Background

Patients (pts) with germinal BRCA mutated (gBRCAm) breast cancer (BC) have an enhanced sensitivity to platinum-based chemotherapy (PBC) and PARP-inhibitors (PARPi). As reported in ovarian cancer, sensitivity and resistance to these treatments partially overlap. In gBRCAm BC, it is unclear if prior exposure to PARPi/PBC affects tumor response to subsequent PBC/PARPi.

Methods

We conducted a retrospective, multicentre observational study to assess the benefit of PARPi post-PBC and viceversa in pts with gBRCAm BC. Pts included received: (neo)adjuvant PBC and then PARPi in advanced setting (group [Gr] 1); PBC followed by PARPi (Gr2), or PARPi followed by PBC (Gr3) in advanced setting. We reported median progression free survival (mPFS) and disease control rate (DCR) for each group. Correlative analyses were provided (significance at p<0.05).

Results

59 pts from 5 centers were included. Pts characteristics and outcomes are reported in the table. PARPi-mPFS in metastatic setting of pts from Gr1 (N=9) was 4.8 months (mo). DCR was of 67%. In Gr2 (N=31), mPFS with PBC and subsequent PARPi were 4.3 and 4.5 mo; DCRs were of 97% and 45%. Age<46 and platinum free interval (PFI)>6mo were associated with longer PARPi-PFS (p=.009 and .016). PBC-PFS>6mo and PFI>6mo were associated with longer PARPi-DCR (p=.031 and .032). Pts in Gr3 (N=21) reported a mPFS of 5.0 with PARPi and 1.8 mo with subsequent PBC, DCRs were of 67 and 14%. PARPi in earlier lines (1-2) was associated with longer PBC-PFS (p=.020). PARPi-PFS>9mo and PARPi-FI>6mo were associated with longer PBC-DCR (p=.015 and .026).

Table: 225P

Pts characteristics and outcomes

Conclusions

Sensitivity and resistance to PARPi and PBC partially overlap in BC. mPFS on PBC/PARPi and PFI/PARPi-FI represent two potential predictive factors of DCR for the subsequent treatment with PARPi/PBC.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

R. Berardi: Financial Interests, Personal, Advisory Board: AstraZeneca, Boeringher Ingelheim, Novartis, MSD, Otsuka, Lilly, Roche, Amgen, GSK, EISAI; Financial Interests, Institutional, Funding: Roche, AstraZeneca. V. Guarneri: Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Amgen, GSK; Financial Interests, Personal, Advisory Board: Eli Lilly, Novartis, MSD, Gilead, Sanofi, merck serono, Exact Sciences, Eisai, Olema Oncology; Financial Interests, Personal, Expert Testimony: Eli Lilly; Financial Interests, Institutional, Invited Speaker: Eli Lilly, Roche, BMS, Novartis, AstraZeneca, MSD, Synton Biopharmaceuticals, Merck, Glaxo Smith kline, Daiichi Sankyo, Nerviano; Non-Financial Interests, Member: ASCO. G. Curigliano: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Daiichi Sankyo, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Daiichi Sankyo, Lilly, Pfizer, Veracyte, BMS, Merck, Exact Sciences, Celcuity; Financial Interests, Personal, Other, Advisory Board: Ellipsis; Financial Interests, Institutional, Research Grant, Investigator Initiated Trial: Merck; Financial Interests, Institutional, Funding, Phase I studies: BMS, Novartis, AstraZeneca, Daiichi Sankyo, Roche, Blueprint Medicine, Kymab, Astellas, Sanofi, Philogen; Financial Interests, Institutional, Invited Speaker, Phase I clinical basket trial: Relay Therapeutics; Non-Financial Interests, Invited Speaker, No compensation for this role. This a public national company for cancer prevention: Lega Italiana Lotta ai Tumori; Non-Financial Interests, Officer, Italian National Health Council as Advisor for Ministry of Health: Consiglio Superiore di Sanità; Non-Financial Interests, Advisory Role, Member of the Scientific Council. Patient advocacy association: Europa Donna; Non-Financial Interests, Advisory Role, Cancer Research Foundation: Fondazione Beretta; Non-Financial Interests, Officer, Member of the Advisory Council: EUSOMA; Non-Financial Interests, Officer, ESMO Clinical Practice Guidelines Chair: ESMO. All other authors have declared no conflicts of interest.

Background

Intracellular signalling pathways play a role for treatment response and outcome for patients with breast cancer (BC).

Methods

We analysed phosphorylated MAPK (pJNK, pERK, pp38) and pAkt with a commercial multiplex enzyme-linked immunosorbent assay (ELISA) (Luminex®) and M30, a marker of apoptosis, in 449 patients with primary ER-positive BC. The aim was to determine the relation between pMAPK, proliferation, apoptosis, and survival in Invasie Lobular Carcinoma (ILC) and non-Invasive Lobular Carcinoma (non-ILC).

Results

Medium follow up was 18.9 years and ILC and non-ILC had an equal Relapse Free Survival (RFS) (p=0.68). In the whole population pAkt was the only kinase with prognostic information; patients with absent/low levels of pAkt had a worse RFS (p=0.016). A multivariate analysis showed tumour size (HR=1.8) (p=0.0016), nodal status (HR=2.8) (p<0.001) and absent/low pAkt (HR=0.69) (p=0.059) as independent prognostic factors. There was a difference between ILC and non-ILC concerning expression of estrogen receptor (ER) (p=0.033), apoptosis (p<0.001), pERK (p=0.004), pJNK (p<0.001) and pp38 (p=0.005) whilst nodal status, Progesteron Receptor (PGR), proliferation rate and pAKT were equal. ILC had a trend towards larger size, but this did not reach statistical significance (p=0.059). Proliferation was correlated to RFS in non-ILC (p<0.001) but not in ILC (p=0.94). pMAPK were not correlated to RFS when patients were split in ILC and non-ILC.

Conclusions

We show differences in expression of activated MAPKs in ILC and non-ILC. Despite lower proliferation and apoptosis, we could not show any correlation to survival in ILC, but this may indicate a more stem cells like behaviour. ER-positive ILC and non-ILC have similar survival, pAkt was the only kinase with prognostic information.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

ILC is the second most common BC type after the invasive carcinoma of no special type (NST). It mostly presents as estrogen receptor (ER) and progesterone receptor (PR) positive, human epidermal growth receptor 2 (HER2) negative and with a low marker of proliferation (Ki67) which results in a luminal A subtype and E-cadherin loss. Additionally, it appears to have a metastatic pattern that differs from the NST. This registry study aims to show clinical and pathological parameters in patients with early and advanced ILC.

Methods

Clinical and pathological data of 683 patients diagnosed with ILC were retrospectively collected and descriptively analyzed. Of these, 206 patients (30.2%) subsequently developed a local recurrence and/or distant metastasis.

Results

The majority of ILC patients presented with low Ki67, positive ER and PR, HER2-negativity and an intermediate grade tumor. E-cadherin loss was detected in 96.2% (n=427, 256 unknown). In summary, 0.4% of patients exhibited a pTis, 45.7% a pT1, 37.3% a pT2, 15.5% a pT3 and 1.1% a pT4 tumor (n=451, 26 unknown), while 68% of patients had pN0, 20.3% pN1, 7.3% pN2 and 4.3% pN3 status (n=438, 39 unknown). ILC tumors with a subsequent metastatic event initially showed similar data to non-metastatic tumors, although metastatic tumors have the highest rate in pT2 with 44.4% but 39.2% presented with pN0 in. Distant metastases were detected at the following sites: bones (43.7%; n=90), local recurrence (33.4%; n =69), peritoneum (12.6%; n=26), liver (11.2%; n=23), gynecological metastasis (10.7%; n=22) (multiple sites per person possible). Patients who progressed showed a slightly different profile, with a particular increase in cerebral lesions (24%, n=24).

Conclusions

This registry study summarizes histopathological data of ILC patients and shows a high rate of metastatic events despite initially good prognostic factors. The metastatic sites in this cohort resemble other studies and differ from NST in the frequency of visceral metastasis or metastasis inside the abdominal cavity (28.2%, n=58) in our cohort. This should be taken into consideration for planning surveillance for ILC patients in survivorship care.

Legal entity responsible for the study

AG Karsten-Speiser, Department of Gynecology with Breast Center, Charité - Universitätsmedizin Berlin.

Funding

Has not received any funding.

Disclosure

P. Jank: Financial Interests, Personal and Institutional, Stocks/Shares: Myriad Genetics Inc. M.M. Karsten: Financial Interests, Personal, Invited Speaker: Roche, Gilead, Sysmex. All other authors have declared no conflicts of interest.

Background

Recent evidence support that the immune system has both positive and negative effects on tumorigenesis. Systemic inflammation has been linked to aggressive tumor growth, metastasis, and drug resistance in breast cancer (BC) patients. Therefore, serum cytokines (SC) may represent an exciting biomarker in the monitoring of BC pathogenesis.

Methods

Pretreatment serum from 204 BC patients (23% Luminal A, 23.6% Luminal B/HER2-, 22.5% Luminal B/HER2+, 10.3% HER2-enriched, and 20.6% Triple-Negative/Basal-like -TNBL-) and 50 healthy donors was collected. Measurement of 62 SC was performed using LEGENDplex immunoassay. Fluorescence intensity was quantified by flow cytometry. The results were correlated with age, tumor size and grade, vascular invasion, necrosis, phenotype, tumor-infiltrating lymphocytes, lymph node status, and Ki67. Statistical analysis was done by Student’s t-test and Mann–Whitney U test.

Results

BC patients showed higher levels of SCF, MIP3α, EPO and 4-1BB but lower levels of IL-2RA, IL-8, IL-12p40, IL-18, IL-23, IL-27, PDGF-AA, Galectin 9, PDGF-BB, B7.2, MIP1β and PD1, compared to the healthy group. Furthermore, IL-23, IL-27, and EPO correlated with younger age (p≤0.041), in contrast to Galectin 9, MCP1, IL-2RA, and MIP1β (p≤0.003). IL-12p40 and IFNγ were elevated in cases with grade I tumors (p≤0.05) and, in addition to IL-11 and IL-27 in low Ki67 tumors (p≤0.030). Moreover, IL-12p40 and IL-23 were associated with positive lymph nodes (p≤0.031). In Luminal tumors, we detected high IL-12p40, IL-15, IL-23, IL-27, and IFNγ (p≤0.048). However, only PDGF-BB was seen in non-Luminal tumor patients (p=0.040). IL-12p40, IL-18, IL-23, IL-27, SCF, and EPO were mainly higher in Luminal A, while PDGF-AA in Luminal B/HER2-. Likewise, MIP1β, MIP3α, and EPO were elevated in Luminal B/HER2+ serum, whereas Galectin9, PDGF-BB, IL-2RA, B7.2, SCF, 4-1BB, and PD1 were found in TNBL, with no specific profile for HER2-enriched.

Conclusions

Our results showed specific serum profiles of SC among BC phenotypes. Moreover, IL-12p40 and IL-23 were correlated with lymph node involvement in Luminal tumors, especially in Luminal A.

Legal entity responsible for the study

The authors.

Funding

Grant (SEAP-Proyecto Semilla; Expt. 200042); Biobank HGUA (21-154) and HUB-ICO-IDIBELL (PT17/0015/0024).

Disclosure

All authors have declared no conflicts of interest.

Background

T-DM1 is standard treatment in patients (pts) with HER2-positive breast cancer with residual disease after neoadjuvant therapy. The GIM26-TRASTHER study of the Gruppo Italiano Mammella (GIM) study group collects data from the Italian compassionate use program that anticipated drug reimbursement.

Methods

Inclusion criteria mirrored the Katherine trial. We registered adverse events (AEs) that were considered to be certainly/probably/possibly related to T-DM1 as per investigators’ judgement. We used descriptive analysis for data presentation.

Results

202 pts were included in 18 centers between Sep 2021 and Dec 2022. Median age was 52 years (IQR 45-59), 30% of the pts (n=61) were premenopausal and 56% (n=113) had at least 1 comorbidity (main: thyroid disorders 13%, hypertension 13%, dyslipidemia 4.5%). Smoking status was available for 156 pts, and 39 (25%) were current or former smokers. As neoadjuvant therapy, 85 % of the pts (n=169) received anthracycline plus taxane chemotherapy and 25 % (n=50) dual anti-HER2 blockade. Overall, 320 T-DM1-related AEs of any grade were registered in 105 pts (52%). G3 AEs were observed in 11 pts (5.4%), while there were no G4-G5 AEs. Most prevalent AEs of any grade were transaminases increase (19.8%), thrombocytopenia (15.3%), nausea and vomiting (13.3%), fatigue (10.9%), myalgia and arthralgia (7.4%), peripheral neuropathy (6.4%) and neutropenia (5%). For 42 out of 202 pts (20.8%), T-DM1 was reduced in dose, delayed or discontinued due to toxicity. Pts experiencing any grade AEs were older (54 vs 51, p=0.046), more frequently current or former smokers (34% vs 16.6%, p=0.034), and were less exposed to anthracyclines (79% vs 92%, p=0.012) as compared to those with no AEs. No impact of menopausal status, pre-existing comorbidities and type of neoadjuvant anti-HER2 therapy was observed.

Conclusions

In this multicentric Italian study, no new safety concerns of adjuvant T-DM1 were observed. Toxicity seems to be mostly linked by patient’s characteristics, underlying the importance of evaluating safety profile of anticancer drugs in a real-world setting in less selected pts. Further analyses, including survival outcomes, are ongoing.

Legal entity responsible for the study

GIM (Gruppo Italiano Mammella).

Funding

Roche.

Disclosure

F. Poggio: Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Pfizer; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Other: Daiichi Sankyo, Gilead. M. Tagliamento: Financial Interests, Personal, Other, travel grants: Roche, Bristol Myers Squibb; Financial Interests, Personal, Other: AstraZeneca; Financial Interests, Personal, Writing Engagements: Novartis, MSD, Amgen. M. De Laurentiis: Financial Interests, Personal, Advisory Board: Roche, Eli Lilly, Novartis, AstraZeneca, Seattle Genetics, Gilead, Ipsen, Takeda; Financial Interests, Personal, Research Grant: Puma Biotechnology, Macrogenics, Bristol Myers Squibb. A. Gennari: Financial Interests, Personal, Invited Speaker: Eisai, Novartis, Roche, Eli Lilly, Daiichi Sankyo, Gilead. M. Lambertini: Financial Interests, Personal, Advisory Board: Roche, Novartis, Eli Lilly, AstraZeneca, Gilead, MSD, Exact Science, Seattle Genetics; Financial Interests, Personal, Speaker’s Bureau: Takeda, Knight Terapeutics, Ipsen, Sandoz, Libbs; Financial Interests, Institutional, Research Grant: Gilead. L. Del Mastro: Financial Interests, Personal, Invited Speaker, Educational meeting: Novartis, Symposia, Andromeda E20, Vyvamed srl; Financial Interests, Personal, Invited Speaker, Lecture: Ipsen; Financial Interests, Personal, Advisory Board, Her2+ and TN breast cancer: Roche; Financial Interests, Personal, Invited Speaker, Consultancy for TNBC text: Roche; Financial Interests, Personal, Advisory Board, denosumab: Amgen; Financial Interests, Personal, Advisory Board, Early and metastatic BC: Eli Lilly; Financial Interests, Personal, Invited Speaker, CDK4-6 inhibitors: Eli Lilly; Financial Interests, Personal, Advisory Board, tucatinib: Seagen Int; Financial Interests, Personal, Advisory Board, Oncotype dx: Exact sciences, Havas life; Financial Interests, Personal, Advisory Board, Neratinib: Pierre Fabre; Financial Interests, Personal, Invited Speaker, Internal training: MSD; Financial Interests, Personal, Invited Speaker, Educational meetings: Accademia Nazionale Medicina; Financial Interests, Personal, Invited Speaker, Author for BC text: Pensiero Scientifico Editore; Financial Interests, Personal, Advisory Board, Breast cancer: Uvet; Financial Interests, Personal, Other, Author slide kits and interviews: Think2it; Financial Interests, Personal, Advisory Board, Palbociclib: Pfizer; Financial Interests, Personal, Invited Speaker, Breast cancer: Aristea, Meeting SrL; Financial Interests, Personal, Other, Author slide kits: Forum service; Financial Interests, Personal, Other, Author text about biosimilars: Edizioni Minerva Medica; Financial Interests, Personal, Other, consultant: Kardo srl; Financial Interests, Personal, Invited Speaker, Breast cancer meetings: Delphi international, Over srl; Financial Interests, Personal, Invited Speaker: Prex Srl, Editree; Financial Interests, Personal, Advisory Board: Uvet, Collage SpA, Daiichi Sankyo, AstraZeneca, Agendia, Gilead; Financial Interests, Personal, Other, Interview: Infomedica srl; Financial Interests, Personal, Other, Consultant: Sharing progress in cancer care - Switzerland; Financial Interests, Personal, Other, Consultancy: Eli lilly; Financial Interests, Institutional, Funding, National coordinating PI: Roche; Financial Interests, Institutional, Funding, Local PI: AstraZeneca, Roche, Eli Lilly, Daiichi Sankyo, Novella Clinical, Novartis; Non-Financial Interests, Institutional, Product Samples, Genomic Test: FoundationOne. All other authors have declared no conflicts of interest.

Background

Young age and pathogenic germline BRCA1 variants (gBRCA1m) are associated with high chemosensitivity and high rates of pathological complete response (pCR), meaning no residual tumor at surgical excision in breast or axilla after neoadjuvant chemotherapy. Yet, there is little data on how these factors interact regarding pCR and clinical subtypes.

Methods

The study included retrospective real-world data of young women with breast cancer before the age of 40 undergoing neoadjuvant chemotherapy. All patients were diagnosed between 2008-2019 and presented at Charité – Universitaetsmedizin Berlin. Patients with missing germline testing, pathogenic germline variants in BRCA2, or other high-risk cancer susceptibility gene variants were excluded from analysis. The association of pCR and gBRCA1m vs. wild-type BRCA1 variants (gBRCA1wt) was explored using a binary logistic regression model. The association was further investigated subtype-specifically with Chi-square tests.

Results

A total of 143 cases were included in the analysis, of which 62 (43.4%) achieved pCR. gBRCA1m was most prevalent in triple-negative patients (38/79) and less prevalent in HR+/Her2- (10/33) and Her2+ patients (2/31). Patients with gBRCA1m achieved pCR more often than patients with gBRCA1wt (58.0% vs. 35.5%). This was associated with a crude odds ratio of 2.51 (95% CI 1.24-5.08, p=0.010). The associated increase of the pCR-rate varied across clinical subtypes. gBRCA1m was associated with a significant increase of the pCR-rate in patients with HR+/Her2- subtype (60.0% vs. 8.7%, p=0.002) and a not significant increase in triple-negative patients (60.5% vs. 39.0%, p=0.056). Among Her2+ patients, both gBRCA1m patients did not achieve pCR and gBRCA1wt patients had a pCR rate of 51.7%.

Conclusions

Triple-negative and especially HR+/Her2- breast cancer in young women might be more chemosensitive if associated with a pathogenic germline variant in BRCA1. Therefore, the germline BRCA1 status should be included in evaluations of pCR in young women with breast cancer.

Clinical trial identification

DRKS00021459.

Legal entity responsible for the study

Charité-Universitaetsmedizin Berlin, Department of Gynecology with Breast Centre, AG Karsten-Speiser.

Funding

Has not received any funding.

Disclosure

J. Blohmer: Financial Interests, Personal and Institutional, Other, honoraria, AdBoard, training event funding: AstraZeneca, Daiichi Sankyo, Gilead, Lilly, MSD, Novartis, Pfizer, Roche, Seagen; Financial Interests, Personal and Institutional, Other, training event funding: BD, SonoScape, Somatex. D. Speiser: Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca. M.M. Karsten: Financial Interests, Personal, Invited Speaker: Roche, Gilead, Sysmex. All other authors have declared no conflicts of interest.