapy (ET) and ≤1 prior chemotherapy regimens for ABC were eligible. Pts were enrolled into cohorts according to glycemia at baseline: (A) pts with normal fasting glycemia < 100 mg/dL and glycosylated hemoglobin (HbA1c) < 5.7%; (B) pts with prediabetic fasting glycaemia 100–140 mg/dL and/or HbA1c 5.7–6.4%. Pts received oral ALP 300 mg/day, starting from C1D8, in combination with ET; fulvestrant, letrozole, or exemestane as per standard of care; and oral MET 1000 mg/day on days 1-3 and 2000 mg/day thereafter. The primary endpoint was G3-4 HG incidence as per NCI-CTCAE v.4.03 at 2 first cycles of treatment. Assessment of glycemia was performed by rigorous self-monitoring blood glucose and local laboratory confirmation in fasting conditions. Secondary endpoints included objective response (ORR), clinical benefit rate (CBR), duration of response (DoR), progression-free survival (PFS), and safety. Sample size was based on a Simon’s two-stage design in cohorts A (H0: G3-4 HG ≥25%; H1: G3-4 HG ≤10%) and B (H0: G3-4 HG ≥40%; H1: G3-4 HG ≤15%). We planned to attain 80% power at the nominal one-sided α level of 0.05 for each cohort. Results: Between Aug 30, 2020, and Mar 10, 2022, 68 pts were enrolled at 18 sites (48 cohort A, 20 cohort B). Median age was 55 (range, 29–79) years and 58.8% pts had visceral disease and an ECOG PS 0. A total of 66 (97.1%) pts had been previously treated with a CDK4/6i and 13 (19.2%) pts had received chemotherapy for advanced disease. Sixty-three (92.6%) pts received fulvestrant as ET (45 cohort A, 18 cohort B). With a median follow-up of 8 (range, 1.6–14.9) months, 28 (41.2%) pts remain on study treatment. Disease progression was the main reason for discontinuation, reported in 32 (47.1%) pts. The primary endpoint of the study was reached, with 1 (2.1%) pts (95%CI, 0.8–9.5; p < 0.001) in cohort A and 3 (15%) pts (95%CI, 4.5–33; p = 0.012) in cohort B experiencing a G3-4 HG episode over the 2 first cycles of treatment. For patients on fulvestrant, G3-4 HG rates were 1 pts (2.2%) and 3 (16.7%) pts for cohorts A and B, respectively. No ALP discontinuation related to HG was reported during the first 2 treatment cycles. Median PFS in all patients was 7.4 months (95%CI, 6–NA). Among pts with measurable disease, ORR was 14 (36.8%) pts (95%CI, 21.8–54). At the time of this analysis, DoR and CBR were still immature. The most common AEs were diarrhea (67.6%; 13.2% G≥3), nausea (67.6%; 0% G≥3), and fatigue (45.6%; 2.9% G≥3). Serious AEs occurred in 15 (22.1%) pts. The main serious AEs were rash (2.9% G≥3) and vomiting (1.5% G≥3). No additional pts reported G≥3 HG after the first 2 cycles. The dose of ALP was reduced according to the protocol in 19 (27.9%) pts. Eight (11.8%) pts permanently discontinued ALP due to AEs, none of whom related to HG. No treatment-related deaths were reported. Conclusions: Prophylactic use of MET substantially reduced the incidence and severity of ALP-related HG with no additional toxicities and could be a new standard for PIK3CA-mutated, HR[+]/HER2[-] ABC pts receiving ALP plus fulvestrant or other ET. Citation Format: Manuel Ruiz Borrego, Pablo Tolosa, Salvador Blanch, Adela Fernández, Ander Urriticoechea, Isabel Blancas, Cristina Saura, Beatriz Rojas, Begoña Bermejo, Jose Ponce, Maria Gión, Elisenda Llabres, Elena Galve, Juan Fernando Cueva, Ana López, José L Alonso-Romero, Santiago González-Santiago, Eduardo Martínez De Dueñas, Fernando Gomez Peralta, Eva Ciruelos, José Manuel Pérez-García, Antonio Llombart-Cussac, Javier Cortés. Metformin (MET) for the prevention of Alpelisib (ALP)-related Hyperglycemia (HG) in PIK3CA-mutated, Hormone Receptor-Positive (HR[+]) HER2-Negative (HER2[-]) Advanced Breast Cancer (ABC): The METALLICA study. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD8-02.

Background The use of PPI among cancer patients (pts) is quite frequent. PAL is an oral, cyclin-dependent kinase 4 and 6 inhibitor recommended to be taken under fed conditions. PAL showed a reduced solubility when gastric pH is >4.5, a level commonly achieved by PPI. Observational, retrospective studies on concomitant PPI with PAL or ribociclib showed a shorter progression-free survival (PFS) among PPI users than nonusers. In the randomized, phase 2 PARSIFAL trial, PAL plus fulvestrant demonstrated no improvement in PFS and overall survival (OS) versus PAL plus letrozole as frontline treatment in HR+/HER2- ABC pts (Llombart-Cussac et al, JAMA Oncol 2021). Here we assessed the impact of PPI on PAL efficacy and safety in pts included in the PARSIFAL study. Methods Pts with endocrine-sensitive HR+/HER2- ABC and no prior therapy in advanced setting were randomly assigned to receive PAL (hard capsule formulation) plus either fulvestrant or letrozole. Pts with ≥1 PPI received over the entire PAL-based regimen were defined as PPI users, or PPI naïve (N-PPI) if no PPI was administered over the whole study treatment. We carried out two analyses considering early PPI users (E-PPI) –composed by pts who were receiving PPI since the PAL-based regimen initiation– and long-term PPI users (LT-PPI) –composed by pts who received PPI over the entire or ≥⅔ of the PAL-based regimen. PPI users defined as neither E-PPI nor LT-PPI were excluded from the analysis to avoid biases due to the PPI limited exposition. PFS, OS, and safety were compared among groups. Landmark analysis at 3, 6, 12, 18, 24, and 30 months (mo) was used for survival estimates conditional on surviving to certain time points and adjust for immortality bias in comparison between N-PPI and PPI users. Analyses were adjusted by stratification factors and patient characteristics. Results Of 486 pts included in the study, 325 (66.9%) were N-PPI. Among 161 (33.1%) PPI users, 64 (13.2%) were E-PPI and 91 (18.7%) were LT-PPI. Omeprazole was the most prescribed PPI in 80.7% (130 of 161) of PPI users. Median exposition to PPI for PPI users, E-PPI, and LT-PPI was 13.6, 15.9, and 19.4 mo, respectively. Compared with N-PPI, E-PPI and LT-PPI were older (median age, 60.5 vs 66.5 vs 67.0 years, respectively; P< 0.001) and had a worse functional status (ECOG PS of 0, 60.0% vs 34.0% vs 43.0%, respectively; P=0.002). Median follow-up for the whole population was 32 mo. Median PFS was 28.7 mo in N-PPI compared with 23.0 mo in E-PPI (HR 1.5; 95%CI 1.1–2.2; P=0.024) and 23.0 mo in LT-PPI (HR 1.4; 95%CI 1.0–1.9; P=0.035). Both PPI groups had poorer median PFS than N-PPI by landmark analysis at 3 and 12 mo. Subgroup analysis showed a consistent trend regardless of endocrine partner. Three-year OS rate was 81.1% in N-PPI compared with 63.5% in E-PPI (HR 2.2; 95%CI 1.3–3.7; P=0.003) and 62.0% in LT-PPI (HR 2.1; 95%CI 1.4–3.4; P=0.001). Both PPI groups had poorer 3-year OS rate than N-PPI by landmark analysis at 3, 6, 12, and 18 mo. Grade ≥3 hematological adverse events (AEs) occurred in 71.7% (233 of 325 pts) of N-PPI compared with 57.8% (37 of 64 pts; P=0.021) of E-PPI and 54.9% (50 of 91 pts; P=0.003) of LT-PPI. Dose reductions and delays due to hematological AEs were reported in 70.8% (230 of 325 pts) of N-PPI compared with 56.3% (36 of 64 pts; P=0.018) of E-PPI and 52.7% (48 of 91 pts; P=0.002) of LT-PPI. At 3 mo, 45.8% (149 of 325 pts) of N-PPI required a dose reduction or delay due to hematological AEs compared with 39.1% (25 of 64 pts; P=0.42) of E-PPI. Conclusions Early and sustained coadministration of PPI with PAL and endocrine therapy were associated with lower efficacy, hematological toxicities, and dose modifications. Despite the post-hoc nature of the study, these findings suggest pharmacokinetic interactions between PPI and PAL capsules. Further confirmatory studies including the tablet formulation of PAL, which is expected to assure its optimal absorption, are needed. Citation Format: Serena Di Cosimo, José Manuel Pérez-García, Meritxell Bellet Ezquerra, Florence Dalenc, Miguel Gil Gil, Manuel Ruiz Borrego, Joaquín Gavilá, Miguel Sampayo-Cordero, Elena Aguirre, Peter Schmid, Frederik Marmé, Joseph Gligorov, Andreas Schneeweiss, Joan Albanell, Pilar Zamora, Duncan Wheatley, Eduardo Martínez De Dueñas, Vicente Carañana, Kepa Amillano, Andrea Malfettone, Javier Cortés, Antonio Llombart-Cussac. PD13-10 Impact of Proton Pump Inhibitors (PPI) on Palbociclib (PAL) Outcomes in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer (HR+/HER2- ABC): Exploratory Analysis of the PARSIFAL Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-10.

Background: Trastuzumab deruxtecan (T-DXd) is approved in the United States and European Union for use in patients (pts) with HER2+ unresectable/metastatic breast cancer (mBC) after ≥1 prior anti–HER2 regimen(s). Approval was based on the randomized, multicenter, open-label, phase 3 DESTINY-Breast03 study (NCT03529110), in which T-DXd demonstrated statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with trastuzumab emtansine (T-DM1). At the primary interim analysis (data cutoff May 21, 2021), the risk of disease progression or death was reduced by 72% with T-DXd (P < 0.001; Cortes et al. N Engl J Med 2022). Overall survival (OS) data were immature for both treatment groups; although the prespecified cutoff for significance was not reached (NR), a trend toward benefit with T-DXd was observed. With further follow-up, we report results from the prespecified OS analysis of DESTINY-Breast03 (data cutoff July 25, 2022), including updated efficacy and safety. Methods: Pts with HER2+ mBC previously treated with trastuzumab and a taxane in either the metastatic setting or (neo)adjuvant setting with progression within 6 mo of therapy, who could have received pertuzumab, were randomly assigned 1:1 to receive T-DXd 5.4 mg/kg every 3 weeks (Q3W) or T-DM1 3.6 mg/kg Q3W until disease progression. The primary endpoint was PFS by blinded independent central review (BICR). The key secondary endpoint was OS (80% powered at 2-sided significance level of 5%); other secondary endpoints included objective response rate (ORR), duration of response (DoR), PFS based on investigator assessment, and safety. Results: 524 pts received either T-DXd (n = 261) or T-DM1 (n = 263). As of the updated data cutoff, median duration of study follow-up was 28.4 mo (range, 0.0-46.9 mo) for T-DXd and 26.5 mo (range, 0.0-45.0 mo) for T-DM1. Median treatment duration was 18.2 mo (range, 0.7-44.0 mo) for T DXd and 6.9 mo (range, 0.7-39.3 mo) for T-DM1. The risk of death was reduced by 36% (HR, 0.64; P = 0.0037) with T-DXd; median OS (mOS) was NR (95% CI, 40.5 mo-not evaluable [NE]), with 72 (27.6%) OS events, for T-DXd vs NR (95% CI, 34.0 mo-NE), with 97 (36.9%) OS events, for T-DM1. Landmark 12-mo OS rate was 94.1% (95% CI, 90.4-96.4) for T-DXd vs 86.0% (95% CI, 81.1-89.8) for T-DM1; 24-mo OS rate was 77.4% (95% CI, 71.7-82.1) for T-DXd vs 69.9% (95% CI, 63.7-75.2) for T-DM1. The P value for OS crossed the prespecified boundary (P = 0.013) and was statistically significant. mPFS by BICR was 28.8 mo (95% CI, 22.4-37.9 mo) with T-DXd, compared with 6.8 mo (95% CI, 5.6-8.2 mo) with T-DM1; HR, 0.33; nominal P < 0.000001. Key efficacy and safety results are shown in the table. Grade ≥3 treatment-emergent adverse events were experienced by 56.4% of T-DXd-treated pts and 51.7% of T DM1-treated pts. Drug-related interstitial lung disease/pneumonitis, as evaluated by an independent adjudication committee, was experienced by 39 pts (15.2%) in the T-DXd arm and 8 pts (3.1%) in the T DM1 arm; no adjudicated drug-related grade 4 or 5 events were observed in pts who received T-DXd. Conclusions: Updated results confirm the superiority of T-DXd compared with T-DM1 for pts with HER2+ mBC previously treated with an anti-HER2 therapy, with highly clinically meaningful and statistically significant benefit in OS and PFS and a manageable safety profile with longer treatment duration. Editorial Acknowledgment Under the guidance of authors, assistance in medical writing and editorial support was provided by Laura Halvorson, PhD, and Rachel Hood, PhD, of ApotheCom, and was funded by Daiichi Sankyo. Funding This study was funded by Daiichi Sankyo and AstraZeneca. Table. Summary of Efficacy Results for T-DXd and T-DM1 Citation Format: Sara Hurvitz, Roberto Hegg, Wei-Pang Chung, Seock-Ah Im, William Jacot, Vinod Ganju, Joanne Win Yang Chiu, Binghe Xu, Erika Hamilton, Srinivasan Madhusudan, Hiroji Iwata, Sevilay Altintas, Jan-Willem Henning, Giuseppe Curigliano, José Manuel Pérez-García, Anton Egorov, Yali Liu, Jillian Cathcart, Shahid Ashfaque, Javier Cortés. GS2-02 Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: Updated survival results of the randomized, phase 3 study DESTINY-Breast03 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS2-02.

Leptin receptor (Ob-R)/leptin axis significantly modulates tumour-infiltrating lymphocytes (TILs) and PD-1 expression in early HER2+ breast cancer (BC) emerging as a new surrogate marker for immunotherapy. Background: There is strong pre-clinical evidence that obesity produces T-cell dysfunction and high PD-1 expression resulting in a paradoxical benefit from immunotherapy. This effect is driven, at least in part, by leptin that exerts its action through binding Ob-R, which is known to be highly expressed in HER2+ BC. TILs correlate with pathological response and long-term outcomes in BC; however the precise mechanism by which these T-cells are activated in and around tumour remains partially unknown. The primary aim of this study was to investigate the role of Ob-R/leptin axis in modulating TILs and PD-1 expression and its effect in pathological response in early HER2+ BC patients who have received neoadjuvant systemic treatment (NST). Methods: Women with HER2+ BC receiving anti-HER2-based NST followed by surgical resection were evaluated. Patient’s height and weight were measured before NST to calculate the body mass index (BMI). Based on the IHC results in diagnostic biopsy, tumors were categorized as HER2+/HR+ and HER2+/HR-. Ob-R expression was routinely measured in the diagnostic biopsy using the BOND RX Research Platform (Leica Biosystems). The Ob-R was classified as over-expressed if there were more than 50% positive cells with weak or strong staining. TILs and PD-1 expression were scored centrally in pre-treatment biopsy. TILs were considered as binary, < 30.0% versus ≥30.0% and PD-1 positive (>1%). Associations with pathological complete response (pCR; ypT0/isN0) were assessed using chi-squared or Wilcoxon test. Results: Of the 74 HER2+ BC patients included in the study, 47 (63.5%) had over-expression of Ob-R, 26 (35.1%) were overweight/obese (BMI ≥25kg/m2), and 42 (56.8%) had pCR status. Ob-R expression was similar regardless of menopausal status, age or HR expression. Patients with Ob-R overexpressed were 21 (80.8%) of 26 with BMI ≥25kg/m2 versus 26 (54.2%) of 48 with BMI < 25Kg/m2 (p=0.023). Tumors with Ob-R overexpressed had significantly higher mean levels of TILs than those with non-overexpressed Ob-R (21.4% [IQR, 7.5-30] vs 12.4% [IQR, 5-10]; p=0.009). Despite higher rates of TILs, the rate of pCR in Ob-R overexpressed tumours (57.4% [27 of 47 patients]) was not higher than in non-overexpressed tumours (55.6% [15 of 27 patients]; p=0.874). This could be due to the fact that Ob-R-overexpressed tumours had a significant higher median PD-1 expression than Ob-R-negative tumours (2% [IQR, 0.5-7.5] vs 0% [IQR, 0-1]; p< 0.001). Finally, no differences were found in terms of Ob-R expression and pathological response by hormone receptor expression. Conclusions: This multidisciplinary clinical study decodes for the first time how obesity, through the OB-R/leptin axis, might activate TILs but apparently dysfunctional as it is not translated into higher pCR; probably due to the presence of exhausted features such as high PD-1 expression. The role of Ob-R together with PD-1 as a potential biomarker for immunotherapy should be further explored. Citation Format: Laura García-Estévez, Adela Fernández, José Palacios, Miguel Sampayo, Isabel Calvo, Eva Díaz, Marta González, Belén Pérez-Míes, Silvia González, José Manuel Pérez-García, Javier Cortés, Gema Moreno-Bueno. Leptin receptor (Ob-R)/leptin axis significantly modulates tumour-infiltrating lymphocytes (TILs) and PD-1 expression in early HER2+ breast cancer (BC) emerging as a new surrogate marker for immunotherapy. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-38.

BACKGROUND: Studies of checkpoint inhibitor monotherapy have shown only modest activity in hormone receptor (HR)-positive (+)/human epidermal growth factor receptor 2 (HER2)-negative (-) metastatic breast cancer (MBC). However, pembrolizumab (P) added to standard neoadjuvant therapy significantly improved the estimated pathologic complete response rate in HR+/HER2- early breast cancer in the I-SPY-2 trial. The KELLY trial aimed to evaluate the efficacy and safety of P in combination with eribulin (E) in anthracycline- and taxane-pretreated patients (pts) with HR+/HER2- inoperable locally recurrent or MBC irrespective of programmed death-ligand 1 (PD-L1) status. METHODS: This is an open-label, single-arm, multicenter phase IIA clinical trial (ClinicalTrials.gov identifier: NCT03222856). Eligible pts had HR+/HER2- inoperable locally recurrent or MBC, who were previously treated with endocrine therapy and at least one, but not more than two, prior chemotherapeutic regimens for treatment of locally recurrent and/or metastatic disease, and with prior anthracycline/taxane exposure either in the early or metastatic setting. Pts received E 1.23 mg/m2 intravenously (IV) on days 1 and 8 with P 200 mg fixed dose IV on day 1 of a 21-day cycle until unacceptable toxicity or disease progression. Primary endpoint was clinical benefit rate (CBR). Secondary endpoints were progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and safety and tolerability of the combination. Exploratory objectives included: (1) the analysis of PFS and ORR based on immune-related RECIST (irRECIST) and (2) the associations of PFS and OS to CBR/ORR, prior exposure to CDK4/6, mTOR, or PI3K inhibitors, PD-L1 status, tumor-infiltrating lymphocytes (TILs), gene signatures, mutational load, and circulating tumor cells. RESULTS: Between January 2018 and October 2018, 44 pts were enrolled in the study. The median age was 54.1 years (range: 46-60.5 years), 70.5% were ECOG 0, 90.1% had visceral disease (86.4% with liver metastases), and 54% with ≥3 involved organ sites. The median number of prior endocrine therapies was two (range: 1-6) and 52.3% of patients had previously received two chemotherapeutic regimens for treatment of locally recurrent and/or MBC. With a median follow-up of 6.64 months (mo.) (range: 1-14.2 mo.), E and P combination met primary endpoint (CBR 53.7%, 95%CI: 36.9-67.3%). ORR and median PFS were 36.4% (95%CI: 22.8-52.3%) and 6.03 mo. (95%CI: 3.7-8.4 mo.), respectively. All-cause adverse events occurred in 100% of pts (G3-4, 56.8%), without treatment-related deaths. ORR and median PFS based on irRECIST were 36.4% (95%CI: 22.8-52.3%) and 6.1 mo. (95%CI: 4.2-8.5 mo.), respectively. OS data are immature (13 deaths, 29.5%). A significant difference in median PFS has been observed between pts with and without clinical benefit (8.5 Vs. 2.2 mo., p TABLE 1Prior treatmentNEvents (%)Median PFS, mo. (95%CI)p-valueCDK4/6 inhibitorsNo2316 (69.2)6 (3.7-10.4)0.832Yes2115 (71.4)6.1 (2.5-NA)mTOR or PI3K inhibitorsNo2620 (76.9)6 (3.7-8.47)0.727Yes1811 (61.1)6 (2.5-NA) Citation Format: José Manuel Pérez-García, Antonio Llombart-Cussac, Esther Holgado, Giuseppe Curigliano, Elena López Miranda, José Luis Alonso-Romero, Begoña Bermejo, Lourdes Calvo, Vicente Carañana, Susana de la Cruz Sánchez, María Gión Cortés, Raúl Márquez Vázquez, Aleix Prat, Manuel Ruiz Borrego, Miguel Sampayo, Miguel Àngel Seguí, Jesus Soberino, Andrea Malfettone, Peter Schmid, Javier Cortés. A phase II study of pembrolizumab and eribulin in patients with HR-positive/HER2-negative metastatic breast cancer previously treated with anthracyclines and taxanes (KELLY study) [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 P3-09-03.

1084 Background: A substantial benefit from adding an immune checkpoint inhibitor to chemotherapy (CT) was reported in mTNBC patients (pts) with PD-L1+ tumors. However, many pts still have a poor outcome. ATRACTIB is exploring the synergism between A (anti-PD-L1 antibody) and B (a VEGF-targeted antibody) with P in mTNBC irrespective of PD-L1 status. We report results from protocol-specified SIA. Methods: ATRACTIB is an open-label, single-arm, phase 2 trial (NCT04408118). Pts aged ≥18 years, with unresectable locally advanced or mTNBC, ECOG performance status of 0–1, who had received no prior systemic therapy or ≥12 months since (neo)adjuvant taxane-based CT are eligible. Pts receive A (840 mg IV, days 1, 15) with P (90 mg/m2 IV, days 1, 8, 15), and B (10 mg/kg IV, days 1, 15) on each 28-day cycle until disease progression, unacceptable toxicity, or patient withdrawal. Primary endpoint is investigator-assessed progression-free survival (PFS) as per RECIST v.1.1. Secondary endpoints include objective response and clinical benefit rates, overall survival, and safety. The trial was designed to detect a treatment effect in terms of median PFS (H0: ≤7 months; H1: ≥9.5 months) and 100 pts are needed to attain 80% power at a nominal one-sided α level of 5%. One SIA was planned for evaluating safety as per CTCAE v.5.0 on the first 20 pts who had completed a 3-month follow-up or reached the end of study. Results: From Oct 5, 2020, through Nov 21, 2021, 34 pts were enrolled at 13 sites in Spain and Germany and received at least 1 dose of study treatment. Median age was 57.5 (range 40–84) years, 23 (67.6%) pts had received prior CT for early disease, and 19 (56.0%) had visceral disease. At data cutoff (Sep 30, 2021), 25 (71.4%) pts were still receiving the drug regimen. Adverse events (AEs) led to drug discontinuation in 3 (8.8%) pts. Mean relative dose intensity was 90.2% for A, 96.5% for P, and 95.7% for B. P dose reduction was reported in 7 (20.6%) pts. Five (14.7) pts required a dose delay due to AEs (11.8% for A, 11.8% for P, and 8.8% for B). The most common AEs of any grade (G) were fatigue (47.1%; 8.8% G≥3), diarrhea (38.2%; 0% G≥3), and neurotoxicity (35.3%; 8.8% G≥3). Anemia (20.6%; 0% G≥3) and neutropenia (17.6%; 8.8% G≥3) were the most frequent hematological AEs. AEs of clinical interest (AECI) for B were hypertension (17.6%; 5.9% G≥3) and pulmonary embolism (2.9%; 0% G≥3). AECI for A were pneumonitis (2.9%; 0% G≥3), autoimmune hepatitis (2.9%; 2.9% G≥3), and alanine aminotransferase increased (2.9%; 2.9% G≥3). No treatment-related deaths were reported. Conclusions: The addition of A to P and B as 1L therapy for mTNBC shows a tolerable safety profile which is consistent with known safety profile of each agent without a significant synergistic toxicity. Based on the independent data monitoring committee recommendation, patient recruitment is ongoing. Clinical trial information: NCT04408118.

Background: Several de-escalation approaches are under investigation in patients with HER2-positive early breast cancer (EBC). We assessed early metabolic responses to neoadjuvant trastuzumab and pertuzumab (HP) using 18F-FDG PET/CT (FDG-PET) and the possibility of chemotherapy de-escalation using a response–adapted strategy. Methods: PHERGain is a randomised, open-label phase 2 trial conducted in 45 centres from seven European countries. Patients aged ≥18 years with FDG-PET–evaluable, centrally confirmed HER2-positive EBC were randomly allocated (1:4) to receive docetaxel (T), carboplatin (C), and HP (arm A) or HP±endocrine therapy (arm B). Randomisation was stratified by hormone receptor status. Centrally reviewed FDG-PET was performed with pre-randomisation and after two treatment cycles. Arm A patients completed six cycles regardless of FDG-PET results. Arm B/FDG-PET–responders continued HP±endocrine therapy for six cycles; arm B/FDG-PET–nonresponders switched to six cycles of TCHP. Co-primary endpoints were the percentage of arm B/FDG-PET–responders with pathologic complete response (pCR) in the breast and axilla (ypT0/is ypN0) and 3-year invasive disease-free survival (iDFS) of arm B patients. Findings: Between 26 June 2017 and 24 April 2019, 356 patients were randomly assigned to arm A (n=71) or arm B (n=285). pCR occurred in 41 patients in arm A (57.7%, 95% Confidence Interval (CI) 47.4–69.4%) and 101 in arm B (35.4%, 95% CI 29.9–41.3%). Among arm B patients, 227 (79.6%) were FDG-PET–responders, 86 (37.9%, 95% CI 31.6–44.5%) of whom obtained pCR. No new safety signals were identified. Global health status declined ≥10% in 65.0% and 35.5% of patients in arms A and B, respectively. Interpretation: FDG-PET identified HER2-positive EBC patients likely to benefit from chemotherapy-free dual HER2 blockade with HP and a reduced impact on global health status. Depending on iDFS results, this strategy could select patients not requiring chemotherapy. Trial Registration: This trial is registered with EudraCT (‎2016-002676-27) and ClinicalTrials.gov (NCT03161353). Funding Statement: The study was conceived and designed by Medica Scientia Innovation Research (MEDSIR) in collaboration with F. Hoffmann-La Roche Ltd, which funded the study and provided the study drugs. MEDSIR, as legal sponsor of the study, is responsible for compliance with all clinical and regulatory procedures and adherence to the study protocol. Declaration of Interests: JMP-G reports to have a consulting role for Roche and Lilly, and travel expenses from Roche. GG reports research funding to the Institution from Roche and that an immediate family member received personal fees from Roche outside the submitted work. MRB reports to have a consulting role for Novartis, Pfizer, MSD, and to be part of speaker bureau for Pfizer, Novartis, Roche, Lilly, Astrazeneca. AS reports to have a consulting role for Roche and EISAI, to be part of speaker bureau for Roche and EISAI, expert testimony for ESIAI and Roche, and travel expenses from Roche and Pfizer. BB reports to have a consulting role for Genentech and MSD, to be part of speaker bureau for Genentech, and travel expenses from Pfizer. SE-de-R reports to have a consulting role for Roche, Pierre-Fabre, Eisai, research funding from Synthon and Roche, and travel expenses from Roche, Pierre-Fabre, and Daiichi Sankyo. AP reports honoraria from Pfizer, Novartis, Roche, MSD Oncology, Lilly, Daiichi Sankyo, Amgen, to have a consulting role for Amgen, Roche, Novartis, Pfizer, Brystol-Myers Squibb, Boehringer, PUMA Biotechnology, Oncolytics Biotech, Daiichi Sankyo, Abbvie, NanoString Technologies, research funding to the Institution from Roche, Novartis, Incyte, PUMA Biotechnology, to have intellectual property (PCT/EP2016/080056: HER2 AS A PREDICTOR OF RESPONSE TO DUAL HER2 BLOCKADE IN THE ABSENCE OF CYTOTOXIC THERAPY; WO/2018/096191. Chemoendocrine score (CES) Based on PAM50 for breast cancer with positive hormone receptors with an intermediate risk of recurrence), travel expenses from Daiichi Sankyo, other relationship with Oncolytics, Peptomyc S.L., and that an immediate family member is an employee of Novartis. MC reports to have a consulting role for Pierre-Fabre, Pfizer, OBI Pharma, Celldex, AstraZeneca, and honoraria from Novartis. NA reports to have a consulting role for Pfizer, Novartis, Roche, AstraZeneca, and Lilly, and travel expenses from Pfizer, Novartis, Roche, and AstraZeneca. MS-C reports honoraria from MEDSIR, Syntax for Science, and Nestle, to have a consulting role for MEDSIR, Syntax for Science, and Nestle, to be part of speaker bureau for MEDSIR, Syntax for Science, Roche, research funding from MEDSIR, Syntax for Science, and Roche, and travel expenses from MEDSIR, Syntax for Science, and Roche. AM is a full-time employee of MEDSIR. JC reports to have a consulting role for Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, Merck Sharp&Dohme, GSK, Leuko, Bioasis, and Clovis Oncology, honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, and Daiichi Sankyo, research funding to the Institution from Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, and Queen Mary University of London, and intellectual property for MEDSIR. AL-C reports leadership for Eisai, Celgene, Lilly, Pfizer, Roche, Novartis, and MSD, intellectual property for MEDSIR and Initia-Research, to have a consulting role for Lilly, Roche, Pfizer, Novartis, Pierre-Fabre, GenomicHealth, and GSK, to be part of speaker bureau for Lilly, AstraZeneca, and MSD, research funding from Roche, Foundation Medicine, and Pierre-Fabre, Agendia, and travel expenses from Roche, Lilly, Novartis, Pfizer, and AstraZeneca. LC, NR, NM, CA, FD, and KK have nothing to declare. Ethics Approval Statement: This study was performed in accordance with guidelines of the International Conference on 205 Harmonization and ethical principles outlined in the Declaration of Helsinki. Written informed 206 consent was obtained before enrolment, and all participants agreed to study-specific procedures. 207 Approvals from appropriate regulatory authorities and ethics committees were obtained.

Introducción: La conducta de «atracón» consiste en consumir, en un período breve de tiempo, más cantidad de alimentos del que se consumiría normalmente en situaciones similares y en un plazo de tiempo igual. Es una conducta desadaptativa caracterizada por episodios compulsivos y que va acompañada por la sensación subjetiva de pérdida de control. Método: Con el objetivo de evaluar la implicación de los sistemas dopaminérgico y adenosinérgico en la conducta de atracón, y averiguar si el patrón de acceso a la comida dulce modifica los niveles de consumo compulsivo, se compararon dos grupos de animales con diferentes condiciones de acceso a pellets de comida dulce (50 % de sucrosa): condición de acceso diario y condición de acceso intermitente (lunes, miércoles y viernes). Los animales tenían una hora de acceso a un número ilimitado de pellets. El resto del tiempo, tuvieron acceso a comida estándar. A cada grupo se le administraron dos manipulaciones farmacológicas: tetrabenazina (inhibidor del transportador vesicular 2 de monoaminas que produce una reducción de los niveles de dopamina) y cafeína (antagonista de los receptores A1/A2A de adenosina). Resultados: Ambos regímenes de acceso a comida dulce produjeron un patrón de atracón. El peso de los animales de ambos grupos incrementó de igual manera. El consumo de comida estándar fue ligeramente superior en el grupo intermitente y el de comida dulce fue ligeramente mayor en aquellos que la consumían a diario. La depleción dopaminérgica, incluso a dosis altas, no produjo cambios en el consumo dulce, ni en condiciones familiares ni en situaciones ansiogénicas. Sin embargo, la cafeína a dosis altas incrementó el consumo de comida dulce en condiciones familiares y la redujo en condiciones ansiogénicas. Conclusiones: El sistema dopaminérgico no parece implicado en el atracón bajo condiciones que no requieren esfuerzo en la búsqueda de comida. El antagonismo adenosinérgico, sin embargo, ejerce una modulación bidireccional dependiendo de los niveles de ansiedad. Introduction: Binge eating is a maladaptative behavior characterized by the consumption of more food in a brief period of time, than would normally be consumed under similar conditions and within a similar period of time. It is accompanied by compulsive episodes and a sensation of loss of control. Method: To investigate the involvement of dopamine and adenosine systems in binge eating behavior, and assess the influence of different patterns of access to sweet food on levels of binge eating, we compared two groups of animals with different access conditions to sweet food pellets (50 % sucrose): daily access group and intermittent access group (Monday, Wednesday and Friday). Mice had an hour of unlimited access to sweet pellets. The rest of the day they had free access to standard food pellets in the home cage. Each group recieved two pharmacological conditions: tetrabenazine (a dopamine depletor) and caffeine (an adenosine receptor antagonist). Results: Both groups of access to sweet food produced a pattern of binge eating. Mice body weight increased independently of the access pattern. Standard food consumption was higher in the intermittent group, but among the daily group, sweet pellets consumption was higher than among the intermittent group. Dopamine depletion, even at high doses, produced no changes in the amount of sweet food consumed, neither under familiar conditions nor under anxiogenic conditions. However, high doses of caffeine increased consumption of sweet pellets under familiar conditions and it reduced consumption under anxiogenic conditions. Conclusions: The dopaminergic system does not seem to be involved in binge eating when getting access to food does not require effort. However, adenosine antagonism has a bidirectional modulation depending on anxiety levels.

Patients with HER2-positive early breast cancer (EBC) preferred subcutaneous (s.c.) trastuzumab, delivered via single-use injection device (SID), over the intravenous (i.v.) formulation (Cohort 1 of the PrefHer study: NCT01401166). Here, we report patient preference, healthcare professional satisfaction, and safety data pooled from Cohort 1 and also Cohort 2, where s.c. trastuzumab was delivered via hand-held syringe.Patients were randomized to receive four adjuvant cycles of 600 mg fixed-dose s.c. trastuzumab followed by four cycles of standard i.v. trastuzumab, or vice versa. The primary endpoint was overall preference proportions for s.c. or i.v., assessed by patient interviews in the evaluable ITT population.A total of 245 patients were randomized to receive s.c. followed by i.v. and 243 received i.v. followed by s.c. (evaluable ITT populations: 235 and 232 patients, respectively). s.c. was preferred by 415/467 [88.9%; 95% confidence interval (CI) 85.7-91.6; P0.0001; two-sided test against null hypothesis of 65% s.c. preference]; 45/467 preferred i.v. (9.6%; 95% CI 7-13); 7/467 indicated no preference (1.5%; 95% CI 1-3). Clinician-reported adverse events occurred in 292/479 (61.0%) and 245/478 (51.3%) patients during the pooled s.c. and i.v. periods, respectively (P0.05; 2 × 2 χ(2)); 16 patients (3.3%) in each period experienced grade 3 events; none were grade 4/5.PrefHer revealed compelling and consistent patient preferences for s.c. over i.v. trastuzumab, regardless of SID or hand-held syringe delivery. s.c. was well tolerated and safety was consistent with previous reports, including the HannaH study (NCT00950300). No new safety signals were identified compared with the known i.v. profile in EBC. PrefHer and HannaH confirm that s.c. trastuzumab is a validated and preferred option over i.v. for improving patients' care in HER2-positive breast cancer.NCT01401166.

Using differente sources such as postmortem inventories, collected from 61 notary´s offices from Pontevedra and Tuy, and taking the Catastro de la Ensenada´s royal books from three parishes, we mean to penetrate in the Bajo Miño´s society for almost three centuries. Before getting into the analysis of this society it was necessary to polish the sources which were being used, which might have been the most ardous part of the present work, and get close to the evolution of key variabilities such as income, yield or the cultivation evolution to delimitate the relation between gross product and average net product per Ha cultivated. The tendence of net productivity per Ha is climbing and, being thus produced in a foral income stability along with the progressive reduction of the seed needed by the growing corn imposition, ends up having the peasant exploiter as the biggest beneficiary. The evolutive study of this society puts us in front a small farming model which shows a deficit in the seventeenth century when the agricultural model, in spite of the impositice success over corn, was incapable of standing up to the growing population, generating a big flood of unsufficient peasents needed in the migratory exits on the quest for complementary resources. On the eighteenth century, in a setting of malthusian situation and the population on a standstill, our society reaches somewhat a maturity and balance, keeping its structures without a substancial alteration other than small advantages thanks to emigration, which reaches its peak, and a complementary cattle raising, with a more equal share than that of the land. On the nineteenth century having improved the productive model, already quite perfected, our shire already produces a surplus and it exports important quantities of cereal and wine. This evolutive march from the shire´s structural insuffiency to the real surplus exportation possibilities happened along with an increasing social polarization in a way that the dominant small farm went back a step but didn´t stop the consolidation and the enforcement of a privileged peasent minority able to accumulate, at the end of our overrun, a net surplus superior to the moderate income which this social model used to have.Con un uso cruzado de fuentes: inventarios post-mortem recogidos de 61 notarías de Pontevedra y Tuy y tres parroquias vaciadas de los libros reales del Catastro de Ensenada (326 explotaciones) pretendemos adentrarnos en la sociedad del Bajo Miño a lo largo de casi tres siglos. Antes de proceder al análisis de esta sociedad propiamente dicha fue necesario pulir las fuentes manejadas, quizás la parte más laboriosa del presente trabajo y aproximarnos a la evolución de variables claves como las rentas, los rendimientos o la evolución de los cultivos para delimitar la relación entre el producto bruto y el producto neto medio por Ha. cultivada. La tendencia de la productividad neta por Ha. es de claro ascenso y al producirse esto en un contexto de estabilidad de la renta foral unido a la progresiva reducción de la semilla necesaria por la imposición creciente del maíz resulta que el mayor beneficiado del avance fuera el propio campesino explotador directo. El estudio evolutivo de la sociedad nos sitúa ante un modelo minifundista y deficitario en el siglo XVII en donde el modelo agrario, a pesar del éxito impositivo del maíz, fue incapaz de hacer frente al impetuoso avance de la población generando una gran marea de campesinos insuficientes necesitados de las necesarias salidas migratorias en la búsqueda de recursos complementarios. En el siglo XVIII, ahora en un cuadro de situación maltusiana y práctico estancamiento de la población, nuestra sociedad alcanza una especie de madurez y equilibrio sin que variasen de manera sustancial sus estructuras salvo pequeños avances y ello gracias a la emigración que alcanza sus topes y a un ganadería complementaria con un reparto más igualitario que el del terrazgo. En el siglo XIX, en el marco de un afinamiento importante de un modelo productivo ya muy perfeccionado, nuestra comarca ya es excedentaria y de hecho exporta notables cantidades de cereales y vino. Esta marcha evolutiva de la insuficiencia estructural comarcal a las posibilidades reales de exportación de excedentes se acompañó de una creciente polarización social de tal manera que el minifundio dominante retrocedió y esto no impidió la consolidación y reforzamiento de una minoría campesina privilegiada capaz de acumular al final de nuestro recorrido unos excedentes netos que son superiores a las moderadas rentas que soportaba este modelo social.

Cet article étudie la relation entre la composition des ménages, l'héritage coutumier et l'évolution de la situation démographique dans une région rurale aux environs de Valence au 18e siècle. Une analyse longitudinale des ménages révèle que dans une large mesure le ménage devient tôt ou tard complexe à cause, surtout, de la cohabitation de parents ou d'enfants mariés. La situation économique de la famille est l'élément qui détermine si le ménage devient, oui ou non, complexe. Cependant tout au long du 18e siècle la proportion des ménages complexes augmente, suite à une plus forte fertilité et à la durée plus longue des mariages et cela conjointement à l'échec de l'augmentation du nombre de maisons parallèlement à l'accroissement de la population. Les coutumes de l'héritage, soit sous forme de priorites (en préférant un enfant aux dépens d'un autre), ou sous forme de donation entre vifs encourage également la formation de ménages complexes. A la fin du 18e siècle toutefois, les usages de l'héritage ont changé et delà afin d'assurer le maintien intact des fermes familiales, malgré le changement de la situation démographique. Ces modifications impliquent une augmentation de la quote-part de la propriété en faveur de la veuve, ainsi qu'au profit des fils plutôt qu'à celui des filles. Jusqu'à quel point la recherche de stratégies particulières a obligé les families de s'écarter des lois réglant l'héritage de la propriété a également retenu l'attention de l'auteur.

[ES] El estudio analiza la historiografía ruralista de la España septentrional durante los últimos 50 años, sus momentos culminantes y las lagunas pendientes. Se centra en el estudio de los sistemas agrarios distinguiendo uno marítimo y dinámico de altas densidades con importantes innovaciones en la larga duración y otro interior menos poblado más estático pero no inmóvil con cambios importantes en su etapa fi nal. Esta economía agrícola y ganadera es el sostén de una sociedad campesina con débil presencia urbana y que se articula entre un modelo más cerealero, propio de las tierras bajas de reducida presión de la renta y otro más ganadero con un producto neto muy inferior que sufre mayores detracciones. El trabajo concluye con una aproximación a las diferenciadas estrategias sociales y territoriales y a los niveles de vida refl ejados en los objetos de bienestar, lujo y civilización., [EN] This work deals with the Rural Historiography of Northern Spain for the last fi fty years, analyzing not only its peaks but also the gaps. It focuses on the study of the agrarian systems: a coastal dynamic one with high densities and signifi cant innovations all through the centuries, and an underpopulated inland one, more static but not immovable, with important changes in its last phase. The mainstay of this rural society is that farming and cattle raising economy. It is a society with slight presence in towns, organized between the lowland cereal-producing model and the cattle raising model with a lower net product but the greatest detractions. Finally, we have considered the different social and territorial strategies as well as the standards of living that are refl ected in welfare, civilization and luxury goods.

Life standards and cultural traditions in the countryside of Léon, 1700-1850 Taking as its field of study a well defined area of the Spanish hinterland, the Esla basin in the province of Léon, this paper analyses the changes affecting living standards from 1700 to 1850. The documentary evidence is provided by a copious sample of some 500 inventories and estate divisions. Beyond the identification of periods either definitely regressive (1730-1759) or conversely characterised by significant expansion (1760-1789), it becomes clear that deep structural changes operate in the long run to decrease the relative weight of core categories (cultivated land), relative to other, expanding ones, which imply a more modern framework (housing and household goods). This evolution goes also hand in hand with a significant process of social polarization., Prenant en référence une région bien délimitée de l’Espagne intérieure - la Vega baja del Esta, dans la province de Leon -, on examine ici les changements survenus dans les niveaux de vie entre 1700 et 1850. La base documentaire repose sur un échantillon copieux de quelque 500 inventaires et partages de succession. En dehors de la caractérisation de périodes de franc recul (1730-1759) et d’expansion évidente (1760-1789), de profondes transformations structurelles dans la longue durée affectent le poids relatif des principaux chapitres (terres cultivées) en faveur d’autres qui impliquent un modèle plus moderne (habitation et effets domestiques). L’évolution s’accompagne d’un processus notable de polarisation sociale., Pérez García José Manuel. Niveaux de vie et traditions culturelles dans les campagnes du León entre 1700 et 1850. In: Histoire & Sociétés Rurales, n°8, 2ème semestre 1997. pp. 61-92.

Pérez García José Manuel. Colectivismo agrario y desigualdad social en la vega baja del Esla en el siglo XVIII. In: Mélanges de la Casa de Velázquez, tome 29-2, 1993. Epoque moderne. pp. 171-192.

Sometemos a la consideración del lector la segunda parte de una encuesta sobre los rendimientos agrícolas, iniciada hace algunos años por nosotros. La presentación de la fuente aquí utilizada—los patrimonios eclesiásticos—, su crítica y la viabilidad de su empleo ya han ocupado nuestra atención, por lo que nos limitaremos ahora a la presentación de los resultados obtenidos. El área geográfica encuestada en este trabajo corresponde a la Galicia occidental, encuadrada desde la gran dorsal al mar y desde la cuenca del Tambre a la del Miño.

Trabajo centrado en la Comarca del Bajo Miño con el empleo cruzado de fuentes para abordar el tema del inculto en una zona superpoblada que condicionó un precoz asalto a los espacios comunales ya muy carcomidos a mediados del XVIII. En la primera parte se analiza la distribución de cultivos y las productividades de las diversas dedicaciones del terrazgo no cultivado en su relación con los precios cerealeros; así se prueban ligeras trasnformaciones en los cultivos y la progresiva extensión del pinar. En la segunda parte se estudia la conflictividad sobre el inculto -aquí muy intensa- desde el doble plano territorial y el económico-social con vistas a demostrar la imposición de la titularidad parroquial y la constante lucha por la privatización exitosa del mismo.