Pathological information for Breast Cancer therapy

Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials

Purpose: Somatic mutations in the tyrosine kinase domain of human epidermal growth factor receptor2 (HER2) have been reported to lead to resistance to HER2-targeted therapies in HER2-positive breast cancer, while activating mutations of HER2 have been described in HER2-negative breast cancer. The prevalence, clinicopathological characteristics, and phenotypes of HER2 mutations are not well established, thus we sought to describe the HER2 mutation profile of Chinese breast cancer patients. Methods: DNA samples were gathered from breast cancer patients undergoing neoadjuvant (N=102) or adjuvant therapy (N=498) at Fudan University Shanghai Cancer Center between January 1, 2006 and December 31, 2012. Sanger sequencing was performed to analyze all exons of HER2 to identify somatic mutations. To determine the phenotypes of novel HER2 mutations, in vitro kinase assays, protein structure analysis, cell culture, and xenograft experiments were conducted. Results: 10 HER2 somatic mutations were observed in 17 patients (17/600, 2.83%). 7 novel HER2 mutations were uncovered, 4 in the transmembrane domain and 3 in the kinase domain. Kinase domain mutations L768S and V773L were detected in HER2-negative tumors, while K753E was found in HER2-positive disease. In vitro kinase assays found that L768S and V773L exhibited a significant increase of tyrosine kinase-specific activity, while Western blots showed that L768S and V773L strongly increased phosphorylation of all signaling proteins in both MCF10A and MCF7cell lines, indicating that they were activating mutations. In Matrigel cultures, L768S and V773L formed acini when seeded in vehicle, but maintained spherical morphology when seeded in culture containing trastuzumab. The addition of lapatinib in Matrigel culture inhibited the growth of all except K753E, which was successfully inhibited by neratinib. Similarly, L768S, V773L and K753E increased the number of cell colonies formed in soft agar, trastuzumab and lapatinib treatment decreased the number of colonies formed by L768S and V773L, but only neratinib could inhibit the colony growth of K753E. Xenograft showed L768S and V773L displayed a more rapid growth, while K753E showed resistance to lapatinib in vivo. MCF10A cells bearing K753E mutation were found to be resistant to lapatinib (IC50>10,000 nmol/L), but could be inhibited by neratinib, though requiring a relatively higher dosage (IC50 of 32 nmol/L) than HER2 WT (IC50 of 480 nmol/L for lapatinib, <2 nmol/L for neratinib) and other HER2 mutations. Meanwhile, clinical follow-up showed that the 2 patients with K753E mutation who received adjuvant trastuzumab treatment presented with either brain or bone metastasis, in their 3rd and 5th year after initial cancer diagnosis, suggesting K753E mutation may have a role in trastuzumab resistance as well. Conclusions: HER2 somatic mutations were found in 2.83% of patients in this study. HER2-positive tumors harboring certain HER2 kinase domain resistance mutations may not benefit from trastuzumab or lapatinib treatment, and neratinib may offer an alternative treatment option for these patients. HER2-negative disease with activating mutations may benefit from HER2-targeted therapies, and may be of interest in prospective clinical trials. Citation Format: Wen-Jia Zuo, Yi-Zhou Jiang, Ke-Da Yu, Zhi-Ming Shao. Activating HER2 mutations promote oncogenesis and resistance to HER2-targeted therapies in breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-04-04.

Background: The combination of CDK 4/6 inhibition and endocrine therapy has emerged as the new first line standard of care treatment for patients with hormone receptor (HR) +ve metastatic breast cancer (MBC)1. Ribociclib plus letrozole has been shown to improve PFS (25.3 vs 16.0 months; log-rank P=9.63x10-8) compared to letrozole alone2. More recently, this benefit has also been demonstrated in pre- and peri-menopausal women in combination with ovarian suppression and tamoxifen or an aromatase inhibitor (AI), with an improved overall survival (40.9 months vs OS not reached; HR = 0.712; p=0.00973) in the MONALEESA-7 study3. Approximately 800 patients in Australia participated in the ribociclib medicine access program (MAP) between May 2017 and June 2018, prior to government funding. Beyond eligibility criteria for the program and clinician name, no patient data was initially captured, consistent with usual practice for MAPs, due to the multiple challenges related to ethics, data ownership, security and patient privacy. We have previously demonstrated the feasibility of successful data collection alongside MAPs4 which can yield benefits for clinicians, industry and the broader medical community. Based on this we plan to retrospectively collect data for patients treated as part of the Australian ribociclib MAP. Trial Design: This is a secondary data use, non-interventional study of patients in Australia who received treatment with the combination of an AI and ribociclib, obtained via a MAP, for HR+ HER2- MBC. The target sample size is 250 patients from ~15 sites. De-identified patient data will be retrieved from the patient’s medical records and entered on to an electronic case report form. Data collection is anticipated to commence in July 2019 with the final treatment and survival outcomes collected in late 2020, thus allowing for a minimum of 24 month follow up for all patients from the start date of treatment with ribociclib and AI (May 2017 - June 2018). Study Aims: The primary aim of the study is to describe real world clinical and tumour characteristics of patients with HR+ HER2-ve MBC in Australia who are recommended and received ribociclib in combination with an aromatase inhibitor in the first line setting. Details of adjuvant therapy received and the tolerability of the treatment combination including dose interruptions, dose reductions and significant adverse events of interest related to ribociclib will be assessed. Secondary aims include time to treatment progression and progression free survival for the ribociclib and AI combination, and to explore the disease course post progression, including clinician choice of subsequent lines of therapy in routine clinical practice.

Safety of adjuvant CDK4/6 inhibitors during the COVID-19 pandemic.

Para-toluenesulfonamide, a novel potent carbonic anhydrase inhibitor, improves hypoxia-induced metastatic breast cancer cell viability and prevents resistance to αPD-1 therapy in triple-negative breast cancer

Emerging role of ferroptosis in breast cancer: New dawn for overcoming tumor progression

Neoadjuvant trials provide endpoints, such as pathological complete response (pCR) to treatment, that will potentially translate into meaningful improvements in overall survival and disease-free survival. Neoadjuvant trials need smaller sample sizes and are less expensive, and the endpoint of pCR is achieved in months, rather than years. For these reasons, the neoadjuvant setting is ideal for testing emerging targeted therapies in early breast cancer. Recently the US Food and Drug Administration has released a draft Guidance to Industry, outlining a pathway to accelerated approval for neoadjuvant breast cancer therapies using pCR. The association between pCR and outcome is clear for chemotherapy in triple-negative breast cancer and for HER2-targeted agents in HER2-positive disease, but might not hold true for other tumor subtypes such as luminal cancers. Since pCR is rarely achieved with either chemotherapy or endocrine therapy in hormone-receptor-positive breast cancer, in this setting we need to identify different intermediate endpoints, which might be translational endpoints within "window-of-opportunity," "residual disease," and "genome forward" trials. Prospective validation of effective noninvasive techniques for monitoring of residual disease burden could enhance the ability to identify promising targeted therapies in the neoadjuvant setting.

Background: The incidence of central nervous system (CNS) metastases in breast cancer is increasing. While local treatments such as surgery and radiation remain standard, systemic therapies have shown promise in HER2-positive disease. However, data on the efficacy of systemic therapy in HER2-low breast cancer with CNS involvement remain limited. This study describes outcomes of upfront systemic therapy in HER2-low breast cancer patients with CNS metastases treated at a single institution. Methods: We retrospectively reviewed breast cancer patients with CNS metastases treated at Henry Ford Health between Jan 2014 and July 2024. HER2-low status was defined as: HER2 immunohistochemistry 1+, or 2+ with negative fluorescent in situ hybridization (FISH). Eligible patients received no concurrent local CNS therapy; prior local treatment was permitted if unrelated to the studied lesions. CNS responses were to be assessed using the Response Assessment in Neuro-Oncology for brain metastases (RANO-BM) or the modified RANO-LM (leptomeningeal metastases) criteria. Results: Sixteen HER2-low patients were included. The median age was 56 years (range, 38-93); 63% (n = 10) were African American. Most (75%) had hormone receptor-positive disease, and 53% presented with de novo metastatic disease. Thirteen patients (81%) had HER2 IHC 1+, and only three had HER2 IHC 2+/FISH-negative disease. The majority (88%) had parenchymal CNS metastases; one patient had leptomeningeal disease, and one had both. Eight patients (50%) had prior CNS metastases, and 38% received local therapy before study inclusion. Notably, a significant proportion of patients (88%) had non-measurable disease by RANO-BM criteria (lesions <10 mm), with 69% having lesions smaller than 5 mm. Systemic therapies for the CNS disease included cytotoxic chemotherapy in seven patients (44%), trastuzumab deruxtecan (T-DXd) in four (25%), abemaciclib in two (13%), other CDK4/6 inhibitors in two (13%), and sacituzumab govitecan in one (6%). Commonly utilized chemotherapy included taxanes (paclitaxel or nab-paclitaxel) in 4 of 7 patients. In the 16 patients, the overall response rate (ORR) was 31.3%, the disease control rate (DCR) was 56.3%, the median duration of response (DOR) was 7 months, and the median progression-free survival (PFS) was 2 months. In a comparison cohort of HER2-positive patients (n=17), ORR was 53%, DCR was significantly higher at 94% (p=0.017), with similar DOR (5 months), and numerically longer PFS (3 months, p=0.351). Outcomes among the African American patients (n=10) mirrored the overall HER2-low group, with ORR 30%, DCR 50%, DOR 5 months, and PFS 1 month. Notably, the patients with HER2 IHC 2+ tumors (n=3; all HR+) experienced higher benefit (ORR 67%, DCR 100%) with no disease progression at last follow-up. HER2-low patients treated with T-DXd (n=4) demonstrated a DCR of 75%, with only one progression. Chemotherapy yielded a poor ORR of 29%, though two patients achieved complete CNS responses with taxane-based regimens. Conclusion: This “real-world” experience highlights modest intracranial activity of systemic therapy in HER2-low breast cancer with CNS metastases. Although response rates were lower than in HER2-positive counterparts, HER2 2+ tumors and patients treated with T-DXd showed encouraging outcomes. These findings support the need for prospective studies focusing on HER2-low CNS disease and suggest T-DXd as a promising therapeutic option, even in the absence of concurrent local treatment. Additionally, our study underscores a unique challenge in the management of breast cancer and brain metastases: CNS lesions are often smaller than the >10 mm threshold typically required for clinical trial eligibility, necessitating special attention and adapted approaches for response assessment. Citation Format: B. Ghimire, L. Rogers, M. Girgis. Efficacy of systemic therapy in HER2-low breast cancer with CNS metastases: a “real-world” experience [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-05-28.

A role of SIPL1/SHARPIN in promoting resistance to hormone therapy in breast cancer

Radiomics Based on DCE-MRI for Predicting Response to Neoadjuvant Therapy in Breast Cancer

Background: Breast cancer is one of the most common cancers in women. Approximately 232,670 new cases of breast cancer (14% of all new cancer cases) and 40,000 breast cancer deaths (6,8% of all cancer deaths) are expected to occur among US women in 2014. Since 1990, breast cancer death rates have dropped by 34%. Continued progress in the control of breast cancer will require sustained and increased efforts to provide high-quality screening, diagnosis, and treatment Recently, the MAMmography with Molecular Imaging (MAMMI) dedicated breast PET (dbPET) has emerged as an additional imaging tool for breast cancer diagnosis, clarification of complex lesions and therapy follow-up. This study is aimed to determine whether correlations exist between physiological images with 18FDG of pre, post-2-cycles and post Neoadjuvant Chemotherapy, with a predictive value of response. Methods: Twenty-five patients, and three scan points: pre, 2 cycle and post Neoadjuvant Chemotherapy were included in this analysis A prone position high-resolution dedicated breast PET (MAMMI-dbPET) was performed 60 min after administration of 90-120 MBq of 18F-FDG. Maximum standardized uptake value (SUVmax) quantification, volume characterization, positioning in all three space-axes, distances to reference points (proximal breast limit, nipple areola complex) were registered. Results: When treatment was successful, a significant difference was found between pre and post neoadyuvant chemotherapy status and the SUVmax (p < 0.001) of breast tumors. Pre Neoadjuvant (mean SUVmax, 11.4) demonstrated a significantly higher SUVmax than did post 2 cycles tumors (median SUV, 4.7) (p= 0.025). No statistical significant difference was found for SUVmax of post-2 cycles vs. post lesions with a mean SUVmax of 4.7 and 3.9 (p=0.25) respectively. A statistically significant difference was found for volume measurement of pre vs. post-2 cycles vs post Neoadjuvant therapy lesions. A clear qualitative difference by three different observers has been reported among dbPET and MRI volume characterization. A 21% of volume (measurement) discrepancies was found, always with a volume over-estimation by magnetic resonance (structural vs functional imaging). An exquisite -and unexpected- millimetric correlation with post-surgical pathology at the end of neoadjuvant theraphy has been found in dbPET images. Conclusions: dbPET MAMMI has proven to be an excellent tool for quantification, 3D spatial localization and monitoring of neoadjuvant therapy, showing, thanks to its functional nature, earlier and better precision and accuracy than conventional techniques (MRI). Post 2-cycle and Post Neodayuvant Chemotherapy breast cancer tumors consistently display lower 18FDG uptake than pre treatment tumors when treatment is successful. This data suggest that SUVmax measurements of 18FDG-dedicated breast PET can provide valuable information about therapy efficiency. Such an association might be of relevant importance to treatment continuity or adjustement. Citation Format: Michel Herranz, Ines Dominguez, Alvaro Ruibal, Elena Brozos, Sze Yiun Teo, Carmela Rodriguez, Jasper Chaal, Maria Teresa Curiel, Juan Cueva, Beatriz Fernandez, Gabriel G Pavón, Marielle Fortier, Rafael Lopez. Dedicated breast PET (dbPET) a unique functional new tool to accurate quantify response to neoadjuvant therapy in breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-11-11.

ImportanceThe androgen receptor (AR) pathway is emerging as a potential therapeutic target in breast cancer. To date, AR-targeted drugs have been approved only for treatment of prostate cancer; however, AR-targeted treatment for breast cancer is an area of active investigation. Through review of preclinical studies, retrospective clinical studies, and clinical trials, we examined the biology of AR and AR-related pathways, the potential for AR-targeted therapies in breast cancer, and potential biomarkers for AR-targeted treatments.ObservationsThe rate of AR positivity in breast cancer is about 60% to 80%. Biologically, the AR pathway has cross-talk with several other key signaling pathways, including the PI3K/Akt/mTOR and MAPK pathways, and with other receptors, including estrogen receptor and human epidermal growth factor receptor-2. The value of AR positivity as a prognostic marker has not yet been defined. Androgen receptor–targeted therapies, including AR agonists, AR antagonists, and PI3K inhibitors, have shown promising results in clinical trials in patients with breast cancer, and combinations of AR-targeted therapies with other agents have been investigated for overcoming resistance to AR-targeted therapies. Biomarkers to stratify patients according to the likelihood of response to AR-targeted drugs are yet to be established. Potential biomarkers of response to AR inhibitors include AR phosphorylation and AR gene expression.Conclusions and RelevanceAndrogen receptor–targeted treatments for breast cancer are in development and have shown promising preliminary results. In-depth understanding of AR and AR-related signaling pathways would improve the treatment strategies for AR-positive breast cancer. Further preclinical and clinical studies of AR-targeted drugs alone and in combination with other drugs are justified and warranted to clarify the biology of AR and inform the development of AR-targeted therapies to improve survival outcome in patients with breast cancer.

Relation between chemotherapy dose, oestrogen receptor expression, and body-mass index

Background: (Metastatic) breast cancer is a heterogeneous entity in which every disease subtype requires an individualized systemic treatment approach. Methods: We reviewed the currently available data regarding systemic therapy of breast cancer and present a review of historical and current treatment approaches, with the publications cited covering a time span from 1896 to the last ASCO 2015. Results: Systemic therapy of metastatic breast cancer may include chemotherapy, endocrine therapy, and targeted therapies (e.g. antibody-based approaches). Based on the patient's breast cancer subtype, these agents may be employed alone or in combination. Therefore, characterization of the phenotype of the disease is necessary and may include biopsy of the metastatic site. Novel therapeutic approaches include immunologic therapies as well as PARP, PI3K and CDK 4/6 inhibitors, which are currently under investigation in clinical trials. Conclusion: Systemic therapy of metastatic breast cancer requires complex and individualized treatment approaches that are best offered in an interdisciplinary setting.

To investigate the value (survival benefit and cost) of first-line chemotherapy and targeted therapy in breast cancer at a population level. Based on guideline recommendations, a model of optimal utilisation was constructed for first-line chemotherapy and targeted therapy in breast cancer, calculating the survival benefit and average cost of all regimens recommended for each treatment indication at 5years and at 10years. Survival benefits from chemotherapy and targeted therapy differ markedly depending on the treatment indications. The cost per life-year gained at 5years is $38,044 for stages I and II, $33,749 for stage III and $ 151,668 for patients presenting with stage IV breast cancer. The cost per life-year gained at 10years is $ 13,587 for early breast cancer. The most expensive chemotherapy indication in breast cancer is the treatment of metastatic HER2-positive breast cancer costing $330,978 per LYG for a survival benefit of 11% at 5years falling to zero survival benefit at 10years. There are large differences in value between the different indications for first-course chemotherapy and targeted therapy in the treatment of breast cancer that should be considered when pricing cancer drugs.