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Open research questions in Breast Cancer Treatment Studies

89 unresolved questions extracted from the limitations and future-work sections of 481 Breast Cancer Treatment Studies papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • In patients with residual isolated tumor cells or micrometastases, contemporary cohorts show substantial variation in the use of completion ALND and clinically relevant rates of additional nodal involvement, but randomized evidence remains lacking.

    Axillary surgical de-escalation after neoadjuvant therapy in breast cancer: current evidence, clinical controversies, and future directions · 2026 · DOI

  • Neoadjuvant therapy (NAT) has expanded opportunities to de-escalate axillary surgery in breast cancer, but the appropriate extent of surgery remains uncertain across pretreatment nodal stages and post-treatment responses.

    Axillary surgical de-escalation after neoadjuvant therapy in breast cancer: current evidence, clinical controversies, and future directions · 2026 · DOI

  • Due to the limited evidence base, treatment recommen- dations lack strong scientific support and rely primarily on clinical experience and extrapolation from other metastatic settings. While epidemiological data on incidence of BMC in breast cancer patients are scarce, monocentric studies suggest that it occurs in approximately 0.

    Real-world insights into bone marrow carcinomatosis in metastatic breast cancer: a retrospective analysis from two large university breast cancer centers · 2026 · DOI

  • Background Axillary reverse mapping (ARM) aims to preserve upper limb lymphatic drainage during breast cancer surgery to reduce lymphedema risk, but the metastatic potential of ARM lymph nodes and its preoperative predictors remain unclear.

    Development and validation of a nomogram for predicting axillary reverse mapping lymph node metastasis in breast cancer patients · 2026 · DOI

  • 11–14 Despite conflicting evidence on the role of locoregional therapy in patients with an intact breast primary, studies show an 18–44% rate of surgery in patients with de novo stage IV breast cancer.

    Variation in Surgical Management of Stage IV Breast Cancer: Local/Institutional and Regional Geographic Considerations · 2026 · DOI

  • Abstract Background/Purpose Optimal surgical management of occult breast cancer (OBC) with N2/N3 nodal disease remains uncertain, but current National Comprehensive Cancer Network guidelines recommend mastectomy.

    Is Mastectomy Necessary in Patients with Occult Breast Cancer and Advanced (N2/N3) Nodal Disease? · 2026 · DOI

  • This study has several limitations. The retrospective design limits the ability to establish causality and precludes assessment of clinical outcomes such as symptomatic RP. The sample size was relatively modest, although statistically significant associations were identified despite this limitation. In addition, left-sided and right-sided breast cancers were analysed together because the primary endpoint was ipsilateral lung dose rather than cardiac exposure. Finally, the study evaluated dosimetric endpoints alone and did not incorporate respiratory motion management, clinical toxicity data, or long-term follow-up outcomes.

    Correlation of Chest Wall Separation and Central Lung Distance With Ipsilateral Lung Dose in Post-operative Breast Cancer Patients Treated With Intensity-Modulated Radiotherapy (IMRT): A Retrospective Study · 2026 · DOI

  • What Planners Can Take Away Today The findings of the present study suggest that CLD remains a clinically relevant geometric predictor of ipsilateral lung dose even in the era of IMRT. Significant positive correlations were observed between CLD and all evaluated lung dose-volume parameters, with the strongest associations identified for lung V20 and MLD. Consequently, early recognition of patients with high CLD during treatment planning may help identify cases at increased risk of lung dose escalation. Such patients may benefit from additional optimization strategies, including modification of beam arrangements, adjustment of segment weighting, or the incorporation of advanced planning techniques aimed at reducing lung exposure. Although CWS demonstrated weaker associations with lung dose parameters, its significant inverse relationship with lung V20 suggests that it may still provide useful supplementary anatomical information, particularly in resource-constrained settings where rapid geometric assessment can assist plan evaluation and quality assurance.

    Correlation of Chest Wall Separation and Central Lung Distance With Ipsilateral Lung Dose in Post-operative Breast Cancer Patients Treated With Intensity-Modulated Radiotherapy (IMRT): A Retrospective Study · 2026 · DOI

  • However, the modest performance of the clinical model alone highlights that macroscopic indicators are insufficient to fully capture these complex biological mechanisms, underscoring the need for quantitative imaging biomarkers (34–39).

    Multi-parametric MRI habitat radiomics with interpretable machine learning for early prediction of axillary lymph node metastasis in triple-negative breast cancer · 2026 · DOI

  • It is worth noting that the reported incidence of breast edema after BCS plus radiotherapy varies widely in the literature, ranging from 0% to 90.

    Influencing factors of significant breast edema in breast cancer patients undergoing breast-conserving surgery during radiotherapy with DIBH · 2026 · DOI

  • The role of internal mammary node (IMN) irradia- tion in node-positive or high-risk breast cancer remains debated, with two key controversies: cardiac safety in left-sided patients, and the necessity of routine IMNI in all right-sided patients despite minimal cardiac dose increase.

    The PRINCE-BC trial: precision regional irradiation of nodal stations for clinical evaluation of high-risk pN0 breast cancer – a phase III, open-label, randomized controlled trial · 2026 · DOI

  • IMpassion030 demonstrated no benefit from adding adjuvant atezolizumab after upfront surgery; the benefit of adjuvant-only pembrolizumab remains unclear, with SWOG 1418 pending.

    Adjuvant immunotherapy following upfront surgery for stage II–III triple-negative breast cancer: A National Cancer Database Study. · 2026 · DOI

  • Abstract Background Postoperative regional nodal irradiation (RNI) is a standard treatment for breast cancer at high risk of regional recurrence; however, the necessity of including the internal mammary node (IMN) region in the radiation field remains unclear.

    Clinical outcomes of postoperative radiotherapy with regional nodal irradiation excluding internal mammary lymph nodes in breast cancer: a multi-institutional retrospective analysis · 2026 · DOI

  • External validation using independent cohorts is necessary to confirm the generalizability of our findings. Standardization of MRI acquisition and interpretation criteria should also be pursued. Additionally, incorporating quantitative MRI-derived parameters (e.g., volumetric tumor shrinkage, signal intensity changes) may further improve objectivity and reproducibility in prediction models (20). Ultimately, integration of these predictive models into routine clinical workflows to guide response-adapted strategies and to dynamically optimize treatment duration and regimens based on interim MRI responses will be essential. Such an approach may enhance personalized breast cancer care by maximizing therapeutic benefit while minimizing unnecessary treatment-related toxicities. In this study, we showed that interim MRI demonstrated predictive performance for pCR in patients with breast cancer that was comparable to that of post-NAC MRI and enabled earlier clinical decision-making, indicating its potential utility as a decision-support tool that can be implemented early in the management of breast cancer.

    Interim Breast MRI for Predicting Pathologic Complete Response After Neoadjuvant Chemotherapy in Early Breast Cancer · 2026 · DOI

  • 540 The publication of multiple overlapping systematic reviews on ultrasound- based ACCEPTED MANUSCRIPT 53 ARTICLE IN PRESS ARTICLE IN PRESS ACCEPTED MANUSCRIPT 541 prediction of NAC response – including Shi et al. (2026), Valizadeh et al. (2025), and the 542 present study – within a short timeframe highlights the need for more efficient knowledge 543 synthesis. Rather than simply duplicating efforts, future research should prioritize: (1) 544 prospective, multicenter validation studies with standardized imaging protocols and outcome 545 definitions; (2) individual participant data meta- analyses, which would allow for nuanced ACCEPTED MANUSCRIPT 54 ARTICLE IN PRESS ARTICLE IN PRESS ACCEPTED MANUSCRIPT 546 subgroup analyses (e.g., by molecular subtype, ultrasound modality, geographic region) that 547 are not possible with aggregate data; and (3) living systematic reviews that are updated 548 continuously as new evidence emerges, thereby preventing research waste and ensuring that 549 clinical decision-making reflects the most current evidence. Additionally, future 550 meta-analyses should move beyond simply pooling AUCs and provide rigorous risk- of-bias 551 assessments using PROBAST, explicitly discuss geographic generalizability, and offer 552 tempered conclusions that acknowledge the current evidence as exploratory and 553 hypothesis-generating rather than practice-changing. 554 Given the high risk of bias, substantial heterogeneity, and geographic limitations 555 identified in this meta-analysis, the current evidence should be considered exploratory and 556 hypothesis-generating rather than practice-changing. Future research should focus on three 557 key areas. First, prospective multi-center cohort studies with pre-registered protocols are 558 essential to fundamentally reduce participant selection bias. Second, during statistical analysis, 559 researchers should ensure adequate sample sizes and employ more rigorous validation 560 strategies, particularly by using completely independent test cohorts for final performance 561 evaluation. Finally, researchers should strictly adhere to international reporting guidelines 562 such as Transparent Reporting of a multivariable prediction model for Individual Prognosis ACCEPTED MANUSCRIPT 55 ARTICLE IN PRESS ARTICLE IN PRESS ACCEPTED MANUSCRIPT 563 Or Diagnosis (TRIPOD) to ensure complete and transparent disclosure of all model 564 parameters and development details. These systematic improvements will significantly reduce 565 the risk of bias. As a result, higher-quality prediction models with greater clinical utility can 566 be developed.

    Ultrasound-based predictive models for response to neoadjuvant chemotherapy in breast cancer: a systematic review and meta-analysis · 2026 · DOI

  • This study is limited by its retrospective design, which introduces selection bias and limits the ability to establish causal relationships. There was variability in systemic therapy regimens including chemotherapy, endocrine therapy, and targeted agents as well as differences in surgical techniques across treating physicians and over time, which may have influenced outcomes. Pathologic and molecular data were occasionally incomplete, with some patients missing HER2 status, Ki67, or other prognostic biomarkers, which could limit risk stratification. Subgroup analyses stratified by receptor subtype were limited by small sample size and event counts and should be considered exploratory. Follow-up duration was hetero- geneous and may not be sufficient to capture late toxicities, second malignancies, or long-term survival differences. Residual confounding from unmeasured variables such as comorbidities, adherence to adjuvant systemic therapy, and socioeconomic factors may have impacted both treatment selection and outcomes. This study also did not collect toxicity or quality of life data, which prevents evaluation of the morbidity associated with postmastectomy radiation therapy such as lymphedema, cardiopulmonary toxicity, and other late effects. These limitations highlight the need for larger prospec- tive multi-institutional studies with standardized treatment protocols, comprehensive molecular profiling, and inclusion of patient-reported outcomes to better define the role of postmastectomy radiation therapy in node positive breast cancer. PLOS One | https://doi.org/10.1371/journal.pone.0341754 June 1, 2026 12 / 15 These factors may limit the generalizability of our findings to broader and more diverse patient populations. Additionally, the study may be underpowered to detect modest but clinically meaningful differences in survival outcomes between treatment groups. While this study does not introduce novel prognostic factors, it contributes to the existing literature by evaluating outcomes in a contemporary, real-world cohort with detailed subgroup analyses, which may help contextualize historical trial data in the setting of modern systemic therapy.

    Postmastectomy radiotherapy in pN1 breast cancer: Survival outcomes and prognostic factors from a single-institution cohort · 2026 · DOI

  • Given the multifactorial nature of treatment response in TNBC, ARTICLE IN PRESS ARTICLE IN PRESS additional factors—such as chemotherapy regimens, body weight management, and other clinical or molecular variables—should be further investigated to comprehensively understand and optimize predictors of pCR.

    Predictors of pathologic complete response in triple‑negative breast cancer treated with neoadjuvant chemotherapy: a systematic review and meta-analysis · 2026 · DOI

  • However, these studies were not specifically designed for patients with HR+/HER2- breast cancer at stage II or T3N1M0, outcomes by molecular subtype, and did not account for differences in response to NACT or advances in contemporary diagnostic and treatment strategies.

    Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in operable breast cancer patients with hormone receptor-positive, HER2-negative · 2026 · DOI

  • Deimplementation strategies Several strategies have been proposed to support omission of SLNB. These include prediction nomograms, cost-focused analyses, provider targeted de-implementation interventions, natural language models, alternative imaging approaches, and tumor genomic profiling. Multiple institutions have developed nomograms to estimate the probability of nodal metastasis. The Memorial Sloan Kettering Cancer Center externally validated model incorporates age, tumor size, type, location, multifocality, lymphovascular invasion, and ER/PR status, achieving an area under the curve (AUC) of 0.754. University of Texas MD Anderson Cancer Center’s externally validated tool uses similar variables, in addition to triple-negative status. Welsh et al identified a low-risk cohort—grade 1, cT1mi–T1c (≤ 2 cm), or grade 2, clinical T1mi–T1b (≤ 1 cm)—with pathologic nodal positivity rate of 7.8%, compared to 22.3% in higher- Articles © The authors | Journal compilation © World J Oncol and Elmer Press Inc™ | https://wjon.elmerpub.com 301 SLNB Omission in Early-Stage Breast Cancer World J Oncol.

    Omission of Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer: Expanding Evidence in Clinically Node-Negative and Neoadjuvant Therapy Responders · 2026 · DOI

  • Alhasan Alobaidi, Vikrant Rai* Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA *Correspondence: Vikrant Rai, Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, 309 E. Second Street, Pomona, CA 91766, USA. [email protected] Academic Editor: Nicola Normanno, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Italy Received: December 12, 2025 Accepted: April 14, 2026 Published: May 14, 2026 Cite this article: Alobaidi A, Rai V. Triple-negative breast cancer: current understanding and future perspectives. Explor Target Antitumor Ther. 2026;7:1002372.

    Triple-negative breast cancer: current understanding and future perspectives · 2026 · DOI

  • The association of high Ki67 expression with better survival in this young cohort is notable and, given the potential for confounding by subtype and treatment pat- terns, warrants further investigation in well-designed prospective studies.

    Integrating machine learning and clinicopathological data to stratify survival risk in young women with localized breast cancer · 2026 · DOI

  • The fist limitation was the relatively small number of patients included in both groups, further studies with larger number of participants from different institutions will improve the accuracy of the results and standardize cut-off values. Secondly, ALNs were not located in the center of the coil field, therefore, the use of axillary coil could be more ideal. Lastly, further studies on 3 T MRI are recommended to allow evaluation of smaller nodes with higher spatial resolution.

    Added value of diffusion tensor imaging in characterizing axillary lymph nodes in breast cancer patients · 2026 · DOI

  • This study has several limitations. First, this was a single- center study with 60 patients and 112 lymph nodes, limiting sta- tistical precision. Multicenter validation with larger cohorts is essential. Second, the SPIO protocol required a 12-h delay between contrast administration and post-contrast imaging, posing logistical challenges for routine clinical implementation including patient compliance and scheduling constraints. The present findings should be viewed as a proof-of-concept rather than a ready-to-deploy clinical protocol. Future studies should evaluate shorter-delay agents such as ferumoxytol. Third, the SPIO agent used (Resovist/ferucarbotran) has been withdrawn from several markets (30). While the diagnostic principle is shared by other iron oxide agents, the specific PSIL thresholds may not transfer directly to other formulations. Fourth, this study did not include direct comparisons with diffu- sion-weighted imaging (DWI) or dynamic contrast-enhanced MRI (DCE-MRI). Future comparative studies are warranted (32). Fifth, MRI–pathology correlation was based on anatomical region and surgical landmarks rather than strict spatial co-registration. Both cervical and axillary nodes were included without site-specific stratification. FIGURE 4 Distribution of VEGF-C expression across lymph node groups. (A) Stacked bar chart showing the proportion of lymph nodes in each VEGF-C immunohistochemical grade category (−, +, ++, +++) for metastatic (n = 47) and hyperplastic (n = 65) groups. (B) Comparison of the rate of high VEGF-C expression (≥++; composite score ≥4) between metastatic (85.1%) and hyperplastic (12.3%) groups (P < 0.001).

    SPIO-enhanced MRI for differentiating metastatic from reactive hyperplastic lymph nodes in breast cancer: diagnostic performance and association with VEGF-C expression · 2026 · DOI

  • The patient cohort was relatively small (85 luminal A, 30 luminal B) with unequal distribution between treatment groups (35 neoadjuvant chemotherapy vs 15 hormone therapy), which may limit statistical power for comparative effectiveness analyses.

    ANALYSIS OF NEOADJUVANT TREATMENT OF HORMONE-DEPENDENT FORMS OF BREAST CANCER (STAGE I-III): RETROSPECTIVE ANALYSIS · 2026 · DOI

  • While the study mentions that genetic array testing or immunohistochemical analyses can define breast cancer subtypes, the paper does not detail which specific methodological approach was used or standardized across all 115 cases.

    ANALYSIS OF NEOADJUVANT TREATMENT OF HORMONE-DEPENDENT FORMS OF BREAST CANCER (STAGE I-III): RETROSPECTIVE ANALYSIS · 2026 · DOI

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89 open questions have been extracted from the limitations and future-work passages of 481 Breast Cancer Treatment Studies papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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