Treatment Of Metastatic Breast Cancer Research Articles

Abstract PO3-06-11: Undated analyses from a Phase Ib open-label study of Pucotenlimab (HX008) in combination with gemcitabine and cisplatin as first-line treatment of metastatic triple-negative breast cancer

Abstract Background: Gemcitabine plus cisplatin (GP) therapy war preferred in China as the first-line therapy for metastatic triple-negative breast cancer (mTNBC), with a median progression-free survival (PFS) of 7.73 months, and a median overall survival (OS) of 19.37 months [1]. Pucotenlimab (HX008) is a novel humanized IgG4 anti-PD-1 monoclonal antibody with an engineered Fc domain. Preliminary results from the phase 1b trial [2] have shown that HX008 combined with GP has a manageable safety profile and demonstrates promising antitumor activity in patients (pts) with mTNBC. Here, we present the updated results from the long-term survival analysis. Methods: Eligible subjects were those who were treatment-naïve mTNBC patients and had measurable lesion. Participants received HX008 at a dose of 3 mg/kg every 3 weeks in combination with chemotherapy (gemcitabine + cisplatin) for 6 cycles and maintained with HX008 until disease progression or unacceptable toxicity occurred. The primary endpoints included overall response rate (ORR) and safety, and the secondary endpoints included duration of response (DoR), PFS, and OS. Results: Between July 2019 and March 2020, a total of 31 pts were enrolled in this study. The median age of patients was 50 years (range 29–69). By the cut-off date (April 24th, 2023), the median follow-up period was 20.7 m (IQR: 12.2, 25.6). The confirmed ORR was consistent with the previously reported data and remains at 74.2% (95% CI: 55.4%, 88.1%). The median PFS was 9.0 months (95% CI, 7.3, 9.3). The median DoR was 7.3 months (95% CI, 5.0, 9.8). The OS was immature, with the result of 23.1 months (95% CI, 13.4, NE), while the 12-m, 24-m and 36-m OS rate was 77.4% (95%CI: 64.0%, 93.6%), 42.7% (95%CI: 28.0%, 65.3%), and 24.4% (95%CI: 11.3%, 52.7%), respectively. The most common grade 3 or 4 treatment-related adverse events included neutropenia (71.0%), leukopenia (45.2%), anemia (38.7%), and thrombocytopenia (32.3%). There was no treatment-related death and no new safety signals were identified. Conclusion: The combination therapy of HX008 plus GP demonstrates favorable clinical efficacy with a manageable safety profile in pts with mTNBC. The combination therapy led to a longer PFS and OS than GP therapy reported previously, regardless of PD-L1 status. The safety profile was consistent with the known toxic effects of each agent. In this updated analysis, no new safety signals were identified. Clinical trial information: NCT04750382

Abstract PO2-11-10: Can chemotherapy-induced peripheral neuropathy be predicted? Implications for future prevention and treatment of this side-effect

Abstract Background: The pain and sensory abnormalities associated with chemotherapy-induced peripheral neuropathy (CIPN) may persist for months or even years after chemotherapy. CIPN has a negative impact on routine activities, functions, and behaviors in the domestic, work, and social lives of cancer patients, adversely affecting the quality of their survivorship. CIPN is a major adverse effect of taxanes and other agents, possibly requiring dose-reduction or early termination of treatment. Taxane-based regimens are first-line treatment in both early-stage and metastatic breast cancer and therefore place numerous women at risk for developing CIPN. Regrettably, taxane-induced neurotoxicity can be arduous to predict, and there are no preventive or curative treatments currently available. Our work aims to assess a predictive tool for identification of patients at high risk of developing neuropathy and the progression of symptoms towards chronic CIPN. We hypothesized that oxidative stress might be a triggering event for the development of CIPN and that changes in glutathione recycling can identify patients at high risk for developing prolonged and severe CIPN. This hypothesis is based on reports in the literature proposing that CIPN is triggered by damage to the myelin sheath, which protects nerves from damage, by drug-induced free radicals in and around the nerves. Damage to myelin, a lipid- and protein rich sheath, by lipid peroxidation can result in loss of signal transmission, false signaling, or signal overload. Prolonged exposure to elevated levels of free radicals might result in structural changes to the nerves. Methods: Cancer patients seeking treatment at the Lankenau Medical Center Cancer center were asked to participate in our Institutional Review Board approved study of adverse effects. In this on-going study, the cohort (Ntotal =352) includes 104 breast cancer patients that are predominantly Caucasian with 14.9% African American. The median age is 56 (range 26 – 82) and 60.9% were treated with a taxane-based regimen. Nearly half the breast cancer group were diagnosed with Stage I disease. All consented patients donated a tube of blood prior to each treatment and filled out the Rotterdam Symptom Checklist (RSCL). Blood samples were analyzed for glutathione recycling using the ChemoTox assay (MNT™ Test, MYNARI Biomedical) and lipid peroxidation using a thiobarbituric acid reactive substances (TBARS) test (Cayman Chemical). All samples were analyzed in duplicate, and results analyzed using GraphPad Prism 8.4.3. Results: Preliminary results from the first 83 breast cancer patients showed African American patients reported a higher rate of NCCN grade 2 and 3 CIPN while Caucasians reported a higher rate of severe, long-lasting CIPN. Our results showed that patients who reported CIPN at later cycles had diminished glutathione recycling capacity already after the first treatment. Drop in recycling capacity had an inverse relationship with lipid peroxidation and grade of CIPN. Both decreased recycling capacity and increase in lipid oxidation were apparent already after the first treatment in patients that reported CIPN after cycle 6-8 or after completion of treatment Discussion: There are many proposed mechanisms for the development of CIPN. One mechanism that is shared by both most agents is damage induced by free radicals released following chemotherapy. We show that patients with reduced ability to neutralize free radicals have elevated and prolonged lipid peroxidation. Both processes precede the development of CIPN by several treatment cycles. Therefore, this test could identify patients that might benefit from other regimens rather than a taxane-based therapy. The test could also aid in the identification of patients for preventive therapy once such agents become available. Citation Format: Alisha Maity, Nolan Metz, Kathryn Fleck, Zonera Ali, Aarthi Shevade, Arezoo Ghaneie, Margaretha Wallon. Can chemotherapy-induced peripheral neuropathy be predicted? Implications for future prevention and treatment of this side-effect [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-11-10.

Abstract PO4-04-06: Exploring the use of tyrosine kinase inhibitors (TKIs) in the management of HER2-positive metastatic breast cancer post trastuzumab emtansine (T-DM1) therapy failure: Insights from a real-world study

Abstract Background Trastuzumab emtansine (T-DM1) is the established standard second-line treatment for HER2-positive metastatic breast cancer (MBC) patients who have previously received trastuzumab. However, there is ongoing debate regarding the subsequent therapeutic options following T-DM1 failure. This study aimed to evaluate the efficacy and safety of tyrosine kinase inhibitors (TKIs)-based therapy in HER2-positive MBC patients with resistance to T-DM1. Methods During the period from September 2018 to October 2021, a multicenter real-world study was conducted, enrolling a total of 53 patients diagnosed with HER2-positive metastatic breast cancer (MBC). These patients underwent TKIs-based therapy following the failure of T-DM1 treatment. The primary focus of the study was on evaluating progression-free survival (PFS) as the main endpoint. Secondary endpoints encompassed objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR), and safety assessments. Results A total of 53 patients received TKIs-based therapy as a second-line or later treatment. The median progression-free survival (PFS) for TKIs-based therapy was 11.9 months (95% CI 7.9-15.9). The objective response rate (ORR) and clinical benefit rate (CBR) were found to be 19.6% and 72.5%, respectively. Among patients with brain metastasis (n=12), a median PFS of 10.5 months (95% CI 7.5-13.5) and an intracranial ORR of 33.3% were observed. Patients treated with pyrotinib (n=21) showed improved PFS compared to those treated with lapatinib (n=30), as well as patients who had derived favorable benefit from T-DM1 (PFS ≥ 6 months). Hormone receptor status (HR) and response to T-DM1 were identified as independent factors affecting the effectiveness of TKIs-based therapy. The most frequently reported adverse events included thrombocytopenia (23.6%), diarrhea (15.7%), leucopenia (15.7%), and hand-foot syndrome (15.7%). Conclusion TKIs-based therapy demonstrated favorable effectiveness and safety in HER2-positive metastatic breast cancer (MBC) patients who had previously received T-DM1 but experienced treatment failure. This includes patients with brain metastases. Notably, individuals who derived favorable benefits from prior T-DM1 treatment displayed significantly prolonged progression-free survival (PFS) when undergoing subsequent TKIs-based therapy. Citation Format: Yongmei Yin, Chunxiao Sun, Yijia Hua, Nan Jin, Wei Li, Xiang Huang. Exploring the use of tyrosine kinase inhibitors (TKIs) in the management of HER2-positive metastatic breast cancer post trastuzumab emtansine (T-DM1) therapy failure: Insights from a real-world study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-06.

Abstract PS12-08: MORPHEUS Hormone Receptor-Positive Breast Cancer: interim analysis of a Phase Ib/II, study of fulvestrant ± atezolizumab and abemaciclib triplet treatment in patients metastatic disease

Abstract BACKGROUND Endocrine therapy (ET) is the mainstay of treatment for metastatic hormone receptor-positive breast cancer (HR+ BC). ET resistance and disease progression are expected, thus novel therapies, like cancer immunotherapy, are needed. Prior data suggest that abemaciclib (abema), a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, has immunomodulatory activity. In the MORPHEUS HR+ BC study (NCT03280563), atezolizumab (atezo; anti–programmed death-ligand 1 [PD-L1]) was tested in combination with fulvestrant (FUL), with and without abema, in patients (pts) with HR+ metastatic BC. We present 24-week interim analyses. METHODS Pts with measurable disease progression during first- or second-line therapy for metastatic or inoperable locally advanced HR+ BC and prior treatment with a CDK4/6 inhibitor were randomized to receive FUL (control) or FUL + atezo (1200 mg intravenous every 3 weeks) or FUL + atezo + abema (150 mg twice a day); prior FUL was not permitted. Pts were treated until loss of clinical benefit or unacceptable toxicity. Primary endpoints were objective response rate (ORR) per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 and safety. Progression-free survival (PFS) was a secondary endpoint. Baseline tumor samples were analyzed for PD-L1 expression (SP263), CD8 T cell infiltration, and gene expression by RNAseq. RESULTS As of Dec 2022, 40, 31, and 25 pts (38, 30, and 20 evaluable pts) were randomized to atezo + abema + FUL, atezo + FUL, and FUL, respectively. Pts were followed for ≥ 24 weeks. Demographics were similar among the groups, with most pts receiving prior palbociclib (palbo) as part of their only prior metastatic therapy. Details and best confirmed ORRs are shown in the table. Median PFS was 6.34 months (95% confidence interval [CI] 5.52, 16.03) in the atezo + abema + FUL arm, 3.15 months (95% CI 1.51, 7.79) in the atezo + FUL arm, and 1.95 months (95% CI 1.45, 4.93) in the FUL arm. The hazard ratio of atezo + abema + FUL vs FUL was 0.43 (95% CI 0.24, 0.78). Safety data are shown in the table. Mild/moderate (grade 1/2) interstitial lung disease (ILD)/pneumonitis (7.7%) was observed in the atezo + abema + FUL arm. At baseline, tumors exhibited low prevalence of PD-L1 (median immune cells: 0.5%, tumor cells: 0%) and CD8 infiltration (12% inflamed phenotype), which did not associate with response in any arm. RNAseq analysis indicated that response to atezo + abema + FUL was strongly associated with low baseline expression levels of proliferation and metabolism signatures and trended with high expression of some immune signatures. CONCLUSIONS The triplet therapy of atezo + abema + FUL showed improved ORR and PFS compared with FUL monotherapy in the second- or third-line setting post-CDK4/6 inhibitor. This combination of atezo + abema + FUL was tolerable, with no unexpected safety signals, including no high-grade ILD/pneumonitis. Efficacy and safety Data are number of patients (%), unless otherwise specified. * Patient was treated in the second line and incorrectly included in this group. Abema, abemaciclib; AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; atezo, atezolizumab; CDK4/6, cyclin-dependent kinase 4/6; CI, confidence interval; ful, fulvestrant; irAE, immune-related adverse event; L, line; ORR, objective response rate; PFS, progression-free survival; TRAE, treatment-related adverse event. Citation Format: Kyung Hae Jung, Seock-Ah Im, Denise Yardley, Sara Hurvitz, Keun Seok Lee, Amir Sonnenblick, Shlomit Shachar, Antoinette Tan, Elizabeth Comen, Einav Gal-Yam, Adam Brufsky, Hope Rugo, Jing Zhu, Kelly DuPree, Vanessa Breton, Fiona Young, Richard Schwab, Edward Cha, Melinda Telli. MORPHEUS Hormone Receptor-Positive Breast Cancer: interim analysis of a Phase Ib/II, study of fulvestrant ± atezolizumab and abemaciclib triplet treatment in patients metastatic disease [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS12-08.

Abstract PO2-20-07: A case report of a severe cutaneous adverse event in triple negative breast cancer treated with chemoimmunotherapy

Abstract Introduction Cutaneous adverse events related to immune checkpoint inhibitors (ICI) are common and most are mild. However, numerous case reports have documented severe ICI-related skin-toxicities such as Stevens-Johnsons Syndrome (SJS) most commonly among patients with melanoma and lung cancer as immunotherapy has now become a mainstay of treatment in these tumors. The use of ICIs in breast cancer treatment has only recently become standard of care for treatment of metastatic and high risk early-stage triple negative breast cancer with the publication of two landmark clinical trials, KEYNOTE-355 and KEYNOTE-522, respectively. While these trials report low rates of severe skin reactions, little is known about ICI-related severe skin toxicities in patients with breast cancer. Case description A 58-year-old female with clinical stage IIB (cT2N0M0) triple negative breast cancer was undergoing neoadjuvant treatment with pembrolizumab, an anti-programmed death (PD-1) monoclonal antibody, coupled with a chemotherapy back-bone of 12 weekly treatments of carboplatin and paclitaxel followed by 4 cycles of doxorubicin and cyclophosphamide. She developed an erythematous and itchy rash on the right breast and axilla approximately 61 days into her treatment course after having received her fourth dose of pembrolizumab. Over the next 10 days, she developed progression of the rash with painful red papules coalescing into reticulated plaques and dusky blistering of the skin involving the right arm, axilla, abdomen, inguinal folds, thigh, and back, totaling < 10% total body surface area. Notably, the rash did not have mucosal involvement. She was hospitalized for close monitoring and treatment. A punch biopsy of the rash revealed interface dermatitis with areas of full thickness skin necrosis consistent with erythema multiforme, SJS, toxic epidermal necrolysis (TEN), or a fixed drug eruption. Her skin continued to slough in the distribution of rash and a diagnosis of SJS was made. The patient had no response to initial treatment with high dose steroids. Cyclosporine was added, resulting in rapid improvement of her rash. The patient’s neoadjuvant treatment was stopped given the grade 3 SJS she experienced. Despite this truncated neoadjuvant treatment, she had excellent clinical response as her tumor was no longer palpable. She proceeded with a partial mastectomy and sentinel lymph node biopsy. Pathology revealed a pathological complete response. She did not receive any further systemic therapy in the adjuvant setting. Three months later, she was evaluated in clinic without evidence of SJS on physical exam. She was rapidly tapered off cyclosporine over one week without recurrence of her rash. Discussion Severe cutaneous adverse events related to ICIs remains an emerging area of study. In SJS, drug-specific CD8+ T lymphocytes utilize granulysin to mediate keratinocyte apoptosis. It is hypothesized that the blocking of the PD-1/PD-L1 interaction by ICIs results in the disruption of T-cell homeostasis leading to self-directed cytotoxic and inflammatory reactions and ultimately epidermal detachment. In contrast, Molina et al 2020 postulate that such ICI-related skin reactions may represent a separate clinical entity from SJS. In their case report of seven patients, they propose the term “progressive immunotherapy-related mucocutaneous eruption” (PIRME), which the authors suggest is characterized by delayed symptom onset, mild initial presentation, rare ocular involvement, benign clinical course, and favorable treatment response. Further characterization of ICI-related cutaneous adverse events is needed to understand the disease course, optimal treatment, and importantly, implications for re-challenging patients with immunotherapy. Clinicians taking care of breast cancer patients treated with ICIs need to be educated to recognize the associated skin toxicities as patients can rapidly worsen without appropriate treatment. Citation Format: Annie Zhang, Mara Beveridge, Bahar Moftakhar. A case report of a severe cutaneous adverse event in triple negative breast cancer treated with chemoimmunotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-07.

Abstract PO4-19-09: Comparison of clinical efficacy between letrozole + ribociclib vs. Fulvestrant + letrozole + ribociclib in Hormone receptor positive, HER2 negative metastatic breast cancer – a randomized, phase 2 study (KCSG BR22-20)

Abstract Background The current standard first-line treatment in advanced or metastatic hormone receptor (HR) positive breast cancer is combination of aromatase inhibitor (AI) and cyclin D kinase-4/6 (CDK4/6) inhibitor. Emergence of ESR1 mutation is a key mechanism of resistance during first-line AI + CDK4/6 inhibitor treatment. Selective estrogen receptor downregulator (SERD) such as elacestrant or fulvestrant is suggested as second-line treatment, but the progression-free survival (PFS) outcome of second-line treatment is reported up to 3.78 months in patients who harbour ESR1 mutation. Recently, early switch of AI + CDK4/6 inhibitor to fulvestrant + CDK4/6 inhibitor at the point of rising ESR1 mutation showed prolongation of PFS up to 6 months, suggesting there may be a new strategy to overcome ESR1 mutation by modifying endocrine treatment. SWOG S0226 suggested that upfront fulvestrant + AI is feasible and associated with prolongation of PFS compared to AI alone. After CDK4/6 inhibitor has been introduced to standard treatment, there were no trials evaluating the role of AI + fulvestrant with CDK4/6 inhibitor. In this trial, we investigated triplet combination of AI + fulvestrant + CDK4/6 inhibitor as a treatment to overcome resistant mechanism such as development of ESR1 mutation when compared to current standard treatment of AI + CDK4/6 inhibitor as the first line treatment in HR positive advanced or metastatic breast cancer. Methods This study is a randomized, multicenter, open-label phase II trial comparing AI plus ribociclib versus AI, fulvestrant plus ribociclib in HR-positive advanced or metastatic breast cancer. De novo patients or patients with treatment-free interval (TFI) over 12 months after completion of adjuvant AI can be enrolled. If patients received adjuvant tamoxifen, patients with TFI less than 12 months can be also enrolled for the study. Prior endocrine treatment or cytotoxic chemotherapy at metastatic setting was not allowed. In cases of premenopausal women, gonadotropin releasing hormone agonist (GnRHa) is administered every 4 weeks with treatment. A total of 202 patients will be enrolled for 30 months, and 30 months of follow-up is planned after last-patient enrolment. Patients are randomized to 1:1, stratified based on the presence of visceral metastasis and previous administration of adjuvant AI. Study treatment of the control arm consists of letrozole 2.5mg daily with ribociclib 600mg (Day 1-Day 21 daily by month, 1 week off) until progression. In the experimental arm fulvestrant 500mg intramuscular injection is added (Day 1, Day 15, Day 29 and every 4 weeks thereafter) until progression. For exploratory analysis of ESR1 mutations, circulating tumor DNA (ctDNA) is collected at baseline, and then every 3 months thereafter. Primary endpoint is to evaluate the difference of 24-months PFS rate. Secondary endpoint included PFS, overall survival (OS), emergence and frequency of ESR1 mutation, overall response rate (ORR) and clinical benefit rate (CBR). The analysis is planned after completion of 30 months of follow-up, which provides approximately 90% power to detect superiority 24 months-PFS rate assumed by Kaplan-Meier curve of letrozole + fulvestrant + ribociclib versus letrozole + ribociclib using a log-rank test, assuming a hazard ratio of 0.64 at a two-sided alpha of 0.2. Citation Format: Jieun Lee, Su-Jin Koh, Jung Hye Kwon, Gun Min Kim, Jee Hung Kim, Ho Young Kim, Hee-Jun Kim, Keon-Uk Park, Kyong Hwa Park, Yeon Hee Park, Mi Sun Ahn, Hee Kyung Ahn, Gyeong-Won Lee, Kyoung Eun Lee, Kyung-Hun Lee, Moon Hee Lee, Sung Sook Lee, Jung Lim Lee, Kyung Hae Jung, Joo Young Jung, In Hae Park. Comparison of clinical efficacy between letrozole + ribociclib vs. Fulvestrant + letrozole + ribociclib in Hormone receptor positive, HER2 negative metastatic breast cancer – a randomized, phase 2 study (KCSG BR22-20) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-19-09.

Abstract PS12-06: A phase 2 study of abemaciclib monotherapy for patients with retinoblastoma-positive (Rb+), triple-negative metastatic breast cancer

Abstract Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors can significantly extend survival when given in combination with endocrine therapy as treatment for hormone receptor-positive metastatic breast cancer. Preclinical studies suggest CDK4/6 inhibitor monotherapy might also be effective in a subset of triple-negative breast cancers (TNBCs), including those that express a functional retinoblastoma (RB) protein and/or those of the Luminal Androgen Receptor (LAR) subtype. Currently, the clinical activity of CDK4/6 inhibitor therapy in TNBC has not been reported. Methods: We conducted a single-arm phase II study of abemaciclib monotherapy in patients with locally advanced or metastatic TNBC. Key eligibility criteria included: (i) Measurable disease by RECIST 1.1; (ii) Between 1-3 prior lines of systemic therapy for advanced TNBC; (iii) RB-positive tumor (defined as ≥ 50% of tumor cells staining positive for RB by immunohistochemistry [archival or fresh sample] on central testing); (iv) ECOG PS 0/1. Patients were treated with abemaciclib 200 mg orally (28-day cycles) twice daily until disease progression, unacceptable toxicity, withdrawal of consent, or death. Tumor biopsies were mandatory at baseline and C2D1 if tumor tissue was safely accessible. The primary outcome was objective response rate (ORR). Key secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR: CR + PR + SD ≥ 24 weeks), and safety and tolerability. The study had a two-stage design. Thirteen patients were enrolled in the first stage, with the plan to enrol a further 25 patients if at least one objective response was observed. Results: One unconfirmed partial response was observed in stage 1, and a total of 27 patients were enrolled before the trial was closed early due to slow accrual. The median age was 61 years and patients had received a median of 2 prior lines of systemic therapy for metastatic disease. Twelve patients had received prior immunotherapy. After a median follow-up of 28.5 months, the confirmed ORR was 0% and the CBR was 15%, with 4 of 27 patients experiencing stable disease for ≥ 24 weeks. The median PFS was 1.94 months (95% CI: 1.8 – 11.5 months), and the median OS was 8.44 months (95% CI: 4.6 – 15.6 months). There was no significant difference in PFS or OS between patients with PD-L1-positive versus PD-L1-negative disease, or Androgen Receptor (AR) positive versus negative tumors by immunohistochemistry. The most common adverse events of grade 2 or higher were diarrhea (41%), neutropenia (41%), anemia (30%), and nausea (30%). RNA-sequencing of baseline biopsies has been performed to identify biomarkers associated with clinical benefit, and results will be presented at the meeting. Conclusions: Abemaciclib monotherapy did not show clinical activity in patients with Rb+ metastatic TNBC. This finding suggests that future trials of CDK4/6 inhibition as monotherapy in TNBC are not warranted. Citation Format: Shom Goel, Bojana Jovanović, Xiangying Chu, Melissa Hughes, Ayesha Mohammed-Abreu, Julie Kasparian, Timothy Erick, Molly DiLullo, Eileen Wrabel, Rinath Jeselsohn, Nabihah Tayob, Stuart Schnitt, Nancy Lin, Sara Tolaney. A phase 2 study of abemaciclib monotherapy for patients with retinoblastoma-positive (Rb+), triple-negative metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS12-06.

Abstract PO3-05-14: Practice patterns for sequential use of antibody-drug conjugate after antibody-drug conjugate in metastatic breast cancer: results from a physician survey

Abstract Introduction: Antibody-drug conjugates (ADCs) have become a key part of metastatic breast cancer (MBC) treatment. Trastuzumab deruxtecan (T-DXd), and Sacituzumab Govitecan (SG) are approved ADCs available for the treatment of MBC. Completed trials that led to the approval of these ADCs did not include patients who had received the other ADC as prior therapy. Little is known about the optimal sequencing of these agents and how clinicians are incorporating ADC sequencing decisions at bedside. Methods: An online survey regarding the use of sequential ADCs was distributed electronically from April 2023 to July 2023 among US clinicians who treat patients with breast cancer. The survey included eight questions assessing clinician practice settings and the use of ADC sequencing and five case-based scenarios (table 1). Descriptive statistics were used to assess survey responses. Results: 107 survey responses were received, out of which 72% were female responders and 93% were medical oncologists. The majority of responders practiced in an academic setting (83%) and reported being involved in clinical research (82%). 58% of responders have been in practice for >10 years and 68% treat >20 breast cancer patients per week. 87% had prescribed an ADC post-ADC for MBC. 46% of responders thought that the degree of benefit for an ADC post-ADC would be similar to the benefit noted in the pivotal ADC trials, and 54% thought that the degree of benefit with sequencing would be lower than in the pivotal trials. Regarding the case-based questions for patients with triple-negative breast cancer and HER2 low disease who had disease progression on first-line metastatic therapy, 64-71% of clinicians opted to give SG as the first ADC followed by T-DXd as the second ADC in sequence, regardless of age, PDL1 status and prior metastatic therapies. For a patient with hormone-positive (HR+), HER2 low MBC, who had received capecitabine as the first metastatic chemotherapy, 50% opted to give T-DXd as the first ADC followed by SG as the second ADC, and 40% opted to give weekly paclitaxel followed by SG as the first ADC. For a patient with HR+, HER2 low MBC who had received two prior chemotherapies for metastatic disease, 77% opted for T-DXd as the first ADC, followed by SG as the second sequential ADC. When grade 1 pneumonitis was added as a comorbidity to the case, only 16% opted to give T-DXd as the first ADC choice. Conclusion: Almost 90% of clinicians report prescribing sequential ADCs for MBC, yet there is little uniformity in how these ADCs are sequenced. More than 50% felt that the benefit of the second ADC in the sequence will be lower than the registration trials that led to the approval of the ADC in a setting of no prior ADC treatment. The optimal sequencing of ADCs remains an area of unmet need and further studies are needed to guide optimal medical decisions regarding sequential ADC-based treatment algorithms for patients with MBC. Table 1. Case-based scenarios for ADC sequencing Citation Format: Yara Abdou, Prarthna Bhardwaj, Rachel Abelman, Laura Spring, Aditya Bardia, Lisa Carey, Priyanka Sharma. Practice patterns for sequential use of antibody-drug conjugate after antibody-drug conjugate in metastatic breast cancer: results from a physician survey [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-05-14.

Abstract PO2-23-12: Innovative Metastatic Breast Cancer Therapy, CBT300, Reverses Drug and Immune Resistance

Abstract For many patients with metastatic breast cancer (MBC), their disease is treatable but incurable. Although the rate of death from MBC has significantly decreased over the last 10 years due to early detection and new treatment options, MBC still accounts for over 40,000 deaths each year in the US that has been consistent for the past 30 years. Recently, it is estimated that 90% of those deaths were due to drug resistant recurrent disease. Nearly 45% of MBC deaths can be attributed to a subpopulation of patients with metastatic triple negative breast cancer (mTNBC). Despite MBC’s initial sensitivity to chemotherapy, it often recurs at greater than 40% in stage I-III patients and greater than 80% in stage IV patients which have a dismal 5-year survival of 12%. African American women have a 40% greater incidence of death from MBC despite a 4% lower risk of diagnosis. Unfortunately, current therapies do little to reduce drug resistance and death for recurrent drug resistant MBC. Currently, the only therapies approved by the FDA for recurrent TNBC patients are Keytruda plus chemotherapy and an Antibody Drug Conjugate (ADC) called Sacituzumab Govitecan. Keytruda (anti-PD-L1) is an immune checkpoint inhibitor(ICI) given with chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin). The second recently approved therapy, Sacituzumab Govitecan (SG), is composed of an antibody to human trophoblast cell-surface antigen 2 (Trpo-2) coupled to SN-38 (topoisomerase I inhibitor). Although these results are very encouraging, the 80% of TNBC patients that either do not have high positive PD-L1 tumors, or don’t respond to these therapies and become drug resistant suggests that most patients with TNBC will have recurrent disease with little or no hope for survival. For contrast, our novel MBC therapy, CBT300, targets cell surface GRP78 that has been found in over 95% of MBC and in 93% of TNBC tumors. We can now show that inhibition of cell surface GRP78 can a) induce apoptosis of drug resistant TNBC cells in vitro and in vivo, b) eliminate drug resistance showing synergistic effects with chemotherapy in vitro and in vivo, c) decrease amount of chemotherapy in combination with CBT300 and d) reduce immune suppression. Recent publications show that GRP78 is found on many types of tumor cell surfaces but not on normal cell surfaces. In fact, tumor cell surface GRP78 (csGRP78) is important for many aspects of MBC development, including cell survival, proliferation, chemoresistance, angiogenesis, metastasis formation, immune suppression, and stem cell formation. Recently, it has been shown that increased cell surface GRP78 expression in TNBC patients was significantly associated with later stage, increased distant metastasis, increased aggressiveness, shorter disease-free survival, and decreased overall survival. In studies to help understand how cell surface GRP78 causes MBC progression and drug resistance, we discovered a novel GRP78 binding transmembrane protein on TNBC cells called Receptor Tyrosine Kinase Orphan Receptor-1 (ROR1). Using the GRP78 binding domain from ROR1 and a human Fc IgG1 domain, we created a biologic fusion protein that is a potent and cell surface specific GRP78 inhibitor, CBT300. We now show that CBT300’s elimination of cell surface GRP78 destabilizes and removes oncofetal proteins ROR1, Cripto-1, and checkpoint protein PD-L1 from tumor cell surfaces resulting in reversal of chemoresistance, reduction in immune suppression, inhibition of stem cell phenotype and increased tumor cell apoptosis. Since ROR1, Cripto-1 and PD-L1 are three of the major redundant pathways for tumor drug resistance, immune suppression and stem cell formation, the ability to inhibit all these pathways with CBT300, a single safe and very efficacious therapy, is very innovative and could be a significant advance for the treatment of MBC. Citation Format: Elizabeth Stolarik, Jorryn Zelek, Mariah Thigpen, Anita Davidson, Donald Davidson. Innovative Metastatic Breast Cancer Therapy, CBT300, Reverses Drug and Immune Resistance [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-23-12.

Abstract PO4-04-14: Change of first-line treatment pattern in metastatic luminal breast cancer: Results from the Austrian AGMT_MBC-Registry

Abstract Background: For patients with HR+/HER2- (luminal) metastatic breast cancer (MBC), international guidelines recommend endocrine-based first-line therapy [ET] in combination with a CDK4/6 inhibitor for most patients. Only for patients with imminent organ failure, first-line chemotherapy should be considered. To clarify changing patterns of first-line treatments over time in an Austrian population of luminal MBC patients, we analyzed the data from the MBC registry of the Austrian Study Group for Medical Tumor Therapy (AGMT-MBC-Registry). Methods: The AGMT-MBC-Registry is an ongoing multicenter registry for MBC patients in Austria. Only patients with luminal MBC and sufficient outcome data were included in this analysis. Patients were assigned to one of the following groups according to the year of start of first-line treatment for MBC: 2001-2010, 2011-2013 (no CDK4/6i available for first-line in both periods), 2014-2016 (CDK4/6i available in early access programs and clinical trials for first-line only), 2017-2019, and 2020-2022 (CDK4/6i available in both periods). Time to first chemotherapy (TTC) defined as start of first-line treatment until first application of a cytotoxic agent, and overall survival (OS) defined as start of first-line treatment until death were calculated by the Kaplan-Meier method and compared using the log-rank test. OS analysis was adjusted for disease free survival (DFS) category (de novo, DFS < 24 month, DFS ≥ 24 month), menopausal status (pre-, postmenopausal, unknown), age at diagnosis of metastatic disease (continuous), number of metastatic sites at diagnosis (1, 2-3, > 3), visceral disease (no, yes), and Charlson comorbidity index at diagnosis (continuous). Results: As of May 16th 2023, 1,330 patients with HR+/HER2- disease receiving at least one treatment-line for MBC were evaluable. First-line treatments significantly changed over time (P < 0.001). In patients diagnosed between 2001 and 2010, 61.4% were treated with first-line chemotherapy compared to 10.0% in patients diagnosed between 2020 and 2022 (Table 1). Additionally, TTC also significantly increased over time (P < 0.001; Table 2). In contrast, the proportion of patients treated with a first-line CDK4/6i plus endocrine therapy combination increased over time from 4.4% in 2014-2016 up to 75.5% in the period of 2020-2022. Additionally, adjusted median overall survival estimates significantly increased over time (P < 0.001; Table 2). Conclusion: In our registry, the proportion of patients with luminal MBC treated with first-line chemotherapy significantly decreased over time, whereas the proportion or patients treated with first-line CDK4-6 inhibitors significantly increased. This is in line with the change of guideline recommendation as well as the availability of CDK4-6 inhibitors over the last 2 decades. The availability of new treatment options has significantly increased median overall survival over time. Table 1: First-line treatment pattern over time Period N ET ET plus CDK4/6i Chemotherapy Others* 2001-2010 220 84 (38.2%) 0 (0.0%) 135 (61.4%) 1 (0.5%) 2011-2013 238 116 (48.7%) 0 (0.0%) 110 (46.2%) 12 (5.0%) 2014-2016 318 174 (54.7%) 14 (4.4%) 99 (31.1%) 31 (9.7%) 2017-2019 293 60 (20.5%) 190 (64.8%) 36 (12.3%) 7 (2.4%) 2020-2022 249 22 (8.8%) 188 (75.5%) 25 (10.0%) 14 (5.6%) Overall 1,318 456 (34.6%) 392 (29.7%) 405 (30.7%) 65 (4.9%) Legend: N - number of patients, ET - endocrine therapy (tamoxifen, aromatase inhibitor and/or fulvestrant), CDK4/6i - CDK4/6 inhibitor; * e.g. endocrine treatment plus everolimus or investigational study treatment Table 2: Time to first chemotherapy (TCC) and overall survial (OS) over time Period Median TTC [months] Adjusted median OS [months] 2001-2010 0.0 (0.0 - 0.0) 49.4 (41.2 - 56.6) 2011-2013 4.3 (0.0 - 13.8) 48.2 (38.3 – 69.7) 2014-2016 20.0 (14.0 - 26.4) 60.3 (50.2 - 77.5) 2017-2019 40.1 (33.3 - 59.8) 60.8 (52.8 - NR) 2020-now 30.4 (27.6 - NR) NR (NR - NR) Legend: N - number of patients, NR - not reached Citation Format: Gabriel Rinnerthaler, Simon Gampenrieder, Angelika Pichler, Walter Herz, Andreas Petzer, Renate Pusch, Marija Balic, Christoph Suppan, Sonja Heibl, Lukas Scagnetti, Margit Sandholzer, Clemens Schmitt, August Zabernigg, Daniel Egle, Petra Pichler, Christopher Hager, Florian Roitner, Johannes Andel, Kathrin Strasser-Weippl, Rupert Bartsch, Michael Hubalek, Michael Knauer, Christian F. Singer, Richard Greil. Change of first-line treatment pattern in metastatic luminal breast cancer: Results from the Austrian AGMT_MBC-Registry [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-14.

Abstract PO3-18-09: OPERA-01: A randomized, open-label, phase 3, study of palazestrant (OP-1250) vs standard-of-care treatment for ER+, HER2- advanced or metastatic breast cancer after endocrine and CDK4/6 inhibitor therapy

Abstract Background: In estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), adding a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor to endocrine therapy (ET) has improved outcomes and is the current standard-of-care treatment in the first-line setting. However, resistance to first-line treatment develops in most patients (pts), which is often attributed to acquired mutations in ESR1. Limited data exist for ET-based treatment options after progression on prior ET and CDK4/6 inhibitors, and most pts will transition to chemotherapy for further treatment. Therefore, there is a significant unmet need for more effective ET in pts with ER-positive, HER2-negative MBC to improve outcomes and delay time to chemotherapy. Palazestrant (OP-1250) is a small molecule oral complete ER antagonist (CERAN) and selective ER degrader (SERD) that binds the ligand binding domain of ER and completely blocks ER-driven transcriptional activity in both wild-type (ESR1-wt) and mutant (ESR1-mut) forms of ER. In preclinical studies, palazestrant demonstrated better tumor shrinkage in ESR1-wt and ESR1-mut models when compared to fulvestrant; it also showed efficacy in brain metastasis models. In a phase 1/2 monotherapy study in pts with heavily pretreated ER-positive, HER2-negative advanced breast cancer (BC) or MBC (NCT04505826), palazestrant showed a tolerable safety profile, promising antitumor efficacy, and favorable pharmacokinetics (PK) supporting once a day (qd) dosing. The recommended Phase 2 dose of palazestrant is 120 mg qd. Methods: The OPERA-01 trial is an international, multicenter, randomized, open-label, phase 3 clinical trial comparing the efficacy and safety of palazestrant as a single agent to standard-of-care ET (fulvestrant, anastrozole, letrozole, or exemestane) in pts with ER-positive, HER2-negative advanced BC or MBC that has relapsed or progressed on 1 or 2 prior lines of ET for MBC, which includes a CDK4/6 inhibitor. Eligible pts are women (pre- or post-menopausal) or men who have a confirmed diagnosis of ER-positive, HER2-negative locally advanced evaluable BC or MBC not amenable to curative therapy. ER and HER2 status are determined according to the American Society of Clinical Oncology/College of American Pathologists guidelines. Patients must have Eastern Cooperative Oncology Group performance status 0 or 1. Prior treatments must include 1 or 2 prior lines of ET as monotherapy or in combination with a CDK4/6 inhibitor for MBC; must have received CDK4/6 inhibitor in combination with ET and have disease progression during or within 28 days of completion of each line of prior treatment for MBC; most recent ET given for ≥6 months. Prior chemotherapy in the metastatic setting is not permitted. Patients (N∼500) are randomized to palazestrant or standard-of-care ET monotherapy, and are stratified by ESR1 mutation status, prior lines of ET for advanced disease (1 vs 2 lines), and presence or absence of visceral disease. The primary endpoint of progression-free survival will be assessed by blinded independent central review in pts with and without ESR1 mutations in the intent-to-treat population. Secondary endpoints include overall survival, antitumor activity (objective response rate, clinical benefit rate, and duration of response), safety, patient-reported outcomes, and PK in pts with and without ESR1 mutations. The study is planned to be conducted globally. Citation Format: Arlene Chan, Jane Meisel, Komal Jhaveri, Joo Hyuk Sohn, Meritxell Bellet- Ezquerra, Jason Schroeder, Mark Shilkrut, Barbara Pistilli. OPERA-01: A randomized, open-label, phase 3, study of palazestrant (OP-1250) vs standard-of-care treatment for ER+, HER2- advanced or metastatic breast cancer after endocrine and CDK4/6 inhibitor therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-18-09.

Abstract PO4-10-04: Treatment differences by race and age in metastatic hormone receptor-positive/HER2-negative breast cancer

Abstract Introduction: Black and younger patients are more likely to have aggressive forms of breast cancer. Endocrine therapy (ET) plus a CDK4/6 inhibitor is the standard of care first-line therapy for patients with hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer (MBC). Recent data has shown better outcomes with this approach compared to chemotherapy, even for patients with aggressive disease. Our study looked at differences in first-line treatment among Black and younger women with HR+/HER2- MBC. Methods: Clinical characteristics, treatment, and outcomes of patients diagnosed with HR+/HER2- MBC between 2011-2022 were retrieved from the UNC Metastatic Breast Cancer Database. Log binomial regression modeling compared treatment choices by group, and Cox proportional hazards regression modeling evaluated progression-free survival (PFS) from the start of treatment. Results: 524 patients were included in this analysis. 30% were young patients (< 50 years of age), 20% were Black patients, 62% had only 1 site of metastasis and 51% had visceral involvement. When looking at first-line treatment for metastatic disease, 21% of overall patients had received chemotherapy. The likelihood of receiving chemotherapy was higher for younger verses (vs) older patients (29% vs 18%, RR=1.63, p=0.004), for Black vs White patients (31% vs 18%, RR=1.71, p=0.002), and for those with visceral vs non-visceral involvement (26% vs 16%, RR=1.67, p=0.004). A model including age, race, and visceral involvement showed similar findings. Among patients who received ET as the first line treatment for metastatic disease, the likelihood of receiving CDK 4/6 inhibitors in addition to ET was lower for young Black patients compared to young White patients (41% vs 74%, RR=0.55, p=0.02). However, among older patients >=50, no significant difference was seen by race (Blacks 60% vs Whites 56%, RR=1.1, p=0.61). Adjusting for visceral involvement showed similar findings. Patients who received ET (with or without CDK 4/6 inhibitors) had better PFS compared to patients receiving chemotherapy as first-line therapy (HR 0.65, 95% CI 0.49, 0.88, p=0.005), this held true after adjusting for age, race, treatment group and visceral involvement (HR 0.7, p=0.02). A stratified analysis showed similar findings within Black patients (HR 0.42, p=0.003), and young patients (HR 0.55, p=0.01). Conclusion: Overall, Black and younger patients were more likely to receive chemotherapy as the first-line treatment for metastatic disease. Among patients who received ET as the first-line treatment for MBC, young Black patients were less likely to receive CDK 4/6 inhibitors compared to young White patients. Further studies are needed to outline the multi-level factors contributing to the identified disparities in care among patients with HR+/HER2- MBC. Citation Format: Yara Abdou, Joannie Ivory, Allison Deal, Ally Wardell, Amy Wheless, Claire Dees, Lisa Carey. Treatment differences by race and age in metastatic hormone receptor-positive/HER2-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-10-04.

Abstract PO2-16-10: Characterising HER2-low status in metastatic breast cancer: a real-world retrospective study of patients at a metropolitan cancer centre in Australia

Abstract Background: Traditionally, breast cancer subtyping has described patients as HER2-negative or HER2-positive, with the latter being those in whom HER2-directed therapies are utilised. A proportion of HER2-negative cancers can be classified as “HER2-low” as they express IHC 1+ or 2+ and are non-amplified on in-situ hybridisation (ISH). Until recently, our widely available HER2-targeted therapies have proven to be ineffective in this subtype. The DESTINY-BREAST04 trial (Modi et al, NEJM 2022) showed progression-free and overall survival efficacy of HER2-directed therapy using the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) in HER2-low disease, suggesting a need to identify this population for selected therapy. This study evaluated a real-world population of metastatic breast cancer (MBC) patients treated according to traditional breast cancer subtypes to determine the frequency of HER2-low histology, with a focus on selection of first-line therapy. Methods: This retrospective audit identified patients being treated for MBC at a single tertiary hospital (Austin Health in Melbourne, Australia) over a 3.5 year period. Patients were identified from an electronic database, with a date of last follow-up as August 2022. Medical records were interrogated for clinicopathological information including review of pathology reports for breast cancer subtypes. Traditional breast cancer subtypes were defined as (i) ER positive and HER2-negative (HER2 0 or 1+, or 2+ and non-amplified); (ii) HER2-positive (HER2 3+ and/or amplified) and (iii) TNBC (negative for ER and PgR, and HER2 0 or 1+, or 2+ and non-amplified). Selection and duration of first-line treatment for MBC was also recorded. Results: Between March 2018 and August 2022, 202 MBC patients were identified. Based on traditional subtypes, 126 (62%) were ER positive and HER2-negative, 46 (23%) were HER2-positive, 26 (13%) were TNBC and 4 (2%) were unknown. In the total population, 87 (43%) were classified as having HER2-low disease based on retrospective pathology reports. HER2-low represented 61% of ER positive, HER2-non amplified patients and 45% of TNBC patients. Metastatic specimen data was known for 172 cases and of these, 95 patients (55%) were re-biopsied on metastatic progression. This occurred more commonly with HER2-positive (81%) and ER positive HER2-negative (78%) primaries. The most common change in subtype was loss of ER, which occurred in 7 patients (3%). Changes in HER2 status occurred in 29 (14%) of patients, most commonly as either an increase from 1+ to 2+ or decrease from 1+ to 0. HER2-low status remained consistent for 67% of patients who underwent biopsy on recurrence. For patients with ER positive HER2-negative MBC, first-line combination therapy with a CDK4/6 inhibitor + AI was preferred (51%), followed by single agent endocrine therapy (30%) and chemotherapy (17%). The majority (84%) of HER2-positive patients received first-line dual HER2 therapy (trastuzumab and pertuzumab) with taxane chemotherapy. Half of TNBC patients received upfront chemotherapy, with physician preference being capecitabine (45%). There was no significant difference in PFS between the HER2-low vs. HER2-0 cohorts, for either ER positive or TNBC subtypes. No patients in this series were treated based on HER2-low definition due to no funded access to such therapies at the time. Conclusion: HER2-low has emerged as an identifier for patients who may respond to HER2-directed therapies using ADCs such as T-DXd. However, its clinical significance as a discrete clinical subtype remains uncertain. In this retrospective audit, HER2-low patients were identified in both ER positive and TNBC subtypes. Dynamic changes in HER2 staining occurred infrequently. Further evaluation is needed to address whether HER2-low expression provides any prognostic value and whether prospective reporting of HER2-low status may alter how these new HER2-directed therapies are used in future. Citation Format: Michelle Li, Belinda Yeo. Characterising HER2-low status in metastatic breast cancer: a real-world retrospective study of patients at a metropolitan cancer centre in Australia [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-16-10.

Retrospective Analysis of Pyrotinib-Based Therapy for Metastatic Breast Cancer: Promising Efficacy in Combination with Trastuzumab.

To evaluate the efficacy and safety of a pyrotinib-based therapy for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) in the real world. Clinical data of 218 patients with HER2-positive MBC who received a pyrotinib-based therapy from January 2020 to March 2023 at the First Affiliated Hospital of Zhengzhou University were retrospectively analyzed. Finally, 195 patients were included in the efficacy cohort. The median progression-free survival (PFS) in the total population is 12.4 months (95% CI, 9.8-15.0 months). More than half of the patients in the efficacy cohort received pyrotinib mono-targeted therapy (103 cases, 52.8%). Among the remaining patients, 74 (37.9%) patients chose a combined trastuzumab-targeted therapy and 17 (8.7%) chose to combine inetetamab. Median PFS in the pyrotinib group vs pyrotinib plus trastuzumab group was 10.5 months vs 20.1 months (P<0.001). The median PFS of primary trastuzumab resistance population reached to 20.1 months in pyrotinib plus trastuzumab group. Double-targets' advantage was also observed in the brain metastases subgroup (17.9 months vs 10.0 months, P=0.386). The patients who received pyrotinib plus inetetamab as second and higher-line treatment reached a median PFS of 7.9 months (95% CI, 4.0-11.8 months). Forty-one (19.8%) of 207 patients included in the safety cohort experienced grade 3 or higher diarrhea, the most common adverse event in safety analysis, and no adverse event-related deaths. The combination of pyrotinib and trastuzumab demonstrated promising efficacy in the treatment of HER2-positive metastatic breast cancer, including those who had primary resistance to trastuzumab and brain metastases. Pyrotinib plus trastuzumab is expected to be a potent option in the first-line. Additionally, the concurrent administration of pyrotinib and inetetamab could be an alternative to consider in the second and higher-line treatment for metastatic breast cancer. The adverse reactions of pyrotinib were tolerable in general.

Deep learning-assisted monitoring of trastuzumab efficacy in HER2-Overexpressing breast cancer via SERS immunoassays of tumor-derived urinary exosomal biomarkers

Monitoring drug efficacy is significant in the current concept of companion diagnostics in metastatic breast cancer. Trastuzumab, a drug targeting human epidermal growth factor receptor 2 (HER2), is an effective treatment for metastatic breast cancer. However, some patients develop resistance to this therapy; therefore, monitoring its efficacy is essential. Here, we describe a deep learning-assisted monitoring of trastuzumab efficacy based on a surface-enhanced Raman spectroscopy (SERS) immunoassay against HER2-overexpressing mouse urinary exosomes. Individual Raman reporters bearing the desired SERS tag and exosome capture substrate were prepared for the SERS immunoassay; SERS tag signals were collected to prepare deep learning training data. Using this deep learning algorithm, various complicated mixtures of SERS tags were successfully quantified and classified. Exosomal antigen levels of five types of cell-derived exosomes were determined using SERS-deep learning analysis and compared with those obtained via quantitative reverse transcription polymerase chain reaction and western blot analysis. Finally, drug efficacy was monitored via SERS-deep learning analysis using urinary exosomes from trastuzumab-treated mice. Use of this monitoring system should allow proactive responses to any treatment-resistant issues.

Efficacy and safety of pyrotinib combined with albumin-bound paclitaxel as first-line treatment for HER2-positive metastatic breast cancer in patients previously treated with adjuvant and/or neoadjuvant trastuzumab therapy: The stage 1 results of a single-arm, phase 2 prospective clinical trial.

It has been observed that the prognosis of patients with HER2-positive metastatic breast cancer has improved significantly with HER2-targeted agents. However, there is still a lack of evidence regarding first-line anti-HER2 treatment options for patients who have received adjuvant and/or neoadjuvant trastuzumab for HER2-positive metastatic breast cancer. Besides, there are no reliable markers that can predict the efficacy of anti-HER2 treatment in these patients. Patients who have received adjuvant and/or neoadjuvant trastuzumab for HER2-positive metastatic breast cancer were enrolled. Pyrotinib plus albumin-bound paclitaxel were used as first-line treatment. The primary endpoint was the objective response rate (ORR). The safety profile was also assessed. In order to explore predictive biomarkers using Olink technology, blood samples were collected dynamically. From December 2019 to August 2023, the first stage of the study involved 27 eligible patients. It has not yet reached the median PFS despite the median follow-up being 17.8 months. Efficacy evaluation showed that the ORR was 92.6%, and the DCR was 100%. Adverse events of grade 3 or higher included diarrhoea (29.6%), leukopenia (11.1%), neutropenia (25.9%), oral mucositis (3.7%), and hand-foot syndrome (3.7%). Toll-like receptor 3 (TLR3) and Proto-oncogene tyrosine-protein kinase receptor (RET) were proteins with significant relevance to PFS in these patients. This study demonstrates that pyrotinib plus albumin-bound paclitaxel as a first-line treatment regimen shows good efficacy and manageable safety for patients who have received adjuvant and/or neoadjuvant trastuzumab for HER2-positive metastatic breast cancer. Besides, a significant association was identified between the expression levels of TLR3 and RET and the PFS in patients.

Impact of COVID-19 on patients with metastatic breast cancer: REthink Access to Care and Treatment survey results.

Aim: Patients with metastatic breast cancer (MBC) may be vulnerable to changes in healthcare management, safety standards and protocols that occurred during the COVID-19 pandemic.Materials & methods: The REthink Access to Care & Treatment (REACT) survey assessed USA-based patient perspectives on COVID-19-related impacts to their MBC treatment experience between 27 April 2021 and 17 August 2021.Results: Participants (n=341; 98.5% females, mean age 50.8years) reported that overall oncology treatment quality was maintained during the pandemic. Delayed/canceled diagnostic imaging was reported by 44.9% of participants while telemedicine uptake was high among participants (80%).Conclusion: Overall, MBC care was minimally affected by the pandemic, possibly due to the expanded use of telemedicine, informing MBC management for future public health emergencies.

Cost-effectiveness of sacituzumab govitecan versus single-agent chemotherapy for metastatic triple-negative breast cancer: a trial-based analysis

BackgroundSacituzumab govitecan (SG) has recently been approved in China for the post-line treatment of metastatic triple-negative breast cancer (mTNBC). SG substantially improves progression-free survival and overall survival compared with single-agent chemotherapy for pretreated mTNBC. However, in view of the high price of SG, it is necessary to consider its value in terms of costs and outcomes. This study aimed to estimate the cost-effectiveness of SG versus single-agent treatment of physician’s choice (TPC) in the post-line setting for patients with mTNBC from a Chinese healthcare system perspective.MethodsThe cohort characteristics were sourced from the ASCENT randomized clinical trial, which enrolled 468 heavily pretreated patients with mTNBC between November 2017 and September 2019. A partitioned survival model was constructed to assess the long-term costs and effectiveness of SG versus TPC in the post-line treatment of mTNBC. Quality-adjusted life-months (QALMs) and total costs in 2022 US dollars were used to derive incremental cost effectiveness ratio (ICER). QALMs and costs were discounted at 5% annually. The willingness-to-pay (WTP) threshold was defined as $3188 per QALM, three times China’s average monthly per capita gross domestic product in 2022. One-way sensitivity analysis, probabilistic sensitivity analysis, and scenario analyses were performed to estimate the robustness of the results.ResultsTreatment with SG yielded an incremental 5.17 QALMs at a cost of $44,792 per QALM, much above the WTP threshold of $3188/QALM in China. One-way sensitivity analysis showed that SG price was a crucial factor in the ICER. Probabilistic sensitivity analysis revealed that the cost-effective acceptability of SG was 0% in the current setting. Scenario analyses indicated that the result was robust in all subgroups in ASCENT or under different time horizons. Furthermore, SG must reduce the price to enter the Chinese mainland market. When the monthly cost of SG reduce to $2298, SG has about 50% probability to be a preferred choice than TPC.ConclusionsSG was estimated to be not cost-effective compared with TPC for post-line treatment for mTNBC in China by the current price in HK under a WTP threshold of $3188 per QALM. A drastic price reduction is necessary to improve its cost-effectiveness.

Intra-arterial Chemotherapy in Patients With Metastatic Breast Cancer: A Scoping Review.

Breast cancer is a common malignancy in women, and the survival rate for this cancer is low once itmetastasized. Currently, chemotherapy is the first-line treatment for metastatic breast cancer (MBC). However, when liver metastases (LM) are present, the response to chemotherapy is poor. Regional intra-arterial chemotherapy (RIAC) delivers a high concentration of anticancer drugs to the malignant tissue, which improves the survival rate of patients with LM. It also decreases systemic side effects associated with chemotherapy. RIAC leads to higher remission rates becauseitdirectly targets the affected area. When RIAC is used alongside systemic chemotherapy, tumor resistance is decreased, increasing the rates of remission. This review aims to introduce the use of RIAC in patients with MBC. RIAC is a relatively new therapy in interventional oncology, and thus, limited research is currently available.

Design, synthesis, and biological evaluation of cathepsin B cleavage albumin-binding SN38 prodrug in breast cancer

Here, we introduce a novel and effective approach utilizing a cathepsin B cleavage albumin-binding SN38 prodrug specifically designed for the treatment of metastatic breast cancer. Termed Mal-va-mac-SN38, our prodrug exhibits a unique ability to rapidly and covalently bind with endogenous albumin, resulting in the formation of HSA-va-mac-SN38. This prodrug demonstrates exceptional stability in human plasma. Importantly, HSA-va-mac-SN38 showcases an impressive enhancement in cellular uptake by 4T1 breast cancer cells, primarily facilitated through caveolin-mediated endocytosis. Intriguingly, the release of the active SN38, is triggered by the enzymatic activity of cathepsin B within the lysosomal environment. In vivo studies employing a lung metastasis 4T1 breast cancer model underscore the potency of HSA-va-mac-SN38. Histological immunohistochemical analyses further illuminate the multifaceted impact of our prodrug, showcasing elevated levels of apoptosis, downregulated expression of matrix metalloproteinases, and inhibition of angiogenesis, all critical factors contributing to the anti-metastatic effect observed. Biodistribution studies elucidate the capacity of Mal-va-mac-SN38 to augment tumor accumulation through covalent binding to serum albumin, presenting a potential avenue for targeted therapeutic interventions. Collectively, our findings propose a promising therapeutic avenue for metastatic breast cancer, through the utilization of a cathepsin B-cleavable albumin-binding prodrug.