Neoadjuvant therapies can result in pathologic complete response (pCR) in patients with breast cancer, which can be predictive of long-term outcomes. Patients with estrogen receptor positive (ER +) tumors may receive either neoadjuvant chemotherapy (NAC) or neoadjuvant endocrine therapy (NET). We sought to compare survival outcomes in those with non-metastatic ER + breast cancer who received NET or NAC and achieved pCR.

All patients diagnosed with ER + /HER2- stage I-III breast cancer, who received neoadjuvant systemic therapy followed by surgery, and achieved pCR, were selected from the National Cancer Database (NCDB, 2010-2021). The Kaplan-Meier method was used to estimate overall survival (OS), and log-rank tests were used to test for differences in OS. Cox Proportional Hazards models were used to estimate the association of NAC vs NET with OS, after adjustment for covariates.

3313 patients met eligibility criteria: 3148 received NAC and 165 NET. The median follow-up for the entire cohort was 82 months (95% CI 80.4-83.1). Patients who received NAC were significantly younger (median age: NAC 49y vs NET 64y; p < 0.001), more likely to have a comorbidity score of 0 (NAC 89.3% vs NET 81.2%, p = 0.004), and more likely to have private insurance (NAC 68.9% vs NET 44.2%, p < 0.001). There were no significant differences between the NAC and NET patients based on race and ethnicity, income, education, or community type (all p > 0.05). The NAC treated patients were more likely to have larger tumors [median tumor size (IQR): NAC 3 cm (2.0-4.3) vs NET 1.3 cm (0.7-2.8); p < 0.001)], ductal histology (NAC 92.6% vs 81.2%, p < 0.001), and grade 3 tumors (NAC 70.2% vs 10.3%, p < 0.001). In the unadjusted Kaplan-Meier analysis, there was no significant difference in OS between NAC vs NET [5-year OS: NAC 0.935 vs NET 0.916; p = 0.08]. After adjustment for demographics, disease characteristics, and treatments, there remained no association between OS and study group (NAC vs NET; p = 0.63).

Patients with ER + /HER2- early-stage breast cancer who achieved pCR had similar OS, regardless of whether they received NAC or NET. As such, pCR appears to have similar prognostic value irrespective of the type of systemic therapy used to obtain this favorable outcome.

Neoadjuvant chemotherapy has been used to evaluate tumor response and downstage hormone sensitive localized breast cancers. However, complete pathological responses are uncommon. Neoadjuvant endocrine therapy (NET) has been used sparingly for the treatment of hormone receptor (HR)-positive breast cancers and frequently for six months or less. There is no clear definition of response to NET nor well-defined parameters for duration of treatment.

A retrospective chart review of patients with HR-positive localized invasive breast cancers treated with NET for at least 2 months was performed at a single institution. Clinical features, drug selection, duration of therapy, type of surgery as well as pathological characteristics, and residual tumor cellularity were analyzed. A multivariable linear regression model was used to examine the association between NET length and residual invasive tumor cellularity.

104 evaluable HR-positive invasive breast cancers were treated with NET over an 11-year period. Median age was 69 (range: 31-89) and 88% were post-menopausal. The median duration of treatment was 8 months, with 61% having at least 7 months. Patients receiving NET for 7 months or longer had a significantly lower residual cellularity (20.4%) compared to those treated 2-6 months (34.9%) (p = 0.006). Both pre-treatment and post-treatment Ki-67 ≤ 10% were associated with a lower residual invasive tumor cellularity. Residual invasive cellularity was not associated with menopausal status or NET agent.

Longer NET duration is associated with greater tumor response. Mean residual invasive tumor cellularity was 42% lower among patients receiving 7 or more months of NET.

Neoadjuvant endocrine therapy (NET) in oestrogen receptor-positive /HER2-negative breast cancer (ER+/HER2- BC) allows real-time evaluation of treatment sensitivity by monitoring tumour response and offers the opportunity of personalised therapy. However, the lack of reproducible biomarkers to assess response and long-term prognosis after NET is a significant barrier to increase its indications.

In this study we searched for clinically relevant molecular reporters of response to NET in a multicentre population of ER+/HER2- BC patients (n = 87) by using: PAM50 gene expression panel and immunohistochemical evaluation of key proteins involved in tumorigenesis.

Our PAM50 analyses show that tumours changing from luminal A to normal-like subtype after NET presented better radiological and pathological tumour responses, a significant larger decrease in Ki67 at surgery, lower preoperative endocrine prognostic index score (PEPI) and lower tumour cellularity size (TCS) than those with persistent luminal A status. Patients with the highest response to NET showed the largest decrease in PAM50-derived risk of recurrence (ROR) following NET. In addition, the percentage of p53 positive cells was associated with decreased response to NET.

Our findings highlight the change of intrinsic subtype from luminal A to normal-like after NET as a putative biomarker characterising the patient population that obtains the highest benefit from NET. Our study also suggests that changes in PAM50-derived ROR score and p53 evaluation could also help to identify those patients. Thus, this study uncovers potential biomarkers of response to NET and prognosis, which should be validated in independent cohorts, helping to the implementation of NET in the clinical practice.

The combination of cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) with endocrine therapy (ET) has emerged as an effective alternative to neoadjuvant chemotherapy (NCT) for patients with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2 (HER2) -negative breast cancer (BC). This single-center study retrospectively evaluated the efficacy and safety of dalpiciclib combined with an aromatase inhibitor (AI) compared to NCT.

The clinicopathological data and treatment details of patients with HR+ HER2 negative BC who underwent either neoadjuvant endocrine therapy (NET) or NCT were collected from the Fourth Hospital of Hebei Medical University. The primary endpoint of the study was the Residual Cancer Burden (RCB), while secondary endpoints included breast pathological complete response (bpCR), clinical response rates (ORR), proliferation markers, and safety profiles.

Between May 2022 and June 2023, a total of 36 patients were treated with dalpiciclib plus AI, while 137 patients received NCT for the final analysis. Prior to propensity score matching (PSM), the rates of RCB 0 were 0% in the NET group and 7.3% in the NCT group (p=0.205). The rates of bpCR were 2.8% for the NET group and 13.1% for the NCT group (p=0.142). The ORR was comparable between the two groups (p=0.397), as were the rates of BCS (p=0.608). Both treatment groups demonstrated significant reductions in Ki-67 levels, although the extent of reduction was similar (p=0.174). Notably, a Ki-67 level of ≤ 10% post-treatment was more prevalent in the NET group (p<0.0001). Only two patients in the NET group achieved a Preoperative Endocrine Prognostic Index (PEPI) 0 score. The incidence of grade 3-4 toxicities was significantly higher in the NCT group compared to the NET group (p<0.05). Following PSM, patients treated with dalpiciclib plus AI exhibited comparable clinical responses and a safety advantage relative to those receiving NCT.

This study indicates that the combination of dalpiciclib and AI elicits comparable responses and demonstrates improved safety profiles when compared to NCT in patients with HR+ HER2 negative breast tumors. Furthermore, RCB and pCR may not serve as optimal endpoints for evaluating the efficacy of CDK4/6i-based NET.

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibition in combination with endocrine therapy is the mainstay of treatment for hormone receptor-positive, HER2-negative (HR  +  /HER2-) advanced breast cancer; the CDK4/6 inhibitors abemaciclib and ribociclib are also approved for high-risk, early-stage, HR  +  /HER2- breast cancer. Numerous studies exploring CDK4/6 inhibitors in the early-stage setting are ongoing, as well as many more exploring novel combinations in the metastatic setting.

Here, we review the basis of CDK4/6 inhibition for HR  +/HER2- breast cancer, the pivotal clinical trials which led to regulatory approval, and ongoing trials evaluating novel combinations to further improve outcomes for those with both early and advanced HR+/HER2- breast cancer. Current literature was reviewed by a comprehensive search of PubMed MEDLINE (1/1/2000-12/31/2024).

CDK4/6 inhibitors are integral in the management of both advanced and high-risk, early-stage HR  +  /HER2- breast cancer. Biomarkers predictive of CDK 4/6 inhibitor (CDK4/6i) benefit remain elusive, and clinical and pathological features remain key to identifying those who are candidates for CDK4/6 inhibition in the early-stage setting. Numerous trials evaluating the role of a CDK4/6i with novel endocrine therapy partners and other targeted agents are ongoing, with the goal of improving outcomes for those with HR  +  /HER2- disease.

Breast cancer is the most common cancer and a leading cause of cancer-related death among women globally. Determining which patients will benefit from chemotherapy remains challenging. Proliferative markers such as Ki-67, mini chromosome maintenance (MCM) proteins, and proliferating cell nuclear antigen (PCNA) offer valuable insights into tumor growth and treatment response. This review evaluates their clinical roles, with a focus on chemotherapy implications and emerging digital pathology techniques for marker quantification.

A narrative review was conducted by searching PubMed, Scopus, and Google Scholar for studies related to Ki-67, MCM, PCNA, breast cancer, and chemotherapy. Studies were thematically categorized into five areas. A bibliometric analysis of publications from 2000 to April 2023 was performed using the Bibliometrix R package and VOSviewer to assess research trends and thematic evolution.

Eighty studies were included in the narrative synthesis. Ki-67 is the most commonly used marker, particularly useful in predicting response to neoadjuvant chemotherapy (NAC). MCM proteins show promise for identifying proliferative potential across tumor grades, while PCNA is associated with aggressive tumor features and poor prognosis. Post-chemotherapy changes in Ki-67 levels are linked to survival outcomes. Bibliometric analysis revealed a shift in research focus from basic mechanisms to clinical applications and digital quantification.

Proliferative markers play an essential role in breast cancer management. Ki-67 remains a key predictor of chemotherapy response, while MCM and PCNA offer complementary prognostic insights. Integration of these markers with digital pathology and AI-driven tools may enhance diagnostic accuracy and personalized treatment strategies. Standardization of assessment methods is crucial for broader clinical application.

Multigene prognostic genomic assays have become essential tools in the management of early breast cancer (BC), providing information that help in risk-stratification, to provide risk-adapted decision-making of adjuvant treatments. Clinical practice guidelines recommend refining the prognostic information provided by clinical and pathology features with the use of genomic tests, such as Oncotype DX®, to classify cancers into risk groups and inform adjuvant treatment strategies. However, the clinical value (i.e., prognostic and/or predictive) and applicability of these assays vary due to differences in the clinical setting, especially in those populations that were underrepresented in pivotal clinical trials. Oncotype DX® is a broadly utilized genomic test for breast cancer, having the highest level of supporting evidence to inform clinical practice. Our manuscript provides a comprehensive overview on this recurrence score assay, evaluates supporting evidence across patient populations, and discusses their impact on treatment decisions in those groups of patients underrepresented in pivotal clinical trials, where evidence is limited with the use of Oncotype DX.

Elacestrant has shown significantly prolonged progression-free survival compared with standard-of-care endocrine therapy in estrogen receptor-positive (ER-positive), HER2-negative metastatic breast cancer, whereas potential benefit in early-stage disease requires further exploration. The SOLTI-ELIPSE window-of-opportunity trial investigated the biological changes induced by a short course of preoperative elacestrant in postmenopausal women with early breast cancer.

Eligible patients with untreated T1c (≥1.5 cm)-T3, N0, ER-positive/HER2-negative breast cancer with locally assessed Ki67 ≥10% received elacestrant at a daily dose of 345 mg for 4 weeks. The primary efficacy endpoint was complete cell cycle arrest, defined as Ki67 ≤2.7%, on day 28.

Overall, 22 patients were evaluable for the primary endpoint. Elacestrant was associated with a complete cell cycle arrest rate of 27.3% and a statistically significant Ki67 geometric mean change of -52.9% (P = 0.007; 95% confidence interval, -67.4 to -32.1). Notably, the treatment with elacestrant led to a shift toward a more endocrine-sensitive and less proliferative tumor phenotype based on PAM50-based gene signatures. Elacestrant increased the expression of immune-response genes (GZMB, CD4, and CD8A) and suppressed proliferation and estrogen-signaling genes (MKI67, ESR1, and AR). These biological changes were independent of the levels of Ki67 suppression on day 28. The most common adverse events were grade 1 anemia (21.7%), hot flushes (8.7%), constipation (8.7%), and abdominal pain (8.7%). One patient experienced a grade 3 cutaneous rash, leading to treatment discontinuation. No other serious adverse events were reported.

Preoperative treatment with elacestrant in early breast cancer demonstrated relevant biological and molecular responses and exhibited a manageable safety profile. These findings support further investigation of elacestrant in the early setting.

Cancer is a rising issue worldwide, and numerous studies have focused on understanding the underlying reasons for its occurrence and finding proper ways to defeat it. By applying technological advances, researchers are continuously uncovering and updating treatments in cancer therapy. Their vast functions in the regulation of cell growth and proliferation and their significant role in the progression of diseases, including cancer. This review provides a comprehensive analysis of ncRNAs in breast cancer, focusing on long non-coding RNAs such as HOTAIR, MALAT1, and NEAT1, as well as microRNAs such as miR-21, miR-221/222, and miR-155. These ncRNAs are pivotal in regulating cell proliferation, metastasis, drug resistance, and apoptosis. Additionally, we discuss experimental approaches that are useful for studying them and highlight the advantages and challenges of each method. We then explain the results of these clinical trials and offer insights for future studies by discussing major existing gaps. On the basis of an extensive number of studies, this review provides valuable insights into the potential of ncRNAs in cancer therapy. Key findings show that even though the functions of ncRNAs are vast and undeniable in cancer, there are still complications associated with their therapeutic use. Moreover, there is an absence of sufficient experiments regarding their application in mouse models, which is an area to work on. By emphasizing the crucial role of ncRNAs, this review underscores the need for innovative approaches and further studies to explore their potential in cancer therapy.

Neoadjuvant chemotherapy (NACT) is an established form of therapy for early breast cancer (BC). The aim of our study was to analyze histopathological parameters before and after receiving NACT and to determine the influence of these changes on prognosis of BC patients.

We retrospectively analyzed data of patients with primary early BC, diagnosed between January 2012 and December 2019, and NACT, followed by primary surgery. Patients achieving pathological complete response (pCR) were excluded. For the outcome analysis, disease-free survival (DFS) and overall survival (OS) were defined.

A total of 237 tumors were analyzed in the study. The conversion rates of tumor grade, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), Ki67 status, and BC subtype were 34.6 %, 3.4 %, 14.3 %, 4.6 %, 30.0 %, and 28.7 %, respectively. After a median follow-up of 58.03 months, we found an association between consistently negative ER/PR with the worst prognosis (DFS and OS) (ER p < 0.0001 for both; PR p = 0.0003, p = 0.0004, respectively). The conversion from Ki67 ≥14 % to <14 % led to an improved outcome compared to a constant Ki67 ≥14 % (DFS p = 0.003, OS p = 0.001). Tumor residuals with a non-triple-negative (nTN) subtype (TN → nTN) showed a better prognosis than those with TN subtype (nTN → TN) (DFS and OS p < 0.0001).

After NACT, tumor grade and Ki67 showed the highest conversion rates between primary biopsy and tumor residual. Depending on changes in ER, PR, Ki67, and subtype, we found significant differences in the prognosis of the patients.

CALGB 40903 (Alliance) was a phase II single arm multicenter trial conducted in postmenopausal patients diagnosed with estrogen-receptor (ER) positive breast ductal carcinoma in situ (DCIS) without invasion. Patients were treated with the aromatase inhibitor (AI) letrozole for 6 months prior to surgery with change in magnetic resonance imaging (MRI) enhancement volume compared to baseline as the primary endpoint. In the current study, we performed sequence analysis of pre- and post-treatment specimens to determine gene expression and DNA copy number parameters associated with treatment and response.

Paraffin sections from pretreatment biopsies and post-treatment surgical specimens were evaluated for presence of DCIS. Proliferation based on KI67 staining was quantified by a study pathologist. Macrodissection of the DCIS components from thin sections was the source of RNA and DNA. Whole-transcriptome RNA and shallow whole-genome DNA sequencing were performed. PAM50 analysis to assign intrinsic subtypes with associated probability of class membership was performed. Differential gene expression comparing responders versus non-responders and pre- versus post-treatment specimens was performed using a two-tiered approach based on candidate genes and a whole genome survey with appropriate multiple testing corrections.

Based on availability of specimens and presence of DCIS component, 29 patients (from the 70 who completed the treatment trial) were included in the final data set, including five who had a pathologic complete response (pCR). Response to treatment was qualified categorically based on a threshold of 10% KI67 in the post-treatment surgical specimen or pCR. Based on this criterion, six of the 29 DCIS were considered non-responders (> 10% KI67) and five subjects with pCR were assigned to the responder group. No standard clinical variables were associated with response. On the basis of gene expression analysis, 19 of the pre-treatment samples were classified as luminal A, all of which were classified as responders. PAM50 classification of the other ten pre-treatment samples included luminal B, HER2, basal, and normal-like, six of which were non-responders. PAM50 class membership shifted from baseline to post-treatment in eight cases, most often from luminal A to normal-like (five cases). Selected genes associated with estrogen receptor levels in invasive breast cancer were higher in AI responsive tumors. AI treatment resulted in reductions in estrogen and proliferation related genes.

Letrozole treatment produced an effective growth response, particularly in DCIS initially classified as luminal A. Study inclusion criteria of DCIS with at least 1% ER positive cells resulted in the inclusion of other subtypes that failed to respond. Treatment also induced both minor and major changes in intrinsic subtype based on PAM50 probabilities. Overall, these data indicate that response to AI treatment in ER( +) DCIS is variable and analogous to that observed in invasive breast cancers.

Treatment for breast DCIS ranges from active surveillance to mastectomy, often combined with adjuvant endocrine therapy. The work presented here based on a unique neoadjuvant trial provides direct information on hormone therapy responsiveness of this disease and further couples the biology of invasive breast cancer to its non-obligate precursor.

ClinicalTrials.gov Identifier: NCT01439711.

Breast cancer (BC) remains a significant global health challenge, highlighting the need for continued research into novel risk factors, diagnostic approaches, and personalized treatments. Among emerging risk factors, viral infections have been implicated as potential contributors to breast carcinogenesis and BC progression. Recent evidence suggests that specific oncogenic strains of human cytomegalovirus (HCMV) may have the capacity to transform human mammary epithelial cells. This review assesses clinical data regarding HCMV presence in both tumor and non-tumor breast tissues, examining the role of HCMV oncoproteins in BC development and progression. Current findings indicate a higher prevalence of HCMV infection in breast carcinomas compared to non-tumor tissues, associated with an elevated risk of BC. Additionally, the HCMV-driven breast carcinogenesis model proposed here suggests that HCMV oncoproteins may activate multiple oncogenic pathways, fostering cell proliferation, survival, and tumor development. A deeper understanding of the role of HCMV in BC could enhance risk stratification and support the creation of targeted therapeutic strategies.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have revolutionized the treatment of hormone-receptor positive (HR+), HER2 negative (HER2-) metastatic breast cancer, and are now also established agents in the treatment of high-risk and intermediate-risk HR+ early breast cancer. Several strategies regarding CDK4/6i combinations or continuation beyond progression have been successfully evaluated in the metastatic setting, and are considered a standard of care. Mechanism of action of and resistance mechanisms against CDK4/6i in addition to endocrine resistance represent an important research topic, important for the treatment of HR+ breast cancer. Clinically, CDK4/6i are efficient substances that are usually well tolerated. However, side effects differing between the substances have been reported, and might lead to treatment discontinuation, including in the early disease setting. In the adjuvant setting, the addition of palbociclib to standard endocrine treatment has not improved outcomes, whereas large randomized phase III trials have demonstrated significant disease-free survival benefit for the addition of ribociclib (NATALEE trial) and abemaciclib (monarchE trial). Patient selection, treatment duration, endocrine backbone therapy, and other study details differ between these pivotal trials. This review focuses on both the scientific background as well as all available clinical data of CDK4/6i, with particular emphasis on their use in early breast cancer.

Estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancers have different genomic architecture and show large-scale gene expression differences consistent with different cellular origins, which is reflected in the luminal (i.e., ER+) versus basal-like (i.e., ER-) molecular class nomenclature. These two major molecular subtypes have distinct epidemiological risk factors and different clinical behaviors. Luminal cancers can be subdivided further based on proliferative activity and ER signaling. Those with a high expression of proliferation-related genes and a low expression of ER-associated genes, called luminal B, have a high risk of early recurrence (i.e., within 5 years), derive significant benefit from adjuvant chemotherapy, and may benefit from adding immunotherapy to chemotherapy. This subset of luminal cancers is identified as the genomic high-risk ER+ cancers by the MammaPrint, Oncotype DX Recurrence Score, EndoPredict, Prosigna, and several other molecular prognostic assays. Luminal A cancers are characterized by low proliferation and high ER-related gene expression. They tend to have excellent prognosis with adjuvant endocrine therapy. Adjuvant chemotherapy may not improve their outcome further. These cancers correspond to the genomic low-risk categories. However, these cancers remain at risk for distant recurrence for extended periods of time, and over 50% of distant recurrences occur after 5 years. Basal-like cancers are uniformly highly proliferative and tend to recur within 3-5 years of diagnosis. In the absence of therapy, basal-like breast cancers have the worst survival, but these also include many highly chemotherapy-sensitive cancers. Basal-like cancers are often treated with preoperative chemotherapy combined with an immune checkpoint inhibitor which results in 60-65% pathologic complete response rates that herald excellent long-term survival. Patients with residual cancer after neoadjuvant therapy can receive additional postoperative chemotherapy that improves their survival. Currently, there is no clinically actionable molecular subclassification for basal-like cancers, although cancers with high androgen receptor (AR)-related gene expression and those with high levels of immune infiltration have better prognosis, but currently their treatment is not different from basal-like cancers in general. A clinically important, minor subset of breast cancers are characterized by frequent HER2 gene amplification and high expression of a few dozen genes, many residing on the HER2 amplicon. This is an important subset because of the highly effective HER2 targeted therapies which are synergistic with endocrine therapy and chemotherapy. The clinical behavior of HER2-enriched cancers is dominated by the underlying ER subtype. ER+/HER2-enriched cancers tend to have more indolent course and lesser chemotherapy sensitivity than their ER counterparts.

Complete pathological response to neoadjuvant treatment (NAT) in breast cancer is associated with prolonged survival. Compared to other breast cancer immunophenotypes, luminal tumors are the least chemosensitive with low rates of pathological response within this molecular subtype. Thus, finding predictors of response in this subset remains challenging. The emerging concept of low human epidermal growth factor receptor 2 (HER2) expression has led to a repurpose of the current prognostic system. Little is known about its correlation with response to NAT.

This study aims to evaluate predictors of response in early-stage luminal breast cancer receiving neoadjuvant chemotherapy.

A total of 252 luminal patients who received NAT were retrospectively assessed in this cohort study.

We analyzed the correlation of ki67 and HER2 low expression with the rate of pathologic response. Using ki67 as a continuous variable and applying the receiver operating characteristic curves method.

We identified that in patients with a ki67 expression level >37%, the probability of having a complete pathological response was 4.80 times higher (odds ratio = 4.80, 95% confidence interval: 1.92-12.04). In Her2-low breast cancer patients, Her2 expression did not correlate with a better response rate.

In our study, a ki67 expression value greater than 37% constitutes a predictive biomarker of pathological complete response in the subgroup of patients with luminal B tumors and could be considered, therefore, an indicator for treatment decisions in this subgroup.

This revised consensus statement of the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathological Anatomy (SEAP) updates the recommendations for biomarkers use in the diagnosis and treatment of breast cancer that we first published in 2018. The expert group recommends determining in early breast cancer the estrogen receptor (ER), progesterone receptor (PR), Ki-67, and Human Epidermal growth factor Receptor 2 (HER2), as well as BReast CAncer (BRCA) genes in high-risk HER2-negative breast cancer, to assist prognosis and help in indicating the therapeutic options, including hormone therapy, chemotherapy, anti-HER2 therapy, and other targeted therapies. One of the four available genetic prognostic platforms (Oncotype DX®, MammaPrint®, Prosigna®, or EndoPredict®) may be used in ER-positive patients with early breast cancer to establish a prognostic category and help decide with the patient whether adjuvant treatment may be limited to hormonal therapy. In second-line advanced breast cancer, in addition, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and estrogen receptor 1 (ESR1) should be tested in hormone-sensitive cases, BRCA gene mutations in HER2-negative cancers, and in triple-negative breast cancer (TNBC), programmed cell death-1 ligand (PD-L1). Newer biomarkers and technologies, including tumor-infiltrating lymphocytes (TILs), homologous recombination deficiency (HRD) testing, serine/threonine kinase (AKT) pathway activation, and next-generation sequencing (NGS), are at this point investigational.

The objective of this study is to assess the efficacy and safety of combining goserelin with anastrozole in neoadjuvant endocrine therapy (NET) for patients diagnosed with premenopausal breast cancer.

A retrospective analysis was conducted on the clinicopathological data of 34 patients diagnosed with premenopausal breast cancer who underwent NET in the Department of Breast Surgery at Baotou Cancer Hospital between March 2016 and December 2019. Additionally, the feasibility of using goserelin combined with anastrozole for premenopausal endocrine therapy was assessed.

The duration of NET ranged from 6 to 72 months, with a mean of 22.5 months and a median of 18 months. In patients with progressive disease, endocrine therapy was assessed over a period of 6 to 18 months, with a mean of 13.1 months and a median of 13 months. Among the 28 patients assessed, 12 (42.86%) were found to have stable disease, subsequently receiving chemotherapy. Of these, seven patients demonstrated good compliance, and 5 achieved a pathological complete response. Including the 2 patients who responded favorably to NET alone, a total of 7 patients attained a pathological complete response. Additionally, 16 patients achieved complete cell cycle arrest following treatment. A significant correlation was observed between the clinical efficacy assessment and the pathological assessment of NET (P < 0.05).

Although NET was safe for patients diagnosed with premenopausal breast cancer, it should not be considered in isolation from chemotherapy. Transitioning to chemotherapy in a timely manner can significantly enhance treatment outcomes. The duration of NET should be guided by clinical assessment rather than being constrained by a predetermined time frame.

In response to the COVID-19 pandemic, the Pandemic Breast Cancer Consortium (PBCC) published recommendations for triage of breast cancer patients. The recommendations included neoadjuvant treatment of early-stage breast cancer patients experiencing delays in surgery. This study evaluated national patterns of neoadjuvant treatment according to triage guidelines.

Patients treated with surgery (upfront or post-neoadjuvant) in 2018-2020 were collected from the National Cancer Database. The proportions of patients treated according to the PBCC triage guidelines were calculated in 2020 and compared with similar cohorts in 2018-2019. Patient and hospital factors were evaluated for association with treatment.

Among cT1N0 ER+/PR+/HER2- patients, those treated in 2020 were more likely to receive neoadjuvant endocrine therapy (NET) compared with those before that time (odds ratio [OR], 3.08; range, 2.93-3.24). Among the patients with cT2N0 or cT1N1 disease, NET was more common in 2020 (OR, 1.76; range, 1.65-1.88). Academic facility, black or Asian race, more comorbidities, and the New England/Middle Atlantic region were associated with NET use.

During the COVID-19 pandemic, expanded utilization of neoadjuvant therapy for surgical breast cancer patients was observed. Health care system limitations during the pandemic contributed to expanded adoption of neoadjuvant therapy for early breast cancer, contrary to usual practice. Long-term outcomes for patients treated according to PBCC recommendations should be closely monitored.

Navigating the complex landscape of breast cancer treatment involves distinct strategies for luminal and triple-negative subtypes. While neoadjuvant chemotherapy historically dominates the approach for aggressive triple-negative tumors, recent evidence highlights the transformative impact of immunotherapy, alongside chemotherapy, in reshaping treatment paradigms. In luminal cancers, endocrine therapy, notably aromatase inhibitors, demonstrates promising outcomes in postmenopausal patients with low-grade luminal A tumors. However, integrating targeted therapies like CDK4/6 inhibitors in neoadjuvant setting remains inconclusive. Identifying predictive factors for treatment response, especially in luminal tumors, poses a challenge, emphasizing the necessity for ongoing research. A multidisciplinary approach, tailored to individual patient profiles, is crucial for maximizing efficacy while minimizing toxicity. As we strive to optimize breast cancer management, a comprehensive understanding of the distinct characteristics and treatment implications of luminal and triple-negative subtypes, including the transformative role of immunotherapy, is essential for informed decision-making and personalized care.

Standard neoadjuvant endocrine therapy (NAET) is used for 6-9 months to downstage hormone-receptor-positive breast cancer. Bridging ET was introduced during the COVID-19 pandemic to delay surgical intervention. There are no data in the literature on the effect of short course therapy on tumour response. We aimed to analyse the effect of bridging ET and validate the previously proposed neoadjuvant ET pathological reporting criteria.

This was a multicentre cohort of 256 patients who received bridging ET between March and October 2020. Assessment of paired pre- and post-NAET hormone receptors and HER2 and posttherapy Ki67 expression was done. The median duration of NAET was 45 days. In all, 86% of cases achieved partial pathological response and 9% showed minimal residual disease. Histological response to ET was observed from as early as day 6 posttherapy. Central scarring was noted in 32.8% of cases and lymphocytic infiltrate was seen in 43.4% of cases. Significant changes associated with the duration of ET were observed in tumour grade (21%), with downgrading identified in 12% of tumours (P < 0.001), progesterone receptor (PR) expression with switch to PR-negative status in 26% of cases (P < 0.001), and HER2 status with a switch from HER2-low to HER2-negative status in 32% of cases (P < 0.001). The median patient survival was 475 days, with an overall survival rate of 99.6%.

Changes characteristic of tumour regression and significant changes in PR and HER2 occurred following a short course of NAET. The findings support biomarker testing on pretreatment core biopsies and retesting following therapy.

Neoadjuvant chemotherapy (NACT) is widely used in the treatment of triple-negative and HER2-positive breast cancer (BC), but its use in estrogen receptor (ER) and/or progesterone receptor (PR) positive/HER2-negative BC is questioned because of the low pathologic complete response (pCR) rates. This retrospective study assessed the mRNA-based MammaTyper® assay's capability of predicting pCR with NACT, and ER, PR, Ki67, and HER2 status at immunohistochemical (IHC) through transcriptomics.

Diagnostic biopsies from 76 BC patients treated at the Cremona Hospital between 2012-2018 were analyzed. Relative mRNA expression levels of ERBB2, ESR1, PGR, and MKI67 were measured using the MammaTyper® kit and integrated into a pCR score. Predicting capability of pCR and standard IHC biomarkers could be assessed with ROC curves in 75 and 76 patients, respectively.

Overall, 68.0% patients obtained a MammaTyper® high-score and 32.0% a MammaTyper® low-score. Among high-score patients, 62.7% achieved pCR, compared to 16.7% in the low-score group (p = 0.0003). The binary MammaTyper® score showed good prediction of pCR in the overall cohort (area under curve [AUC] = 0.756) and in HR+/HER2-negative cases (AUC = 0.774). In cases with residual disease, the continuous MammaTyper® score correlated moderately with residual tumor size and decrease in tumor size. MammaTyper® showed substantial agreement with IHC for ESR1/ER and ERBB2/HER2, and moderate agreement for PGR/PR and MKI67/Ki67.

Overall, MammaTyper® pCR score may serve as a standardized tool for predicting NACT response in HR+/HER2-negative BC, potentially guiding treatment strategies. Additionally, it could provide a more standardized and reproducible assessment of ER, PR, HER2, and Ki67 status.

Chemotherapy is used as neoadjuvant therapy for all subgroups of breast cancer, including ER-positive, and HER2-negative cases. However, studies have suggested that using aromatase inhibitors combined with CDK4/6-inhibitors might be an appropriate alternative in selected patients. Thus, the NEOLETRIB trial evaluates the response of ER-positive, HER2-negative luminal A/B breast cancer to the combination of letrozole and ribociclib in the neoadjuvant setting. Comprehensive molecular biology procedures, including sequential single-cell RNA-sequencing of tumor biopsies, are performed during 6 months of treatment with extensive biobanking of blood samples, tumor biopsies and gut microbiome specimens. Our findings will hopefully contribute to an improved selection of patients who may benefit from this drug combination and give new insights into the intra-tumoral changes during this treatment.Trial registration number: NCT05163106 (ClinicalTrials.gov).

Oestrogen receptor (ER)-positive breast cancer (BC) is generally well responsive to endocrine therapy. Neoadjuvant endocrine therapy (NAET) is increasingly being used for downstaging ER-positive tumours. This study aims to analyse the effect of NAET on a well-characterised cohort of ER-positive BC with particular emphasis on receptor expression. This is a retrospective United Kingdom (UK) multicentre study of 391 patients who received NAET between October 2012 and October 2020. Detailed analyses of the paired pre- and post-NAET morphological changes and hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) expression were performed. The median duration of NAET was 86 days, with median survival and overall survival rates of 380 days and 93.4%, respectively. A total of 90.3% of cases achieved a pathological partial response, with a significantly higher rate of response in the HER2-low cancers. Following NAET, BC displayed some pathological changes involving the tumour stroma including central scarring and an increase in tumour infiltrating lymphocytes (TILs) and tumour cell morphology. Significant changes associated with the duration of NAET were observed in tumour grade (30.6% of cases), with downgrading identified in 19.3% of tumours (p < 0.001). The conversion of ER status from positive to low or negative was insignificant. The conversion of progesterone receptor (PR) and HER2 status to negative status was observed in 31.3% and 38.1% of cases, respectively (p < 0.001). HER2-low breast cancer decreased from 63% to 37% following NAET in the paired samples. Significant morphological and biomarker changes involving PR and HER2 expression occurred following NAET. The findings support biomarker testing on pre-treatment core biopsies and post-treatment residual carcinoma.

Anthracycline- and taxane-based chemotherapy regimens are established treatments for human epidermal growth factor receptor (HER)2-negative early-stage breast cancer with high risk of recurrence. This study examined the prevalence of these chemotherapy regimens as perioperative therapy, the patterns of retreatment, and factors influencing prescription choices in Japan.

This observational cohort study focused on high-risk early-stage breast cancer patients not undergoing anti-HER2 therapy, utilizing data from a hospital-based claims database in Japan spanning from April 2008 to September 2021.

Of 42,636 high-risk patients who underwent breast cancer surgery, 32,133 (75.4%) were categorized as having luminal-type (received endocrine therapy) and 10,503 (24.6%) as having triple-negative cancer (not receiving any endocrine therapies). Most patients (98.7%) with luminal-type breast cancer received perioperative therapy, and 40.3% of those received anthracycline/taxane. In the triple-negative group, 57.0% of all patients received perioperative therapy and of those, 93.4% received anthracycline/taxane. Being over 40 years old, having an early stage (clinical stage ≤ II), and receiving treatment in non-specialized facilities were associated with less use of anthracycline/taxane in the luminal-type group. For the triple-negative group, associated factors with less use of anthracycline/taxane included being over 60 years old, treatment in small hospital (capacity < 200 beds), and treatment in non-specialized facilities.

Approximately half the patients in both the luminal-type and triple-negative groups were prescribed anthracycline and/or taxane for perioperative chemotherapy. The choice was associated with patient age, cancer stage, and the scale and specialization of the treatment facilities. This study sheds light on the current state of breast cancer treatment practices in Japan.

To assess the efficacy and safety of tucidinostat plus exemestane as a neoadjuvant strategy in early-stage breast cancer.

This prospective, open-label, single-arm phase II trial enrolled patients with stage II-III breast cancer with hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative. Eligible patients received tucidinostat plus exemestane, and then breast-conserving surgery (BCS) or modified radical mastectomy.

Among 20 enrolled patients, 3 of them achieved preoperative endocrine prognostic index (PEPI) score of 0. Additionally, complete cell cycle arrest was observed in 7, radiologic objective response rate in 10, and disease control rate in 20 patients, pathological complete response in 1 patient, and 5 patients performed BCS. Ki67 suppression from baseline to surgery was observed in 17 of patients, with the Ki67 change ratio of -73.5%. Treatment-emergent adverse event included neutropenia, leukopenia, thrombocytopenia, lymphopenia, hypoalbuminemia, aspartate aminotransferase elevation, glutamyl transpeptidase elevation, anemia, and alanine aminotransferase elevation.

Despite the rate of PEPI score 0 was not high, tucidinostat plus exemestane as a neoadjuvant therapy might be well tolerated and showed promising clinical responses in patients with early hormone receptor-positive, HER2-negative breast cancer. To clarify the safety and efficacy of this strategy, further investigation is warranted.

ChiCTR2100046678.

The International Collaboration on Cancer Reporting (ICCR), a global alliance of major (inter-)national pathology and cancer organisations, is an initiative aimed at providing a unified international approach to reporting cancer. ICCR recently published new data sets for the reporting of invasive breast carcinoma, surgically removed lymph nodes for breast tumours and ductal carcinoma in situ, variants of lobular carcinoma in situ and low-grade lesions. The data set in this paper addresses the neoadjuvant setting. The aim is to promote high-quality, standardised reporting of tumour response and residual disease after neoadjuvant treatment that can be used for subsequent management decisions for each patient.

The ICCR convened expert panels of breast pathologists with a representative surgeon and oncologist to critically review and discuss current evidence. Feedback from the international public consultation was critical in the development of this data set.

The expert panel concluded that a dedicated data set was required for reporting of breast specimens post-neoadjuvant therapy with inclusion of data elements specific to the neoadjuvant setting as core or non-core elements. This data set proposes a practical approach for handling and reporting breast resection specimens following neoadjuvant therapy. The comments for each data element clarify terminology, discuss available evidence and highlight areas with limited evidence that need further study. This data set overlaps with, and should be used in conjunction with, the data sets for the reporting of invasive breast carcinoma and surgically removed lymph nodes from patients with breast tumours, as appropriate. Key issues specific to the neoadjuvant setting are included in this paper. The entire data set is freely available on the ICCR website.

High-quality, standardised reporting of tumour response and residual disease after neoadjuvant treatment are critical for subsequent management decisions for each patient.

Residual disease after neoadjuvant chemotherapy (NAC) in breast cancer patients predicts worse outcomes than pathological complete response. Differing prognostic impacts based on the anatomical site of residual tumors are not well studied.

The study aims to assess disease-free survival (DFS) in breast cancer patients with different residual tumor sites following NAC and to develop a nomogram for predicting 1- to 3-year DFS in these patients.

A retrospective cohort study.

Retrospective analysis of 953 lymph node-positive breast cancer patients with residual disease post-NAC. Patients were categorized into three groups: residual disease in breast (RDB), residual disease in lymph nodes (RDN), and residual disease in both (RDBN). DFS compared among groups. Patients were divided into a training set and a validation set in a 7:3 ratio. Prognostic factors for DFS were analyzed to develop a nomogram prediction model.

RDB patients had superior 3-year DFS of 94.6% versus 85.2% for RDN and 81.8% for RDBN (p < 0.0001). Clinical T stage, N stage, molecular subtype, and postoperative pN stage were independently associated with DFS on both univariate and multivariate analyses. Nomogram integrating clinical tumor-node-metastasis (TNM) stage, molecular subtype, pathological response demonstrated good discrimination (C-index 0.748 training, 0.796 validation cohort), and calibration.

The location of residual disease has prognostic implications, with nodal residuals predicting poorer DFS. The validated nomogram enables personalized DFS prediction to guide treatment decisions.

Chromosomal instability (CIN), defined by variations in the number or structure of chromosomes from cell to cell, is recognized as a distinctive characteristic of cancer associated with the ability of tumors to adapt to challenging environments. CIN has been recognized as a source of genetic variation that leads to clonal heterogeneity (CH). Recent findings suggest a potential association between CIN and CH with the prognosis of BC patients, particularly in tumors expressing the epidermal growth factor receptor 2 (HER2+). In fact, information on the role of CIN in other BC subtypes, including luminal B BC, is limited. Additionally, it remains unknown whether CIN in luminal B BC tumors, above a specific threshold, could have a detrimental effect on the growth of human tumors or whether low or intermediate CIN levels could be linked to a more favorable BC patient prognosis when contrasted with elevated levels. Clarifying these relationships could have a substantial impact on risk stratification and the development of future therapeutic strategies aimed at targeting CIN in BC. This study aimed to assess CIN and CH in tumor tissue samples from ten patients with luminal B BC and compare them with established clinicopathological parameters. The results of this study reveal that luminal B BC patients exhibit intermediate CIN and stable aneuploidy, both of which correlate with lymphovascular invasion. Our results also provide valuable preliminary data that could contribute to the understanding of the implications of CIN and CH in risk stratification and the development of future therapeutic strategies in BC.

After decades of research, improving the efficacy of adjuvant endocrine therapy (ET) for early-stage breast cancer becomes increasingly difficult. Beyond technological breakthroughs and the availability of new classes of drugs, further improvement of adjuvant ET will require applying a rigorous research approach in poorly investigated areas. We critically discuss some key principles that should inform future research to improve ET efficacy, including identifying specific subgroups of patients who can benefit from escalating or de-escalating approaches, optimizing available and new treatment strategies for different clinical contexts, and dissecting the direct and indirect biological effects of therapeutic interventions. Four main issues regarding adjuvant ET were identified as relevant areas, where a better application of such principles can provide positive results in the near future: (i) tailoring the optimal duration of adjuvant ET, (ii) optimizing ovarian function suppression for premenopausal women, (iii) dissecting the biological effects of estrogen receptor manipulation, and (iv) refining the selection of patients to candidate for treatments escalation.

Neoadjuvant endocrine therapy (NAE) offers a breast-conserving surgery rate and clinical response rate similar to those of neoadjuvant chemotherapy (NAC), while presenting fewer adverse events and lower pathological complete response rates. The assessment of pathological response determines degenerative changes and predicts the prognosis of breast cancer treated with NAC. This study clarified the degenerative changes occurring in breast cancer following NAE.

Our study encompassed two groups: NAE, consisting of 15 patients, and NAC, comprising 18 patients. Tissue samples were obtained from core needle biopsies and surgeries. Nuclear and cell areas were calculated using Autocell analysis. Furthermore, we assessed markers associated with microtubule depolymerization (KIF2A) and initiators of apoptosis (caspase-9).

In the NAC group, we observed significant increases in both cytoplasmic and cell areas. These changes in cytoplasm and cells were notably more pronounced in the NAC group compared to the NAE group. After treatment, KIF2A exhibited a decrease, with the magnitude of change being greater in the NET group than in the NAC group. However, no discernible differences were found in caspase-9 expression between the two groups.

Our findings indicate that NAE induces condensation in cancer cells via cell cycle arrest or apoptosis. Conversely, NAC leads to cell enlargement due to the absence of microtubule depolymerization. These discrepancies underscore the importance of accounting for these distinctions when establishing criteria for evaluating pathological responses.

The histological grade is an important factor in the prognosis of invasive breast cancer and is vital to accurately identify the histological grade and reclassify of Grade2 status in breast cancer patients.

In this study, data were collected from 556 invasive breast cancer patients, and then randomly divided into training cohort (n = 335) and validation cohort (n = 221). All patients were divided into actual low risk group (Grade1) and high risk group (Grade2/3) based on traditional histological grade, and tumor-infiltrating lymphocyte score (TILs-score) obtained from multiphoton images, and the TILs assessment method proposed by International Immuno-Oncology Biomarker Working Group (TILs-WG) were also used to differentiate between high risk group and low risk group of histological grade in patients with invasive breast cancer. Furthermore, TILs-score was used to reclassify Grade2 (G2) into G2 /Low risk and G2/High risk. The coefficients for each TILs in the training cohort were retrieved using ridge regression and TILs-score was created based on the coefficients of the three kinds of TILs.

Statistical analysis shows that TILs-score is significantly correlated with histological grade, and is an independent predictor of histological grade (odds ratio [OR], 2.548; 95%CI, 1.648-3.941; P < 0.0001), but TILs-WG is not an independent predictive factor for grade (P > 0.05 in the univariate analysis). Moreover, the risk of G2/High risk group is higher than that of G2/Low risk group, and the survival rate of patients with G2/Low risk is similar to that of Grade1, while the survival rate of patients with G2/High risk is even worse than that of patients with G3.

Our results suggest that TILs-score can be used to predict the histological grade of breast cancer and potentially to guide the therapeutic management of breast cancer patients.

Adding fulvestrant to anastrozole (A+F) improved survival in postmenopausal women with advanced estrogen receptor (ER)-positive/ERBB2 (formerly HER2)-negative breast cancer. However, the combination has not been tested in early-stage disease.

To determine whether neoadjuvant fulvestrant or A+F increases the rate of pathologic complete response or ypT1-2N0/N1mic/Ki67 2.7% or less residual disease (referred to as endocrine-sensitive disease) over anastrozole alone.

A phase 3 randomized clinical trial assessing differences in clinical and correlative outcomes between each of the fulvestrant-containing arms and the anastrozole arm. Postmenopausal women with clinical stage II to III, ER-rich (Allred score 6-8 or >66%)/ERBB2-negative breast cancer were included. All analyses were based on data frozen on March 2, 2023.

Patients received anastrozole, fulvestrant, or a combination for 6 months preoperatively. Tumor Ki67 was assessed at week 4 and optionally at week 12, and if greater than 10% at either time point, the patient switched to neoadjuvant chemotherapy or immediate surgery.

The primary outcome was the endocrine-sensitive disease rate (ESDR). A secondary outcome was the percentage change in Ki67 after 4 weeks of neoadjuvant endocrine therapy (NET) (week 4 Ki67 suppression).

Between February 2014 and November 2018, 1362 female patients (mean [SD] age, 65.0 [8.2] years) were enrolled. Among the 1298 evaluable patients, ESDRs were 18.7% (95% CI, 15.1%-22.7%), 22.8% (95% CI, 18.9%-27.1%), and 20.5% (95% CI, 16.8%-24.6%) with anastrozole, fulvestrant, and A+F, respectively. Compared to anastrozole, neither fulvestrant-containing regimen significantly improved ESDR or week 4 Ki67 suppression. The rate of week 4 or week 12 Ki67 greater than 10% was 25.1%, 24.2%, and 15.7% with anastrozole, fulvestrant, and A+F, respectively. Pathologic complete response/residual cancer burden class I occurred in 8 of 167 patients and 17 of 167 patients, respectively (15.0%; 95% CI, 9.9%-21.3%), after switching to neoadjuvant chemotherapy due to week 4 or week 12 Ki67 greater than 10%. PAM50 subtyping derived from RNA sequencing of baseline biopsies available for 753 patients (58%) identified 394 luminal A, 304 luminal B, and 55 nonluminal tumors. A+F led to a greater week 4 Ki67 suppression than anastrozole alone in luminal B tumors (median [IQR], -90.4% [-95.2 to -81.9%] vs -76.7% [-89.0 to -55.6%]; P < .001), but not luminal A tumors. Thirty-six nonluminal tumors (65.5%) had a week 4 or week 12 Ki67 greater than 10%.

In this randomized clinical trial, neither fulvestrant nor A+F significantly improved the 6-month ESDR over anastrozole in ER-rich/ERBB2-negative breast cancer. Aromatase inhibition remains the standard-of-care NET. Differential NET response by PAM50 subtype in exploratory analyses warrants further investigation.

ClinicalTrials.gov Identifier: NCT01953588.