Pathway-based signatures predict patient outcome, chemotherapy benefit and synthetic lethal dependencies in invasive lobular breast cancer.

BACKGROUND: Invasive Lobular Carcinoma (ILC) is a morphologically distinct breast cancer subtype that represents up to 15% of all breast cancers. Compared to Invasive Breast Carcinoma of No Special Type (IBC-NST), ILCs exhibit poorer long-term outcome and a unique pattern of metastasis. Despite these differences, the systematic discovery of robust prognostic biomarkers and therapeutically actionable molecular pathways in ILC remains limited. METHODS: Pathway-centric multivariable models using statistical machine learning were developed and tested in seven retrospective clinico-genomic cohorts (n = 996). Further external validation was performed using a new RNA-Seq clinical cohort of aggressive ILCs (n = 48). RESULTS AND CONCLUSIONS: mRNA dysregulation scores of 25 pathways were strongly prognostic in ILC (FDR-adjusted P < 0.05). Of these, three pathways including Cell-cell communication, Innate immune system and Smooth muscle contraction were also independent predictors of chemotherapy response. To aggregate these findings, a multivariable machine learning predictor called PSILC was developed and successfully validated for predicting overall and metastasis-free survival in ILC. Integration of PSILC with CRISPR-Cas9 screening data from breast cancer cell lines revealed 16 candidate therapeutic targets that were synthetic lethal with high-risk ILCs. This study provides interpretable prognostic and predictive biomarkers of ILC which could serve as the starting points for targeted drug discovery for this disease.

Breast surgery after neoadjuvant chemotherapy in patients with lobular carcinoma: surgical and oncologic outcome.

INTRODUCTION: Breast cancer patients with invasive lobular carcinoma (ILC) have an increased risk of positive margins after surgery and often show little response to neoadjuvant chemotherapy (NAC). We aimed to investigate surgical outcomes in patients with ILC treated with NAC. METHODS: In this retrospective cohort study, all breast cancer patients with ILC treated with NAC who underwent surgery at the Netherlands Cancer Institute from 2010 to 2019 were selected. Patients with mixed type ILC in pre-NAC biopsies were excluded if the lobular component was not confirmed in the surgical specimen. Main outcomes were tumor-positive margins and re-excision rate. Associations between baseline characteristics and tumor-positive margins were assessed, as were complications, locoregional recurrence rate (LRR), recurrence-free survival (RFS), and overall survival (OS). RESULTS: We included 191 patients. After NAC, 107 (56%) patients had breast conserving surgery (BCS) and 84 (44%) patients underwent mastectomy. Tumor-positive margins were observed in 67 (35%) patients. Fifty five (51%) had BCS and 12 (14%) underwent mastectomy (p value < 0.001). Re-excision was performed in 35 (33%) patients with BCS and in 4 (5%) patients with mastectomy. Definitive surgery was mastectomy in 107 (56%) patients and BCS in 84 (44%) patients. Tumor-positive margins were associated with cT ≥ 3 status (OR 4.62, 95% CI 1.26-16.98, p value 0.021) in the BCS group. Five-year LRR (4.7%), RFS (81%), and OS (93%) were not affected by type of surgery after NAC. CONCLUSION: Although 33% of ILC breast cancer patients undergoing BCS after NAC required re-excision for positive resection margins, it is considered safe given that five-year RFS remained excellent and LRR and OS did not differ by extent of surgery.

Molecular and Clinical Portrait of HER2-low Invasive Lobular Carcinomas.

Invasive lobular carcinomas (ILCs) have a low frequency of ERBB2 amplification, therefore restricting the use of conventional anti-HER2 therapies for this histologic special type. Conversely, ILCs with low HER2 overexpression may represent a broader target for the use of emerging antibody drug conjugate therapies targeting HER2, since these treatments have proven effective in HER2-low breast cancers. Very scarce data about HER2-low ILCs have been so far published, although these tumors could have different prevalence and histomolecular specificities compared with invasive breast carcinoma of no special type (IBC-NST). Our aims in that context were to decipher the clinicopathological and molecular features of a large series of HER2-low ILCs. Comparative evaluation of HER2-low prevalence was done based on a retrospective series of 7970 patients from Institut Curie, with either primary invasive lobular (N = 1103) or no special type (N = 6867) invasive carcinoma. Clinicopathological and molecular analyses of HER2-zero, HER2-low, and HER2-positive ILCs were performed on a subgroup of 251 patients who underwent surgery for a primary ILC between 2005 and 2008. The mutational profile of these 251 cases was determined from RNAseq data. Compared with HER2-negative IBC-NSTs, the HER2-negative ILCs were found to display a higher frequency of HER2-zero cases (59.4% vs 53.7%) and a lower frequency of HER2-low (40.6% vs 46.3%) (P < .001). Clinicopathological features associated with HER2-low status (vs HER2-zero) in ILC were older age, postmenopausal status, nonclassic ILC histological types, higher grade, proliferation, and estrogen receptor expression levels. Survival curve analysis showed a significantly lower risk of local recurrence for HER2-low (vs HER2-zero) ILCs, but no association was found between HER2 status and either breast cancer-specific survival or distant metastasis-free interval. ERBB3 was the unique mutated gene exclusively associated with HER2-low ILCs yet being mutated at a low frequency (7.1%) (false discovery rate < 0.05). In conclusion, HER2-low ILCs exhibit their own particularities, both on clinical-pathological and molecular levels. Our findings call for larger multicenter validation studies.

Effect of histological breast cancer subtypes invasive lobular versus non-special type on survival in early intermediate-to-high-risk breast carcinoma: results from the SUCCESS trials.

BACKGROUND: Invasive lobular breast carcinomas (ILC) have different histological features compared to non-special type carcinomas (NST), but the effect of histological subtypes on survival is controversial. In this study, we compared clinicopathological characteristics and outcomes between ILC and NST based on a large pooled data set from three adjuvant breast cancer trials (SUCCESS A, B, and C) and investigated a potential differential effect of recurrence risk related to nodal stage on survival. METHODS: From 2005 to 2017, the large randomized controlled SUCCESS A, B, and C trials enrolled 8190 patients with primary, intermediate-to-high-risk breast carcinoma. All patients received adjuvant chemotherapy, and endocrine and/or HER2-targeted treatment was given where appropriate. Survival outcomes in terms of disease-free survival (DFS), overall survival (OS), breast cancer-specific survival (BCSS), and distant disease-free survival (DDFS) were estimated using the Kaplan-Meier method and analyzed using log-rank tests as well as univariable and adjusted multivariable Cox regression models. RESULTS: In the SUCCESS trials, 6284 patients had NST and 952 had ILC. The median follow-up time was 64 months. ILC patients were older, more likely to receive mastectomy, and more likely to have larger tumor sizes, lymph node infiltration, hormone receptor-positive, HER2neu-negative, and luminal A-like tumors than NST patients. In the overall cohort, no significant differences between ILC and NST were detectable regarding the four survival endpoints, with hazard ratios obtained in adjusted multivariable cox regressions of 0.96 (95% CI 0.77-1.21, p = 0.743) for DFS, 1.13 (95% CI 0.85-1.50, p = 0.414) for OS, 1.21 (95% CI 0.89-1.66, p = 0.229) for BCSS, and 0.95 (95% CI 0.73-1.24, p = 0.689) for DDFS. However, a differential effect of nodal stage on survival was observed, with better survival for ILC patients with pN0/pN1 tumors and worse survival for ILC patients with pN2/pN3 tumors compared to NST patients. CONCLUSIONS: Our results revealed that ILC was associated with worse survival compared to NST for patients at high risk of recurrence due to advanced lymph node infiltration. These findings should be taken into account for treatment decisions and monitoring.

Real-World Analysis of the Clinical and Economic Impact of the 21-Gene Recurrence Score (RS) in Invasive Lobular Early-Stage Breast Carcinoma in Ireland.

Background: This study, using real-world data, assesses the impact of RS testing on treatment pathways and the associated economic consequences of such testing. This paper pertains to lobular breast cancer. Methods: A retrospective, observational study was undertaken between 2011 and 2019 on a cross-section of hormone receptor-positive (HR+), HER2-negative, lymph node-negative, early-stage breast cancer patients. All patients had ILC and had RS testing in Ireland. The patient population is representative of the national population. Patients were classified as low (RS ≤ 25) or high (RS > 25) risk. Patients aged ≤50 were stratified as low (RS 0-15), intermediate (RS 16-25), or high risk (RS > 25). Results: A total of 168 patients were included, most of whom had grade 2 (G2) tumors (n = 154, 92%). Overall, 155 patients (92.3%) had low RS (≤25), 12 (7.1%) had high RS (>25), and 1 (0.6%) had unknown RS status. In 29 (17.5%) patients aged ≤50 at diagnosis, RS was ≤15 in 16 (55%), 16-20 in 6 (21%), 21-25 in 5 (17%), >25 in 1 (3.5%), and unknown in 1 (3.5%). Post RS testing, 126 patients (78%) had a change in chemotherapy recommendation; all to hormone therapy. In total, only 35 patients (22%) received chemotherapy. RS testing achieved a 75% reduction in chemotherapy use, resulting in savings of €921,543.84 in treatment costs, and net savings of €387,283.84. Conclusions: The use of this test resulted in a 75% reduction in chemotherapy and a significant cost savings in our publicly funded health system.

Efficacy of Neoadjuvant Chemotherapy in Lobular and Rare Subtypes of Breast Cancer.

OBJECTIVE: To determine the predictive factors for the pathological complete response (pCR) in patients with non-ductal invasive breast cancer (ND-BC) receiving neoadjuvant chemotherapy. STUDY DESIGN: Observational study. Place and Duration of the Study: Departments of Medical Oncology, Tekirdag Namik Kemal University, Sirnak State Hospital, Aydin Adnan Menderes University, Marmara University, Bakirkoy Sadi Konuk Hospital, Basaksehir Cam and Sakura Hospital, Sakarya University, Balikesir Ataturk Hospital, Turkiye, from April 2016 to December 2022. METHODOLOGY: A total of 222 non-metastatic breast cancer patients who received neoadjuvant chemotherapy were included in this retrospective multicentric study. The clinicopathologic data were obtained from the hospitals' electronic-record-system. The logistic regression models were used to identify predictive factors for pCR. RESULTS: One hundred and twenty-six patients (56.8%) had invasive lobular carcinoma and 28 patients (12.6%) had signet ring cell/mucinous carcinoma. A total of 45 patients (20.3%) achieved pCR. The pCR rate was 14.3% for lobular carcinoma and 17.9% for signet ring cell/mucinous carcinoma. The univariate analysis showed that estrogen receptor-negative tumours (p = 0.017), high Ki-67 (p = 0.008), high histologic grade (p<0.001), HER2+ expression (p<0.001), and non-lobular histologic type (p = 0.012) were predictive factors for pCR. The multivariate model revealed that HER2 expression (p<0.001) and Ki-67 (p = 0.005) were independent predictors. CONCLUSION: Neoadjuvant chemotherapy demonstrated effectiveness in ND-BC patients, leading to favourable pCR rates and enabling breast-conserving surgery. Predictive markers for pCR varied depending on histologic types, with HER2 expression, ER status, Ki-67, and histologic grade showing significance in non-ductal subtypes, while HER2 status alone was predictive in lobular carcinoma. KEY WORDS: Neoadjuvant chemotherapy, Non-ductal breast cancer, Lobular carcinoma.

Invasive lobular carcinoma of the breast; clinicopathologic profile and response to neoadjuvant chemotherapy over a 15-year period.

INTRODUCTION: Invasive lobular carcinoma (ILC) accounts for 5-15% of invasive breast cancers. Typical ILC is oestrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) negative. Atypical biomarker profiles (ER- and HER2+, ER+ and HER2+ or triple negative) appear to differ from typical ILCs. This study compared subtypes of ILC in terms of clinical and pathological parameters, and response to neoadjuvant chemotherapy (NACT) according to biomarker profile. METHODS: All patients with ILC treated in a single centre from January 2005 to December 2020 were identified from a prospectively maintained database. Clinicopathologic and outcome data was collected and analysed according to tumour biomarker profile. RESULTS: A total of 582 patients with ILC were treated. Typical ILC was observed in 89.2% (n = 519) and atypical in 10.8% (n = 63). Atypical ILCs were of a higher grade (35% grade 3 vs 9.6% grade 3, p < 0.001). A larger proportion of atypical ILC received NACT (31.7% vs 6.9% p < 0.001). Atypical ILCs showed a greater response to NACT (mean RCB (Residual Cancer Burden Score) 2.46 vs mean RCB 3.41, p = 0.0365), and higher pathological complete response rates (15% vs 0% p = 0.017). Despite this, overall 5-year disease-free survival (DFS) was higher in patients with typical ILC (91% vs 83%, p = 0.001). CONCLUSIONS: Atypical ILCs have distinct characteristics. They are more frequently of a higher grade and demonstrate a superior response to NACT. Despite the latter, atypical ILCs have a worse 5-year DFS which should be taken into consideration in terms of prognostication and may assist patient selection for NACT.

Relationship between food perceptions and health-related quality of life in a prospective study with breast cancer patients undergoing chemotherapy

OBJECTIVE: To correlate the perceptions related to dietary intake with the domains and subscales of health-related quality of life (HRQL) in women with breast neoplasms receiving chemotherapy. METHODS: In this prospective study, 55 women with breast cancer were followed up during chemotherapy at three different times (T0, T1, T2). Before chemotherapy, perceptions related to food consumption were evaluated. HRQL was analyzed with the EORTC QLQ-C30 and Br23 instruments 21 days after each investigated cycle. The differences (T2-T0) in the subscales and HRQL domains were correlated with the differences (T2-T0) in the appetite scores. Spearman's correlation was used to verify a possible correlation between differences in functional and overall HRQL domains (T2-T0) and differences in appetite scores for certain foods and between the differences in some subscales of EORTC QLQ-C30 and Br23 (T2-T0) and differences in appetite scores for certain food groups (T2-T0). RESULTS: Correlations between pain and appetite for bitter taste and between an increased appetite for juices and pain intensification or fatigue were identified, and pain was correlated with an appetite for starchy foods. An appetite for vegetables, legumes and meat/eggs was correlated with physical function. The only significant correlation with social functions occurred between the appetite for sweet foods and these functions. We found a correlation between overall health, emotional function, social function and physical function and the appetite for juices. CONCLUSION: Chemotherapy alters the individual's relationship with food and, consequently, the individual's HRQL.

Metástasis vulvar de carcinoma lobulillar de mama: reporte de un caso / Vulvar metastases of lobulillar carcinoma of breast: a case report

El objetivo del presente trabajo es el de presentar un caso de metástasis a vulva de primario de mama derecha carcinoma lobulillar estadio IIB, en paciente de 46 años con tratamiento quirúrgico y adyuvancia con quimioterapia, radioterapia y hormonoterapia, vista y tratada en el servicio de patología mamaria del Instituto de Oncología “Dr. Luis Razetti” Caracas, Venezuela. Se revisa la literatura. Se describe una lesión metastásica en labio mayor de hemivulva izquierda de 1,5 cm de diámetro en una paciente con carcinoma lobulillar de mama derecha estadio IIB con intervalo libre de enfermedad de 5 meses después de tratamiento quirúrgico y adyuvante completo. Las metástasis a vulva del cáncer de mama son infrecuentes. La vigilancia ginecológica cuidadosa en pacientes con cáncer de mama permite evidenciar sitios infrecuentes de metástasis, para poder ser diagnosticados precozmente y tratados apropiadamente.

The objective of this present work is to report a case of metastases to vulva of primary of right breast lobulillar carcinoma classified as stadium IIB, in 46 years old patient with surgical and adjuvant treatment with complete chemotherapy, radiotherapy and hormonal therapy she was seen and treated in breast pathology service of Oncology Institute “Dr. Luis Razetti”, Caracas, Venezuela. We review the literature. Describe a metastatic tumor in left lip bigger of the vulva of 1.5 cm primary of the right breast lobular cancer, stadium IIB, with 5 months interval free of illness, after surgical and adjuvant complete treatment. The metastases to vulva of breast cancer are less frequent. The careful gynecological surveillance in patient with breast cancer allows us to evidence an unusual place of metastasis, to be able to be diagnosed precociously and tried appropriately.

Es carcinoma lobulillar infiltrante igual a carcinoma ductal infiltrante?: seguimiento a largo plazo / Is lobulillar infiltrante carcinoma equal to ductal infiltrante carcinoma?: long term follow

Comparar carcinoma lobulillar infiltrante y carcinoma ductal infiltrante a largo plazo según estadio, tratamiento quirúrgico, terapia neoadyuvante, adyuvante. Estudiamos en la base de datos de CECLINES 841 pacientes, el lobulillar representa 7,25% (61) y ductal 51,24% (431). El seguimiento global 22 años con promedio de 5 años. La sobrevida global: lobulillar 68,1% vs. 60,9% ductal (P=0,772), por estadio fue: I lobulillar 96,3% ductal 90,5 II 94,4% y 88,4% III 90,5% 83,2% (P=0,023). La expresión de receptores de estrógenos positivos en comparación a los CDI fue 87,7% vs. 74,7%,(P=0,031) sobrevida 96,9% vs. 94,0% (P=0,033). El tratamiento preservador del lobulillar en comparación aductal 57,4% vs. 63,2% (P=0,949) y la sobrevida 85,4% vs. 82,9% (P=0,001). La sobrevida de lobulillar sometidos a quimioterapia primaria, quimioterapia adyuvante, radioterapia y hormonoterapia adyuvante en relación al grupo ductal fue 93,4% vs. 91,3%, 91,5% vs. 89,7%, 92,5% vs. 89,8% 92,5% vs. 88,4%, respectivamente (P<0,05). La sobrevida global es igual, la sobrevida por estadio favorece al lobulillar estos presentan más receptores positivos y sobrevida mejor. La tendencia a tratamiento preservador en lobulillar es mayor encontrando excelentes cifras de sobrevida. Dado el perfil hormonal y sobrevida según receptores las pacientes con lobulillar infiltrante son candidatas a participar en protocolos de hormonoterapia primaria. Generalmente el tratamiento para ambos grupos es similar.

Compare infiltrante lobulillar carcinoma and ductal carcinoma in long-term follow up as stage surgical treatment, neoadyuvante, adjuvant therapy. We studied in CECLINES data base 841 patients; lobulillar represents 7.25% (61) and 51.24% ductal (431). The overall followup was up to twenty two years with an average of five years. The overall survival for lobulillar was 68.1%and for ductal 60.9% (P=0.772), the survival according to state was: I lobulillar 96.3% ductal 90.5, II 94.4% vs. 88.4 III 90.5 and 83.2 respectively (P=0.023). Estrogen receptors positive expression for lobulillar compared to ductal was 87.7% vs. 74.7%, (P=0.031) and its survival 96.9% vs. 94.0% (P=0.033). The breast conserving surgery for lobulillar compared to ductal was 57.4% vs. 63.2% (P=0.949) survival 85.4% vs. 82.9% (P=0.001). The survival reported for patients with lobulillar who received neoadyuvante chemotherapy adjuvant chemotherapy radiotherapy and adjuvant hormonotherapy compared to ductal was 93.4% 91.3%, 91.5% 89.7%, 92.5% 89.8% 92.5% 88.4%, respectively P<0.05. The overall survival is equal, survival favors. The lobulillar have more positive receptors and survival is better. The tendency to conservative treatment in lobulillar is increasingly. Given the hormonal profile and survival according to estrogen receptors patients with ILC, are probably good candidates to participate in neoadyuvante hormone therapy protocols. Usually the treatment is the same or similar for both groups.

Quimioterapia no carcinoma lobular invasivo: qual a evidência? / Chemotherapy in lobular invasive breast cancer: is there an evidence?

O carcinoma lobular invasivo é o segundo tipo histológico mais freqüente de câncer de mama, e sua incidência parece estar aumentando. O carcinoma lobular invasivo apresenta características clínicas, biológicas e moleculares distintas das do carcinoma ductal, sendo freqüentemente de baixo grau e quase sempre positivo para receptores de estrógeno. A taxa de resposta à quimioterapia neo-adjuvante do carcinoma lobular invasivo é mais baixa que a do carcinoma ductal invasivo. Apesar disso, a quimioterapia adjuvante é rotineiramente indicada para pacientes com carcinoma lobular invasivo, com base nos mesmos critérios utilizados para carcinoma ductal invasivo. Neste artigo, revisaram-se os estudos randomizados de quimioterapia em câncer de mama localizado e não se encontraram dados suficientes para alicerçar ou banir o uso de quimioterapia em pacientes com carcinoma lobular invasivo. O benefício da quimioterapia sistêmica para pacientes com carcinoma lobular invasivo precoce está pouco claro na literatura. O carcinoma lobular invasivo é uma classe clínica e molecularmente distinta dos cânceres de mama, que deve ser investigada separadamente em estudos prospectivos, para que se possa oferecer o tratamento ideal para pacientes com essa doença.

Invasive lobular carcinoma is the second most frequent histological type of breast cancer, and on whose incidence seems to be increasing. Invasive lobular carcinoma displays unique clinical and biological features, when compared with invasive ductal carcinoma, and a significantly lower response rate to neoadjuvant chemotherapy. However, adjuvant chemotherapy is indicated for patients with invasive lobular carcinoma using the same criteria utilized for invasive ductal carcinoma. In this article, we provide an overview of the randomized trials of neoadjuvant and adjuvant chemotheraphy; at the present time, there is little evidence to support or to withhold chemotherapy for patients with early-stage, invasive lobular carcinoma. We thus suggest that the role of systemic chemotherapy for such patients is currently unclear, and an issue well deserving of more thorough investigation in future trials.