Writing in the open-access journal Heliyon, a team of pathologists and clinicians led by Van De Nguyen reports one of the first systematic analyses of invasive lobular carcinoma variants in a Vietnamese cohort, conducted according to the 2019 World Health Organization classification of breast tumors. Their central finding is striking: the pleomorphic variant of lobular carcinoma, marked by wildly abnormal nuclei and brisk cell division, acts as an independent predictor of axillary lymph node metastasis, the spread of cancer to the lymph nodes under the arm. That independence matters, because it means the variant signals danger even after accounting for tumor size and histological grade, the two conventional yardsticks oncologists reach for first.

The study examined 167 consecutive patients with primary invasive lobular carcinoma who underwent definitive breast surgery with axillary lymph node dissection at K Hospital’s Tan Trieu campus in Hanoi between January 2019 and July 2023. The researchers excluded mixed ductal-lobular tumors, pure in situ lesions, patients who had received neoadjuvant systemic therapy, and recurrent or metastatic disease. Crucially, rather than relying on prior diagnostic reports, two experienced breast pathologists independently re-reviewed hematoxylin and eosin stained sections from archival tissue blocks in a blinded fashion, reaching consensus diagnoses by joint re-review against WHO criteria. Where mixed growth patterns existed, the predominant pattern, occupying at least half of the invasive component, determined the variant assignment.

The cohort split into four groups: classic lobular carcinoma made up 53.9 percent of cases, the pleomorphic variant 22.8 percent, the solid variant 8.4 percent, and a composite category of rare variants, including alveolar, tubulo-lobular, histiocytoid, and signet-ring cell forms, 15 percent. That pleomorphic prevalence is remarkable. In most Western series, pleomorphic lobular carcinoma accounts for only a small minority of lobular cases, often between 2 and 4 percent and rarely exceeding 10 to 15 percent. The authors caution that their figure likely reflects referral bias at a tertiary oncology center, which attracts advanced and biologically aggressive tumors, rather than a true population-level difference, but the enrichment gave them statistical power to interrogate the variant’s behavior in detail.

The molecular portrait of the pleomorphic group diverged sharply from its classic counterpart. While 96.7 percent of classic tumors expressed the estrogen receptor and only 4.4 percent were HER2 positive, the pleomorphic tumors showed estrogen receptor positivity in just 63.2 percent of cases and HER2 positivity in 31.6 percent. Progesterone receptor loss followed the same trend, and the Ki67 proliferation index, a measure of how many tumor cells are actively dividing, averaged 28.2 percent in pleomorphic cases versus 19.3 percent in classic ones. Translated into molecular subtypes using St. Gallen criteria, half of classic tumors were Luminal A, the most indolent category, whereas the pleomorphic group was enriched for HER2-enriched and triple-negative phenotypes, which together made up more than a third of pleomorphic cases but were almost absent among classic tumors.

These molecular differences translated into clinical behavior. The pleomorphic variant was overwhelmingly high grade, with 71.1 percent of cases classified as Grade 3 under the Nottingham system, while not a single classic tumor reached that grade. Most tellingly, 84.2 percent of pleomorphic cases had already spread to axillary lymph nodes at surgery, compared with 58.9 percent of classic tumors and just 42.9 percent of solid variant tumors. Pleomorphic patients also carried the heaviest nodal burden, with 42.1 percent showing four or more involved nodes. On the Nottingham Prognostic Index, which combines tumor size, nodal stage, and grade into a single score, the pleomorphic group averaged 5.61, well into the poor-prognosis range above 5.4, and 65.8 percent of pleomorphic patients fell into the poor category, versus 15.6 percent of classic cases.

The statistical centerpiece of the study is a multivariable logistic regression model. In univariate analysis, larger tumor size, pleomorphic histology, and Grade 3 morphology were all associated with nodal spread. But when the variables were entered together, with the classic variant and Grade 1 as references, only tumor size and histological variant retained significance. Each additional centimeter of tumor raised the odds of nodal metastasis by 73 percent, while the pleomorphic variant carried roughly five times the odds of nodal involvement compared with classic lobular carcinoma, an odds ratio of 5.12 with a confidence interval of 1.11 to 23.62 and a p-value of 0.036. Grade, the traditional prognostic mainstay, lost its independent significance entirely once subtype was accounted for, a result the authors interpret as evidence that grading’s prognostic power in lobular carcinoma depends heavily on which variant is being graded.

The findings align with genomic studies showing that high-grade and pleomorphic lobular carcinomas accumulate dangerous alterations beyond the canonical 1q gain and 16q loss pattern of classic disease, including ERBB2 amplification, TP53 mutations, and complex copy number changes resembling those of high-grade ductal carcinomas. High Ki67 expression in hormone receptor positive disease has also been repeatedly linked to late recurrence and endocrine resistance. The practical implication is that patients with pleomorphic lobular carcinoma may be inadequately served by endocrine therapy alone and, when HER2 positive or otherwise high risk, may require chemotherapy and anti-HER2 targeted agents alongside carefully tailored endocrine strategies, consistent with current treatment guidelines for aggressive breast cancer subtypes.

Equally instructive is what the study found about the solid variant, which some earlier series had lumped with aggressive non-classic forms. In this cohort, solid-pattern tumors were predominantly intermediate grade, strongly hormone receptor positive, HER2 negative, and Luminal A-like, with the lowest nodal metastasis rate of any group and prognostic index scores comparable to classic disease. The authors suggest that solid-pattern lobular carcinoma lacking marked nuclear pleomorphism may behave as an indolent, endocrine-responsive cousin of classic ILC rather than a dedifferentiated high-grade lesion, though the subgroup was small at 14 patients and the conclusion awaits external validation. The study’s limitations, including its single-center retrospective design, modest numbers in rare variant groups, and the absence of long-term survival follow-up, temper firm conclusions. Still, the message for pathology practice is clear: reporting the specific histological variant of invasive lobular carcinoma, not just its grade, could identify high-risk patients who need more intensive axillary staging and systemic therapy, while sparing those with biologically indolent tumors from unnecessary treatment.

Subject of Research: Pleomorphic invasive lobular carcinoma as an independent predictor of axillary lymph node metastasis in breast cancer

Article Title: Pleomorphic variant as an independent predictor of axillary lymph node metastasis in invasive lobular carcinoma

Article References: Pleomorphic variant as an independent predictor of axillary lymph node metastasis in invasive lobular carcinoma. (n.d.). https://doi.org/10.1016/j.heliyon.2026.e45533

Image Credits: AI Generated

DOI: 10.1016/j.heliyon.2026.e45533

Keywords: invasive lobular carcinoma, pleomorphic variant, axillary lymph node metastasis, breast cancer, histological grading, HER2, Ki67 proliferation index, Nottingham Prognostic Index, molecular subtypes, WHO classification, Vietnam, pathology

Triple-negative breast cancer is defined by the absence of the three molecular handles that anchor most modern breast cancer therapy: the estrogen receptor, the progesterone receptor, and HER2. Without those targets, endocrine agents and HER2-directed drugs are ineffective, leaving cytotoxic chemotherapy as the systemic backbone of treatment. Although triple-negative tumors account for only about 10 to 15 percent of breast cancers, they carry a disproportionate share of the disease’s mortality because they tend to grow quickly, are more likely to metastasize, and historically have fewer therapeutic options. For patients whose tumors are caught early, the central treatment question is not whether chemotherapy helps but when it should be given.

That question is most acute for T1c tumors, which measure between one and two centimeters and have not spread to regional lymph nodes or distant sites. The T1cN0M0 designation describes a small, node-negative cancer, yet even at this stage triple-negative biology demands systemic therapy to reduce recurrence risk. The debate concerns sequencing. Neoadjuvant chemotherapy, delivered before surgery, offers the chance to shrink the tumor, potentially enabling less extensive operations, and provides real-time information about how the cancer responds to treatment. Adjuvant chemotherapy, given after surgery, achieves the same cytotoxic goal but leaves the surgeon operating on a tumor that has never been exposed to drugs. National guidelines leave room for either approach in this small-tumor setting, and practice varies considerably across institutions.

The reason sequencing remains contested is that neither strategy has demonstrated superior overall survival. Multiple prior analyses, including studies of the same National Cancer Database, have found that patients with clinically node-negative T1 triple-negative tumors fare equally well whether chemotherapy comes first or last. If survival outcomes are equivalent, the choice between the two approaches hinges on secondary benefits: the possibility of breast-conserving surgery, the prognostic information embedded in treatment response, and patient preference. The Johns Hopkins team, led by breast surgical oncology researcher Andrew Venardi, set out to sharpen that calculus by asking a more granular question: within this seemingly uniform early-stage population, which patients are actually likely to benefit from going first with chemotherapy?

The answer, they hypothesized, might lie in Ki-67, a nuclear protein expressed by cells that are actively dividing. Pathologists measure Ki-67 by immunohistochemistry, staining tumor samples and counting the percentage of positive cells, which yields a proliferation index reflecting how fast the cancer is growing. The logic connecting Ki-67 to neoadjuvant strategy is mechanistically straightforward: chemotherapy agents such as anthracyclines and taxanes preferentially kill rapidly proliferating cells, so tumors with a high fraction of dividing cells should, in principle, be more sensitive to upfront drug treatment. Previous studies have associated high Ki-67 expression with better responses to neoadjuvant chemotherapy in triple-negative disease, but the specific threshold that separates responders from non-responders in the earliest tumor category had not been clearly defined using large-scale national data.

To conduct the analysis, the researchers queried the National Cancer Database for female patients aged 18 and older diagnosed with T1N0M0 triple-negative breast cancer between 2018 and 2022 who underwent both chemotherapy and surgery. The National Cancer Database, jointly maintained by the American College of Surgeons and the American Cancer Society, captures roughly 70 percent of newly diagnosed cancer cases in the United States, providing the statistical power that single-institution series cannot match. Patients were divided into a neoadjuvant chemotherapy cohort and an adjuvant chemotherapy cohort. Because the two groups differ systematically in tumor size, grade, and other characteristics—surgeons and oncologists tend to select patients for upfront chemotherapy based on perceived risk—the team applied inverse probability of treatment weighting, a statistical technique that re-weights the cohorts to mimic the balance of a randomized trial.

The survival analysis produced a finding consistent with the existing literature: overall survival did not differ significantly between the neoadjuvant and adjuvant groups. Multivariate Cox regression, which adjusts for competing variables simultaneously, instead identified three factors associated with worse survival. Lymphovascular invasion, the presence of tumor cells within small blood or lymphatic vessels, signaled a higher risk of microscopic spread. The invasive lobular subtype, which arises in the milk-producing lobules rather than the ducts, and mixed lobular-ductal tumors were also linked to poorer outcomes. Lobular triple-negative cancers are rare and biologically distinct, and recent registry-based studies have shown they can carry worse survival despite appearing indolent, so their emergence as an adverse marker in this dataset aligns with a growing body of evidence.

The most consequential result came from the response analysis. Among patients who received neoadjuvant chemotherapy, those who achieved a pathologic complete response—meaning no residual invasive cancer was found in the breast or lymph nodes at the time of surgery—had markedly better survival than those who did not. Non-responders faced a hazard ratio of 3.59 for worse overall survival compared with patients who achieved a complete response. This echoes the findings of a large meta-analysis showing that pathologic complete response in triple-negative breast cancer is strongly associated with improved long-term event-free and overall survival. In other words, while the timing of chemotherapy may not change survival on average, achieving eradication of the tumor before surgery identifies a subgroup whose prognosis is transformed.

That is where the Ki-67 threshold enters. Using a receiver operating characteristic curve, the researchers plotted the relationship between Ki-67 expression and pathologic complete response and applied the maximum Youden index, a standard method for finding the cutoff point that best balances sensitivity and specificity. The threshold that emerged was 45.8 percent. Patients whose tumors expressed Ki-67 at or above that level achieved a pathologic complete response rate of 45.3 percent, while those below it responded at a rate of only 21.8 percent. Expressed differently, a high proliferation index more than doubled the odds that upfront chemotherapy would completely eliminate the tumor. Logistic regression confirmed Ki-67 expression as an independent predictor of complete response, suggesting the association held after accounting for other tumor characteristics.

The clinical implications are tangible for a patient population that often faces an anxious choice. A woman with a 1.5-centimeter, node-negative triple-negative tumor whose biopsy shows a Ki-67 index of 50 percent now has registry-scale evidence that chemotherapy before surgery is likely to produce a complete response, with the dual benefits of maximal prognostic information and a survival outcome that appears markedly better than that of non-responders. Conversely, a patient with a low proliferation index may reasonably opt for surgery first, since her probability of achieving a complete response is lower and adjuvant chemotherapy delivers equivalent survival. The authors emphasize that the study is retrospective and that Ki-67 measurement itself has well-known variability between laboratories and staining protocols, so the 45.8 percent cutoff should be validated prospectively before it reshapes guidelines. Still, as the field moves from one-size-fits-all recommendations toward personalized sequencing in stage I triple-negative breast cancer, a routine pathology marker already on every diagnostic report may prove to be the deciding variable.

Subject of Research: Ki-67 expression as a predictor of pathologic complete response to neoadjuvant chemotherapy in early-stage triple-negative breast cancer

Article Title: Ki-67 expression and rates of pathologic complete response in T1cN0M0 triple-negative breast cancer: a national cancer database analysis

Article References: Venardi, A., Shojaeian, F., Diaz, S., Schuster, C. R., Rath, P., Shaid, I., Singh, A., Santa-Maria, C., & Sogunro, O. (2026). Ki-67 expression and rates of pathologic complete response in T1cN0M0 triple-negative breast cancer: a national cancer database analysis. Breast Cancer Research and Treatment, 219(3), Article 21. https://doi.org/10.1007/s10549-026-08086-1

Image Credits: AI Generated

DOI: 10.1007/s10549-026-08086-1

Keywords: triple-negative breast cancer, Ki-67, neoadjuvant chemotherapy, pathologic complete response, National Cancer Database, T1cN0M0, proliferation index, biomarker, breast surgical oncology, lymphovascular invasion, invasive lobular carcinoma, personalized treatment

The publication of selected abstracts marks an important milestone for a field that has historically struggled for recognition. Lobular breast cancers account for roughly 10 to 15 percent of all invasive breast cancers, yet they behave in ways that standard diagnostic and treatment frameworks often fail to capture. Unlike ductal carcinomas, lobular tumors typically lack the cell adhesion molecule E-cadherin, which allows cancer cells to grow in single-file patterns rather than forming discrete masses. This growth pattern makes lobular cancers notoriously difficult to detect on mammography and to measure accurately on imaging, meaning many patients are diagnosed at later stages than women with ductal tumors.

The symposium itself has grown from a small gathering of specialists into a biannual international event that draws researchers from across oncology, pathology, radiology, and computational biology. The abstract review committee for the 2026 meeting, which held full responsibility for selecting the presentations featured in the supplement, evaluated submissions spanning the full spectrum of lobular carcinoma research, from molecular mechanisms of metastasis to novel imaging strategies and clinical trial design tailored specifically to lobular biology.

One of the central themes running through lobular carcinoma research is the disease’s distinctive metastatic behavior. While ductal breast cancers most often spread to bone, lung, liver, and brain, lobular carcinomas show a striking predilection for unusual metastatic sites, including the gastrointestinal tract, gynecologic organs, and the leptomeninges. These patterns have historically led to delayed or missed diagnoses of metastatic disease, and several presentations at the symposium addressed improved surveillance strategies and the molecular drivers behind this unusual organ tropism.

Imaging challenges also featured prominently in the meeting program. Because lobular tumors infiltrate tissue diffusely rather than forming well-defined lumps, standard mammography frequently underestimates tumor size, and magnetic resonance imaging has emerged as a critical tool for surgical planning. Research presented at the symposium explored how advanced imaging modalities can improve the accuracy of tumor measurement, reduce the need for repeated surgeries, and help clinicians monitor response to neoadjuvant therapy in a disease where conventional response criteria often fall short.

The publication of the abstract collection was sponsored by the University of California San Francisco and funded through a National Cancer Institute grant, reflecting growing institutional support for lobular-specific research. The National Institutes of Health has historically allocated research funding based on disease prevalence and mortality, and advocates for lobular carcinoma patients have argued that the disease’s distinct biology warrants dedicated research investment rather than being folded into general breast cancer programs. The R13 conference grant mechanism that supported the symposium publication is specifically designed to foster scientific meetings that advance research in defined areas.

Genomic research has been a particular driver of the field’s recent momentum. Lobular carcinomas frequently harbor mutations in the CDH1 gene, which encodes E-cadherin, and they also show characteristic alterations in the PI3K signaling pathway and in the transcription factor FOXA1. These molecular features open potential avenues for targeted therapies, and clinical trials of PI3K inhibitors and endocrine therapy combinations in lobular-specific cohorts have been a recurring focus of recent symposia. The abstracts published from the seventh meeting reflect continued interest in translating these genomic insights into treatment strategies that account for the disease’s unique biology.

Another important dimension of the symposium is its role in building a coordinated international research community. Because lobular carcinoma is less common than ductal disease, individual institutions often lack sufficient patient numbers to run robust studies. Collaborative networks formed through the symposium have enabled multi-institutional clinical trials, shared tissue banking efforts, and harmonized data collection, all of which are essential for advancing a disease that requires larger cohorts to generate statistically meaningful results. The supplement’s collection of abstracts serves as a snapshot of this collaborative enterprise, documenting work from laboratories and clinics around the world.

Patient advocacy has also been woven into the symposium’s evolution. Lobular patients often describe a diagnostic odyssey marked by negative mammograms, vague imaging findings, and a lack of disease-specific information. Advocacy organizations have pushed for greater awareness among clinicians and for research that addresses the questions most relevant to patients, including how to monitor for recurrence, how to manage the anxiety of a disease that is hard to image, and how to counsel women with hereditary CDH1 mutations about their cancer risks. The growing visibility of the symposium reflects this advocacy in action.

As the field moves forward, researchers hope that the momentum generated by meetings like the seventh biannual symposium will translate into meaningful clinical improvements: earlier and more accurate detection, better prediction of metastatic risk, and therapies designed specifically for the molecular vulnerabilities of lobular cancer cells. The published abstracts offer a window into that effort, capturing the questions, methods, and early findings that will shape the next generation of lobular carcinoma research. For a disease that has long been understudied relative to its clinical impact, the sustained growth of this international gathering signals that invasive lobular carcinoma is finally getting the focused scientific attention that patients have long called for.

Subject of Research: Selected research abstracts on invasive lobular carcinoma biology, detection, and treatment presented at the 7th biannual international symposium

Article Title: Selected abstracts from the 7th Biannual International Invasive Lobular Carcinoma Symposium: Oral and Poster Presentations

Article References: Selected abstracts from the 7th Biannual International Invasive Lobular Carcinoma Symposium: Oral and Poster Presentations. (2026). Breast Cancer Research and Treatment, 219(S1), Article 17. https://doi.org/10.1007/s10549-026-08047-8

Image Credits: AI Generated

DOI: 10.1007/s10549-026-08047-8

Keywords: invasive lobular carcinoma, breast cancer, symposium abstracts, E-cadherin, CDH1, metastasis, breast imaging, Breast Cancer Research and Treatment, National Cancer Institute, lobular breast cancer research, clinical trials, molecular biology