Precision oncology is an emerging approach in cancer care. It aims at selecting the optimal therapy for the right patient by considering each patient’s unique disease and individual health status. In the last years, it has become evident that breast cancer is an extremely heterogeneous disease, and therefore, patients need to be appropriately stratified to maximize survival and quality of life. Gene-expression tools have already positively assisted clinical decision making by estimating the risk of recurrence and the potential benefit from adjuvant chemotherapy. However, these approaches need refinement to further reduce the proportion of patients potentially exposed to unnecessary chemotherapy. Nuclear magnetic resonance (NMR) metabolomics has demonstrated to be an optimal approach for cancer research and has provided significant results in BC, in particular for prognostic and stratification purposes. In this review, we give an update on the status of NMR-based metabolomic studies for the biochemical characterization and stratification of breast cancer patients using different biospecimens (breast tissue, blood serum/plasma, and urine).

Currently, there is limited data regarding the effectiveness of standard subsequent line therapies such as endocrine therapy, chemotherapy, or targeted agents after progression on CDK4/6 inhibitor-based regimens. This paper describes time-to-treatment failure beyond progression on palbociclib or palbociclib+endocrine therapy in patients enrolled in the phase II, multicenter TREnd trial. Our results indicate that there is limited benefit from post-palbociclib treatment, regardless of the type of therapy received. A small population of long responders were identified who demonstrated ongoing benefit from a subsequent line of endocrine therapy after progression to palbociclib-based regimens. A translational research program is ongoing on this population of outliers.

The evolution of therapeutic landscape of human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC) has led to an unprecedented outcome improvement, even if the optimal sequence strategy is still debated. To address this issue and to provide a picture of the advancement of anti-HER2 treatments, we performed a large, multicenter, retrospective study of HER2-positive BC patients. The observational PANHER study included 1,328 HER2-positive advanced BC patients treated with HER2 blocking agents since June 2000 throughout July 2020. Endpoints of efficacy were progression-free survival (PFS) and overall survival (OS). Patients who received a first-line pertuzumab-based regimen showed better PFS (p < 0.0001) and OS (p = 0.004) than those receiving other treatments. Median PFS and mOS from second-line starting were 8 and 28 months, without significant differences among various regimens. Pertuzumab-pretreated patients showed a mPFS and a mOS from second-line starting not significantly affected by type of second line, that is, T-DM1 or lapatinib/capecitabine (p = 0.80 and p = 0.45, respectively). Conversely, pertuzumab-naïve patients receiving second-line T-DM1 showed a significantly higher mPFS compared with that of patients treated with lapatinib/capecitabine (p = 0.004). Median OS from metastatic disease diagnosis was higher in patients treated with trastuzumab-based first line followed by second-line T-DM1 in comparison to pertuzumab-based first-line and second-line T-DM1 (p = 0.003), although these data might be partially influenced by more favorable prognostic characteristics of patients in the pre-pertuzumab era. No significant differences emerged when comparing patients treated with ‘old’ or ‘new’ drugs (p = 0.43), even though differences in the length of the follow-up between the two cohorts should be taken into account. Our results confirmed a relevant impact of first-line pertuzumab-based treatment and showed lower efficacy of second-line T-DM1 in trastuzumab/pertuzumab pretreated, as compared with pertuzumab-naïve patients. Our findings may help delineate a more appropriate therapeutic strategy in HER2-positive metastatic BC. Prospective randomized trials addressing this topic are awaited.

1002 Background: P is approved for treatment of HR+/HER2− mBC combined with ET. There is paucity of clinical data of single-agent P in ET resistant pts. Pre-clinical data suggest P may partially reverse endocrine resistance, though this is yet to be tested in pts. Methods: This Phase II, open-label, multicenter study enrolled post-menopausal pts with HR+ HER2− mBC who progressed on 1 or 2 prior ETs. Pts were randomized to P (125 mg/d 3 w on/1 w off) alone or to continue their current ET (aromatase inhibitor or fulvestrant) in combination with P (same schedule as P arm). The primary endpoint was clinical benefit rate (CBR) [complete response (CR), partial response (PR) and stable disease (SD) for > 6 months (mo)]. Secondary endpoints were adverse events (AE) and additional measures of efficacy. A two-stage optimal design assessed treatment activity in each arm assuming activity as CB≥40% (α and β = 10%). Exploratory comparisons were planned for safety and efficacy endpoints. Results: 115 pts were enrolled (ITT population) 58 in the P arm and 57 in the P+ET arm. In both arms, 67% of pts had the study treatment as second line ET, 33% as third line, and about 1/3 of pts also received 1 prior chemotherapy for mBC. CBR was similar in both arms: 54% (95% CI 42 - 67%) with P+ET, and 60% (95% CI 48 -73%) with P alone. Median duration of CB was longer with P+ET (11.5 mo; 95% CI 8.6 – 17.8) than with P (6 mo; 95% CI 3.9 - 9.9) (HR 0.31, 95% CI 0.1 - 0.7, p-value 0.001, exploratory). Objective response rate (ORR; CR, PR) was 11% (95% CI 3 - 19%) and 7% (95% CI 0.4 -13%) with P+ET and P, respectively. PFS was 10.8 mo (95% CI 5.6 - 12.7) with P+ET and 6.5 mo (95% CI 5.4 - 8.5) with P alone (HR 0.69, 95% CI 0.4 - 1.1, p-value 0.13, exploratory). AEs were in line with previous data. Conclusions: Single agent P has clinical activity in ET pre-treated HR+/HER2– mBC pts. The observed increase in PFS and duration of CB with P+ET may suggest that P could reverse resistance to the prior line of ET. Translational studies are ongoing to explore potential biomarkers in this setting. Clinical trial information: NCT02549430.