Higher Pathological Complete Response Research Articles

Abstract PO3-25-07: Characterization of tertiary lymphoid structures and its association with response to immune checkpoint inhibitors in triple negative breast cancer using spatial transcriptomics

Abstract Background Tertiary lymphoid structures (TLS) are ectopic lymphoid organs playing a role in adaptive antitumor immune response. They were shown to be associated with favorable outcome and appears to be a promising biomarker for response to immune checkpoint inhibitors (ICI). Yet, there is no consensus for their detection and quantification. Here we aimed to derive a specific TLS signature using high resolution spatial transcriptomics data from a large series of triple negative breast cancer (TNBC) samples and to assess its clinical relevance including response to ICI. Methods Spatial transcriptomics (ST) was performed on a series of 94 early-stage TNBC surgical samples with detailed clinicopathological and outcome data. TLS and tumor infiltrating lymphocytes (TILs) were scored using hematoxylin and eosin and double immunohistochemistry (CD3/CD20) stained slides by a dedicated breast pathologist. Regression based on morphological annotations and deconvolution methods estimated the fraction of gene expression related to TLS in each ST spot allowing to derive specific TLS signature. Its prognostic and predictive value of response to ICI was assessed using publicly available breast cancer (METABRIC, SCAN-B, and I-SPY2) and other tumor type datasets treated with ICI (Bareche et al. Ann Oncol, 2022) from bulk gene expression data. Results Deconvolution of the TLS compartments using the ST gene expression data showed that TLS are enriched in all B cell subsets, CD4+ (central) memory and naïve T cells, as well as mast cells. A functional analysis showed an enrichment of ‘vascular endothelial cell proliferation’, ‘mitotic G2/M transition checkpoint’, ‘V/D/J recombination’ and ‘regulation of cell chemotaxis to fibroblast growth factor’ suggesting that TLS aggregates are associated with angiogenesis, immune cell proliferation, adaptative humoral response and tissue remodeling. A comparison of gene expression data between TLS and non-aggregated TILs led to the development of a specific TLS gene signature comprising B and T cell-specific genes, immunoglobulin genes as well as genes associated with TLS initiation. Its projection on tumor slides overlapped with the regions annotated as TLS by the pathologist, demonstrating its specificity for TLS detection. As expected, the highest levels of the TLS signature were observed in the immunomodulatory TNBC molecular subtype and fully inflamed tumors, whereas the lowest levels were observed in the mesenchymal molecular subtype and immune desert tumors (p< 0.05). Of note, high levels of the TLS signature were associated with better prognosis in TNBC patients from METABRIC (p=6.5 10−5) and SCAN-B datasets (p=1.6 10−3) as well as with higher pathological complete response rates in all breast cancer patients treated with neoadjuvant pembrolizumab in the I-SPY2 study (p=0.026). Similar results were found in other tumor types treated with immunotherapy in the metastatic setting including metastatic melanoma, pancreatic and bladder cancers (PFS, p=6 10−6). Of interest, the TLS signature outperformed the predictive value of other immune-related signatures including TILs suggesting a key role of TLS in obtaining a sustainable, adaptive antitumor immune response in the vicinity of the tumor area. Conclusion By leveraging the potential of spatial transcriptomics, we have successfully developed a unique TLS gene signature that demonstrates a strong correlation with the response to ICI in breast cancer and various other tumor types. This TLS gene signature outperforms other immune biomarkers, underscoring the pivotal role of TLS in eliciting a robust antitumor immune response. The universality of this TLS signature makes it a potent biomarker capable of identifying patients who would benefit from immunotherapy, pending further validation. Citation Format: Xiaoxiao Wang, David Venet, Frédéric Lifrange, Denis Larsimont, Mattia Rediti, Linnea Stenbeck, Floriane Dupont, Ghizlane Rouas, Andrea Joaquin Garcia, David Gacquer, Ligia Craciun, Laurence Buisseret, Nayanika Bhalla, Yuvarani Masarapu, Kim Thrane, Eva Gracia Villacampa, Lovisa Franzén, Sami Saarenpää, Linda Kvastad, Joakim Lundeberg, Françoise Rothé, Christos Sotiriou. Characterization of tertiary lymphoid structures and its association with response to immune checkpoint inhibitors in triple negative breast cancer using spatial transcriptomics [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-25-07.

Abstract PO4-03-12: De-escalating treatment with neoadjuvant chemotherapy in early triple-negative breast cancer

Abstract Neoadjuvant chemotherapy (NAT) is a standard treatment in early triple-negative breast cancer, but the regimen and duration of this treatment are controversial. We analyze a cohort of early triple negative breast cancer treated with NAT with different schemas to determine its efficacy. 272 patients treated with NAT since 2001 to 2020 were selected. The median age of the group was 57 years (27-85), initial size 30 mm (9-122) and Ki67 expression was 60 (7-100). 107 patients (39.3%) had histologically confirmed initial axillary involvement and the regimens of chemotherapy used were carboplatin AUC 5 + weekly paclitaxel (80 mg/m2) x 4 cycles in 56 cases (21%) (SCHEME A), same scheme followed by 4 cycles of adriamycin 50 mg/m2 + cyclophosphamide 500 mg/m2 in 85 cases (31%) (SCHEME B), Adriamycin 50 mg/m2 + cyclophosphamide 500 mg/m2 × 4 cicles in 44 (16%) (SCHEME C) and Adriamycin 50 mg/m2 + cyclophosphamide 500 mg/m2 × 4 cicles followed by docetaxel 100 mg/m2 × 4 cicles in 87 (32%) (SCHEME D). We achieved a 51% of pathologic complete response (pCR),and a total of 24% of recurrences. The proportion of PCR and recurrence according to the different schemes is represented in the following table. The clinical factors associated with recurrence were the initial size (OR 8.6), the initial axillary involvement (OR 4.21) and the absence of pCR (OR 8.14), and for patients with pCR it was only the initial axillary involvement (OR 3.4). Patients that received schema A in NAT only presented a total of 5% of recurrence (3/56), only in patients with initial axillary involvement. The NAT schema with carboplatin AUC 5 + weekly paclitaxel (80 mg/m2) x 4 cycles is safe in patients without initial nodal involvement with high pathologic complete response (62%) and lower recurrence rate (9% in nonPCR and 3% in pCR). Therefore, it could be considered as a standard scheme of neoadjuvant chemotherapy for patients without axillary involvement. Table. SCHEMA A (20%) B (31%) C (16%) D (32%) Pcr 62% 63% 41% 37% Recurrence in pCR 3% 7% 16% 9% Recurrence in nonpCR 9% 16% 50% 63% Citation Format: Serafin Morales Murillo, Ariadna Gasol Cudós, Noemí Tuset Der-Abrain. De-escalating treatment with neoadjuvant chemotherapy in early triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-03-12.

Abstract PO2-20-11: Safety and efficacy of KEYNOTE-522 in combination with anti-retroviral therapy in a patient with HIV and triple-negative breast cancer

Abstract Introduction: Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) that does not express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER-2), accounting for about 15% of all BC. TNBC is more aggressive than other BC with a higher risk of recurrence and mortality. The current standard of care for high-risk, early-stage TNBC based on the KEYNOTE-522 trial is neoadjuvant multidrug chemotherapy (paclitaxel and carboplatin [TCb] weekly x 12 weeks and doxorubicin and cyclophosphamide [AC] Q3 weeks) with pembrolizumab (P). The trial demonstrated patients who received chemotherapy plus P had a higher pathological complete response and event-free survival compared to patients who received chemotherapy plus placebo. However, the trial excluded patients with any autoimmune disease requiring treatment within 2 years, a diagnosis of immunodeficiency or steroids within 7 days before the first treatment, or a known history of human immunodeficiency virus (HIV). While limited data exist on immune checkpoint inhibitors (ICI) in patients with immunodeficiencies, subsequent data demonstrate that patients with HIV have similar efficacy and immune-related adverse events (irAE) compared to patients without HIV, and 2017 consensus recommendations encouraged broader eligibility in clinical trials to include patients with HIV. We present one of the first reported clinical cases of a patient with HIV diagnosed with stage IIB TNBC, treated per KEYNOTE-522 and anti-retroviral therapy (ART). Clinical Case: A 55-year-old female with a medical history significant for HIV, self-detected a mass in her left breast. Diagnostic imaging demonstrated a suspicious 4.0 cm mass in the left breast without adenopathy. An ultrasound-guided biopsy of the mass revealed grade 3 invasive ductal carcinoma with ER 0%, PR < 1%, and HER-2 1+. The clinical stage was cT2N0M0, prognostic stage IIB. Genetic testing was positive for germline BRCA2 pathogenic variant. HIV PCR < 20 copies/mL and CD4 count 1.298 K/uL prior to neoadjuvant chemotherapy. The patient was adherent to HIV ART with bictegravir, emtricitabine, and tenofovir alafenamide. The patient received KEYNOTE-522, including 11 cycles of TCb-P, followed by four cycles of AC-P. Following neoadjuvant treatment, the patient underwent a left segmental mastectomy and sentinel lymph node biopsy and achieved a pathological complete response. She completed left whole breast radiation (RT) with 3DCRT plus 3DCRT tumor bed boost to a total dose of 48.06 cGy and one-year of adjuvant P. Treatment-related adverse events included grade 4 febrile neutropenia after cycle one AC without growth factor, requiring a 5-day hospitalization; and grade 3 peripheral neuropathy, resulting in discontinuation of week 12 of TCb. The patient also developed paronychia, and a pulmonary embolism after week 11 of TCb. She had no irAE. Radiation-related adverse events included grade 1 left breast dermatitis and fatigue and mild left breast soreness. Discussion: Among the subset of patients diagnosed with TNBC, the percentage of patients with HIV or immunodeficiency receiving active BC treatment is low. Safety and efficacy data for novel cancer therapeutics including ICI are limited since historically patients with HIV and other immunodeficiency states were excluded from trials. Anti-PD-1 ICI has become a key part of the standard of care for the treatment of breast cancer. Patients with HIV experience rare infectious complications and have a life expectancy near the general population with ART. We support the inclusion of patients with HIV in future clinical trials for TNBC and/or ICI and recommend treatment of patients with HIV and TNBC per standard of care in multi-disciplinary collaboration with HIV clinicians. Citation Format: Stephanie Haddad, Stephanie Graff, Matthew Hadfield, Yihong Wang, Charu Taneja, Kara Leonard, Martha Sanchez, Robert Ward, Ana Lourenco, Mary Anne Fenton. Safety and efficacy of KEYNOTE-522 in combination with anti-retroviral therapy in a patient with HIV and triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-11.

Abstract PO2-15-08: Exploring Essential Immune Genes Linked to Pathological Complete Response and Survival in Early-Stage Triple-Negative Breast Cancer (TNBC) after Chemotherapy Treatment

Abstract Background: De-escalation and escalation of systemic therapy in early-stage TNBC will require the implementation of biomarkers to guide therapy. To date, high expression of a variety of immune genes has been associated with higher pathological complete response (pCR) rates following neoadjuvant chemotherapy or with improved survival, or both, in early-stage TNBC. However, it is currently unknown which are the key genes influencing survival (i.e., the Core Immune Genes [CIG]) and if combinations of these genes can improve their association with both clinical endpoints. Methods: The expression of up to 185 genes was evaluated on pre-treatment tumor biopsies from 3 independent publicly available datasets of early-stage TNBC: CALGB40603 (n=388) (NCT00861705), BrighTNess (n=482) (NCT02032277), and SCAN-B (n=498). Patients in CALGB40603 and BrighTNess were treated with neoadjuvant chemotherapy-based therapy and had response data. Patients in CALGB40603 and SCAN-B had survival outcome data (event-free survival [EFS] or relapse-free interval [RFi]). Each individual gene was associated with each clinical endpoint within each dataset using Cox model and logistic regression analyses, adjusting for treatment arm. Genes found in common across datasets were selected as CIG, except for PDCD1, which was not available in BrighTNess. Using the CIGs, we evaluated whether combinations of 2 genes enhance their association with each clinical endpoint using different methods: adding, subtracting, multiplying, and ratio. Likelihood ratio testing was used to evaluate the added contribution of each gene in 2 combined cohorts evaluating pCR (i.e., CALGB40603 and BrighTNess) and survival (i.e., CALGB40603 and SCAN-B). Results: 10 CIGs related to B-cells and T-cells (i.e., IRF4, LAX1, POU2AF1, CD274, CD79A, TNFRSF17, PIM2, PDCD1, CXCR6, and SLAMF1) were associated with higher pCR rates and improved survival outcome across datasets. Of note, 5 (50%) genes are known components of the 14-gene immunoglobulin/B-cell (IGG) signature. The correlation coefficient among the 10 CIG genes was 0.63 (moderate). In general, the sum of 2 CIGs provided more prognostic information than a single gene (p< 0.001). Specifically, the sum of 2 CIGs provides more prognostic information than a single gene in 30 of 45 (66.6%) cases. Two-gene subtraction, multiplication or ratio decreased the amount of prognostic information (p< 0.001). The top 10 2-gene CIGs associated with prognosis (p< 0.001) were CD274_TNFRSF17, IRF4_CD274, PDCD1_TNFRSF17, CD79A_CD274, CD274_POU2AF1, CXCR6_TNFRSF17, LAX1_TNFRSF17, SLAMF1_TNFRSF17, CD274_LAX1 and CD79A_CXCR6. In general, the sum of 2 CIGs provided more information about pCR than a single gene (p< 0.001). Specifically, the sum of 2 CIGs provided numerically more information about pCR than 1 gene in 17 of 36 (47.2%) cases. Two-gene subtraction, multiplication or ratio decreased the amount of information about pCR (p< 0.001). The top 10 2-gene CIGs associated with pCR were CD274_PIM2, CD274_POU2AF1, CXCR6_PIM2, CD274_CXCR6, IRF4_CD274, CXCR6_POU2AF1, CD274_LAX1, IRF4_CXCR6, CXCR6_LAX1, and POU2AF1_SLAMF1. Conclusion: The expression of CIGs associated with B-cell and T-cell adaptive immune response is closely linked to pCR and survival outcomes following (neo)adjuvant chemotherapy. When combining the expression of 2 specific CIGs through addition, we found that this method provides more informative insights into pCR and survival outcomes compared to other combination methods. This approach enhances the predictive power of CIGs, enabling a better understanding of treatment response and patient prognosis, ultimately contributing to improved clinical decision-making and patient outcomes. Citation Format: Fara Brasó-Maristany, Laia Paré, Benedetta Conte, Laura Angelats, Ana Vivancos, Joel S Parker, Charles M. Perou, Patricia Villagrasa, Aleix Prat. Exploring Essential Immune Genes Linked to Pathological Complete Response and Survival in Early-Stage Triple-Negative Breast Cancer (TNBC) after Chemotherapy Treatment [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-15-08.

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

IntroductionInvasive 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. MethodsAll 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. ResultsA 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). ConclusionsAtypical 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.

Effect of neoadjuvant concurrent three-dimensional conformal chemoradiotherapy with conventional two-dimensional chemoradiotherapy in locally advanced rectal cancer

Background: Rectal carcinoma is a prevalent clinical condition, and treatment hinges on factors like tumor specifics, staging, grading, and histopathological characteristics. While surgery remains the primary treatment, neoadjuvant chemoradiotherapy, particularly using 3D-CRT, has proven effective in reducing local recurrence rates for locally advanced cases. Alternatively, 2D-RT is considered for neoadjuvant treatment. This study aimed to compare the impact of neoadjuvant concurrent three-dimensional conformal chemoradiotherapy with conventional two-dimensional chemoradiotherapy in the context of locally advanced rectal cancer. Methods: In this multicentre quasi-experimental study, 60 patients with biopsy-proven adenocarcinoma and clinically confirmed locally advanced rectal cancer, were divided into Group A (receiving oral capecitabine with three-dimensional conformal radiotherapy) and Group B (receiving the same capecitabine dose with 50 Gy two-dimensional radiotherapy). After surgery within 6-12 weeks, outcomes were analysed. Results: After neoadjuvant chemoradiotherapy, clinical complete response rates were 16.7% in Group A and 10.0% in Group B, with a higher pathological complete response in Group A (10.0% vs. 3.3%). Tumor downsizing occurred in 83.3% of Group A and 73.3% of Group B, and sphincter-sparing surgery was achieved in 73.3% of Group A and 56.7% of Group B. Grade 2 toxicities included anemia (10.0% vs. 13.3%), leucopenia (13.3% vs. 20.0%), diarrhoea (10.0% vs. 16.7%), proctitis (13.3% vs. 40.0%), and urinary toxicity (10.0% vs. 20.0%). Grade-1 toxicities were nausea (20.0% vs. 40.0%), vomiting (20.0% vs. 36.7%), mucositis (56.7% vs. 60.0%), hand-foot syndrome (33.3% vs. 40.0%), and urinary toxicity (43.3% vs. 56.67%), with significant proctitis in Group A (p=0.012). Other toxicities showed non-significant p-values (&gt;0.05). Conclusions: Tumour response was not statistically significant between the patients of concurrent 3D-CRT and 2D-RT Arms. But the patients of 3D-CRT arm showed better response arithmetically. Also, there was an observable significant reduction of toxicities (lower gastrointestinal) in the 3D-CRT arm.

[Organ preservation in locally advanced colorectal cancer with microsatellite instability-high after immunotherapy].

Neoadjuvant immunotherapy has achieved exciting efficacy with high clinical complete response (cCR) and pathologic complete response (pCR) rates and durable long-term effects. PD-1 checkpoint blockade-based immunotherapy has been highly successful in microsatellite instability high (MSI-H)/mismatch repair deficiency (dMMR) colorectal cancer and has been recommended as the first-line treatment for metastatic colorectal cancer by domestic and international guidelines. Several studies have shown that immunotherapy can be a potentially curable treatment for MSI-H rectal cancer and has even shown promise in organ preservation in colon cancer. In this study, we first clarified the feasibility of the watch-and-wait strategy after PD-1 checkpoint blockade treatment by indirect and direct evidence. Then from the assessment tools (including digital rectal examination, endoscopy, radiology, and lymph node assessment), the viable assessment methods of cCR for immunotherapy and related difficulties are proposed. Finally, the medication choices of immunotherapy, the treatment regimen, and the follow-up strategy are further discussed. We hope that neoadjuvant immunotherapy could be appropriately applied in MSI-H/dMMR colorectal cancer so that more patients can achieve organ preservation.

Omission of breast surgery in selected breast cancer patients with excellent response to neoadjuvant systemic therapy

Modern neoadjuvant systemic therapy (NST) can result in high pathologic complete response rates (pCR) in triple negative (TN) and human epidermal growth factor receptor 2 positive (HER2+) breast cancer. The role of surgery is, therefore, being reconsidered in this rapidly evolving field. This report presents oncological outcomes of seven patients with TN or HER2+ breast cancer, with exceptional response to NST, and a post-NST image-guided vacuum assisted biopsy showing no residual disease (ypT0), who opted not to have breast surgery. The median age was 49 (IQR 36–61) years and the median tumour size at diagnosis was 50 (IQR 16–65) mm. All patients received breast radiotherapy and continued adjuvant systemic therapies as appropriate. At a median follow-up of 67 (IQR 61–77) months, all patients were alive and free of disease. This small case series supports the need for further research in ‘exceptional responders’ to provide safe, individualized patient-centred care.

Abstract A004: Identification of genetic susceptibility loci for ErbB2-driven mammary tumor development and metastasis using Collaborative Cross mice and human relevant validation

Abstract Introduction Epidermal growth factor receptor 2 (HER2)-targeted therapies are effective treatments for HER2+ breast cancers (BC), but intrinsic and acquired resistance hampers their clinical benefit. Therefore, new biological insights into HER2-driven cancers are needed to conquer drug resistance. Here, we used a genetically diverse and population-based Collaborative Cross (CC) mouse model to identify genetic susceptibility to tumor development and metastasis driven by HER2. Materials and methods 732 F1 hybrid mice were generated from a cross between FVB/N MMTV-ErbB2 and 30 CC strains and were monitored for mammary tumor development within two years. Tumor onset, multiplicity and metastasis were assessed. Genome wide association study (GWAS) was used to identify genetic variations controlling different tumor phenotypes. Polygenetic risk score was created for each phenotype using multivariate analysis. We systematically evaluated the clinical value regarding prognosis and therapeutic responses of mouse tumor susceptibility gene signature (mTSGS) in human breast cancer (BC) using publicly available cohorts including I-SPY2 clinical trial cohorts. Results We observed huge differences in tumor onset, multiplicities, and metastasis across 30 CC strains. In addition to lung metastasis, we found liver/kidney metastasis in some CC strains. GWAS identified 1,525 SNPs significantly associated with tumor onset (p&amp;lt;1.00E-30) corresponding to 287 known genes, 800 SNPs significantly associated with number of tumors (p&amp;lt;1.00E-15) corresponding to 203 known genes, 568 SNPs significantly associated with lung metastasis (p&amp;lt;1.00E-4) corresponding to 189 known genes, and 23 SNPs significantly associated with liver metastasis (p&amp;lt;1.00E-4) corresponding to 12 known genes. Multivariate analyses identified the SNPs in 8 genes (Stx6, Ramp1, Traf3ip1, Nckap5, Pfkfb2, Trmt1l, Rprd1b and Rer1) independently associated with age onset, in 11 genes (Stx6, Sepsecs, Rhobtb1, Tsen15, Abcc3, Arid5b, Tnr, Dock2, Tti1, Fam81a and Oxr1) independently associated with number of tumors, and in 2 genes (Plxna2 and Tbc1d31) independently associated with tumor metastasis, which were pooled together as mTSGS. To evaluate the impact of mTSGS on human BC, we established mTSGS score (mTSGSS) based on their transcriptional levels in BC. We found that mTSGSS is significantly and independently associated with overall, disease free and progression free survival compared to clinical factors and PAM50 molecular subtype in different cohorts. Additionally, patients with low mTSGSS have a higher pathological complete response (pCR) rate in comparison to these with high mTSGSS for 6 of 13 treatment regimens in I-SPY2 cohort. Multivariate logistic regression analysis showed that predictive value of mTSGSS in pCR is independent of MammaPrint (MP) score in these treatment regimens. Conclusion Our findings lead significantly to biological insights into ErbB2-driven cancers and indicate that mTSGSS can serve as a biomarker for tailoring treatment to BC patients. Citation Format: Hang Chang, Jamie L Inman, Antoine M Snijders, Jian-Hua Mao. Identification of genetic susceptibility loci for ErbB2-driven mammary tumor development and metastasis using Collaborative Cross mice and human relevant validation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A004.

Long-Term Survival and Recurrence Patterns in Locally Advanced Esophageal Squamous Cell Carcinoma Patients with Pathologic Complete Response After Neoadjuvant Chemotherapy Followed by Surgery.

The higher pathologic complete response (pCR) after neoadjuvant chemoradiotherapy compared with neoadjuvant chemotherapy for locally advanced esophageal squamous cell carcinoma (ESCC) has not translated into significant gains in overall survival. Data on the long-term survival of patients who obtained a pCR after neoadjuvant chemotherapy are scarce. Therefore, this study aimed to evaluate the long-term prognosis and recurrence patterns in these patients. The study enrolled patients with locally advanced ESCC after neoadjuvant chemotherapy followed by surgery in the authors' hospital between January 2007 and December 2020. The factors predictive of pCR were analyzed. Furthermore, propensity score-matching was performed for those who did and those who did not have a pCR using 1:5 ratio for a long-term survival analysis. Finally, the survival and recurrence patterns of patients obtaining pCR after neoadjuvant chemotherapy were analyzed. A pCR was achieved for 61 (8.70%) of the 701 patients in the study. Univariate analysis showed that the patients without alcohol drinking had a higher possibility of obtaining a pCR, although multivariate analysis failed to confirm the difference as significant. After propensity score-matching, the 5-year overall survival was 84.50% for the patients who had a pCR and 52.90% for those who did not (p < 0.001). Among the 61 patients with a pCR, 9 patients (14.80%) experienced recurrence, including 6 patients with locoregional recurrence and 3 patients with distant metastasis. Advanced ESCC patients with pCR after neoadjuvant chemotherapy had a favorable prognosis, yet some still experienced recurrence, particularly locoregional recurrence. Therefore, for this group of patients, regular follow-up evaluation also is needed.

Neoadjuvant PD-1 Plus Chemotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma.

Clinical studies have shown that programmed cell death-1 (PD-1) inhibitors can activate T cells and inhibit cancer growth. Therefore, the use of a PD-1 inhibitor plus chemotherapy as neoadjuvant chemotherapy for locally advanced esophageal cancer is worth further exploration. Patients with locally advanced esophageal squamous cell carcinoma were enrolled in this study to receive two cycles of a preoperative combination of toripalimab, paclitaxel, and cisplatin. Efficacy was evaluated after two treatment cycles. The patients' postoperative pathological staging was analyzed and compared. Surgery was performed within 42 days of the start date of the last chemotherapy cycle. Neoadjuvant immunochemotherapy achieved a high pathologic complete response (pCR) rate (29.0%), major pathological response rate (41.9%), and objective response rate (80.6%) and demonstrated statistically significant downstaging after neoadjuvant therapy (P < .05) with manageable treatment-related adverse effects. No significant association was found between PD-L1 level and pCR (P = .365). In addition, R0 resection was achieved in all 31 (100%) patients during surgery. For all the included patients, the one-year progression-free survival rate was 87.1% (95% CI: 75.3%-98.9%), the one-year overall survival (OS) rate was 96.8% (95% CI: 79.8%-95.9%), and the two-year OS rate was 83.9% (95% CI: 71.6%-92.2%). Our findings indicate that this combination may be a potential neoadjuvant therapy regimen in this setting.

Breast cancers with high proliferation and low ER-related signalling have poor prognosis and unique molecular features with implications for therapy

BackgroundLuminal breast cancers with high proliferation (MKShi) and low ER-related signalling (ERSlo) have a poor prognosis. We investigated treatment responses and molecular features of MKShi/ERSlo tumours to inform potential therapies.MethodsGene expression data from patients who received neoadjuvant chemotherapy (NAC) without (MDACC, N = 199) or with pembrolizumab (I-SPY2, N = 40), or endocrine therapy (NET) without (POETIC, N = 172) or with palbociclib (NeoPalAna, N = 32) were analyzed to assess treatment response by MKS/ERS-subgroups. TCGA was used to assess the mutational landscape and biomarkers associated with palbociclib-resistance (Cyclin-E, RBsig, IRPR) and immunotherapy-response (TMB, TILs, T-cell inflamed) by MKS/ERS-subgroups.ResultsCompared to MKShi/ERShi tumours, MKShi/ERSlo tumours had higher pathological response rates to NAC (22% vs 8%, p = 0.06) but a higher recurrence risk (4-year metastasis-free survival 70% vs 94%, p = 0.01). MKShi/ERSlo tumours frequently harboured TP53 (34%) and PIK3CA (33%) mutations, and showed high expression of Cyclin-E, RBsig and IRPR, high TMB and elevated TIL and T-cell inflamed metagene expression. MKShi/ERSlo tumours retained high proliferation after NET with or without palbociclib but had higher pathological complete response rates when pembrolizumab was added to NAC (42% vs 21%, p = 0.07).ConclusionsMKShi/ERSlo tumours have dismal outcomes and are enriched in chemotherapy-sensitive but ET- and palbociclib-resistant tumours. Biomarker analysis and clinical data suggest a potential role for immunotherapy in this group.

Is Total Neoadjuvant Treatment Beneficial for Locally Advanced Rectal Cancer? A Meta-Analysis of Randomized Controlled Trials

Background: Total neoadjuvant therapy (TNT) is a new strategy combining neoadjuvant therapy and chemotherapy to enhance tumor shrinkage and systemic control. Its effectiveness remains debated. Objectives: This study conducts a meta-analysis of randomized controlled trials (RCTs) to assess TNTs impact and provide high-quality evidence for rectal cancer treatment decisions. Method: We searched China National Knowledge Infrastructure, VIP Database, Wanfang Database, China biomedical literature database, PubMed database, Embase database, and The Cochrane Library for RCTs comparing TNT with neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer. The included trials were screened and assessed for quality based on inclusion and exclusion criteria, and meta-analysis was performed using RevMan 5.3 software. Results: A total of 11 RCTs reported in 14 articles, with 1,624 cases in the TNT group and 1,541 cases in the CRT group. The results of the meta-analysis showed that compared with the CRT group, the TNT group had a higher pathological complete response rate (risk ratio [RR] = 1.65, 95% confidence interval [CI]: [1.40, 1.94], p < 0.00001), higher T0 downstaging rate (RR = 1.51, 95% CI: [1.29, 1.77], p < 0.00001), higher 3-year overall survival (hazard ratio [HR] = 0.81, 95% CI: [0.67, 0.98], p = 0.03), and higher 3-year disease-free survival (HR = 0.82, 95% CI: [0.70, 0.95], p = 0.008). However, there was no statistically significant difference between the two groups in terms of R0 resection rate (RR = 1.02, 95% CI: [0.99, 1.05], p = 0.14), sphincter preservation rate (RR = 0.94, 95% CI: [0.88, 1.01], p = 0.12), anastomotic leakage rate (RR = 1.42, 95% CI: [0.85, 2.38], p = 0.18), and grade 3 or higher adverse events (RR = 1.21, 95% CI: [0.95, 1.54], p = 0.13). Conclusions: In the treatment of locally advanced rectal cancer, TNT offers greater survival benefits compared to neoadjuvant CRT and does not significantly increase the incidence of adverse events. However, further data and studies with long-term outcomes are still required.

Long-Term Outcomes and Predictors of Response in Breast Cancer Patients with Advanced Nodal Involvement.

Advanced nodal disease is associated with poor prognosis. However, modern neoadjuvant systemic therapy (NST) regimens have resulted in higher pathologic complete response (pCR) rates, which are associated with improved survival. We sought to assess contemporary outcomes in patients with advanced nodal involvement and response to NST. We conducted a single-institution, retrospective study of 521 patients with cN2-3 primary nonmetastatic breast cancer treated with NST followed by surgery and radiation from 2012 to 2018. Descriptive statistics, multivariate Cox regression, and Kaplan-Meier analyses were performed. The mean age was 50.5 years, and median follow-up was 61 (4.7 to 197) months. The majority of patients had hormone receptor-positive (HR+)/HER2-negative tumors (HER2-; n = 242, 47.8%). Most were cT2 (n = 243; 46.6%) or cT3 (n = 139; 26.7%) and 73.3% (n = 382) had cN3 disease. Rate of axillary pCR was 34.2%, and breast and axillary pCR was 19.4% (n = 101). Event-free survival (EFS) at 5 years was 75.1% (95% CI, 0.71 to 0.79). Rate of locoregional recurrence was 6.7%; distant metastatic rate was 29.4%. Axillary pCR with or without breast pCR was significantly associated with longer EFS (p = 0.001). Achieving breast/axillary pCR was an independent predictor of improved EFS (hazard ratio 0.22, p < 0.0001). Having triple-negative disease was associated with worse EFS (hazard ratio 1.74, p = 0.008). In a high-risk cohort of patients with cN2-3 disease, trimodality therapy was effective in achieving durable EFS. Approximately one-third of patients achieved axillary pCR, which was associated with improved survival. Further studies are needed to accurately determine axillary response in cN2-3 breast cancer after NST in order to develop de-escalation strategies to reduce morbidity associated with axillary surgery.

Survival outcomes of different neoadjuvant treatment regimens in patients with locally advanced rectal cancer and MRI-detected extramural venous invasion.

MRI-detected extramural venous invasion (mrEMVI) is associated with poor survival outcomes in patients with locally advanced rectal cancer (LARC). An mrEMVI-positive status is considered a strong indication for neoadjuvant treatment, but the optimal regimen is unknown. We retrospectively compared pathological and survival outcomes of 584 patients diagnosed with mrEMVI-positive rectal cancer between January 2013 and October 2021, and receiving either neoadjuvant chemotherapy (NCT) alone, neoadjuvant chemoradiotherapy (nCRT) alone, or nCRT plus NCT, prior to total mesorectal excision. Propensity score matching (PSM) was used to balance clinical bias between groups, which were compared using chi-square testing and Kaplan-Meier curves. Median follow-up was 33.9 (range, 10.2-100.4) months. The 3-year overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRFS) rates for all patients were 90.4%, 57.5%, 61.1%, and 85.7%, respectively. Of 584 mrEMVI-positive patients at the time of diagnosis, 457 (78.3%) were EMVI-negative on surgical pathology, and they had significantly better 3-year OS, DMFS, DFS, and LRFS rates (all p < 0.001) than patients who remained EMVI-positive. After PSM was applied, patients receiving nCRT alone had significantly better 3-year OS (96.8% vs. 86.5%, p = 0.005) and DMFS (67.1% vs. 53.5%, p = 0.03) rates than those receiving NCT alone. Patients receiving NCT plus nCRT had higher pathological complete response (PCR) (10.8% vs. 2.7%, p = 0.04) and downstaging (33.8% vs. 5.3%, p < 0.001) rates than those receiving nCRT alone, but survival rates did not differ (all p > 0.05). Most EMVI-positive patients with LARC converted to EMVI-negative after neoadjuvant treatment, resulting in improved OS and DFS. Patients receiving nCRT had more favorable survival outcomes than those receiving NCT, suggesting the importance of including neoadjuvant radiotherapy. Patients receiving NCT in addition to nCRT had higher rates of PCR and downstaging, but their survival rates were not better.

Dose-Dense Docetaxel-Cyclophosphamide and Epirubicin-Cisplatin(ddDCEP): Analysis of an Alternative Platinum-Containing Regimen in 116 Patients with Early Triple Negative Breast Cancer

We assessed the efficacy, tolerability, and cost-effectiveness of a novel neoadjuvant regimen comprising docetaxel-cyclophosphamide alternating with epirubicin-cisplatin (ddDCEP) administered biweekly for 16 weeks in 116 patients with early triple-negative breast cancer. This regimen achieved a high pathological complete response (ypT0/TisN0) rate of 55.2% and favorable survival outcomes (30-month event-free survival, 91.2%; overall survival, 97%). Febrile neutropenia was observed in 4.3% of patients, and 98% completed at least six of eight cycles. ddDCEP was more cost-effective than contemporary carboplatin-based regimens. This novel approach offers an economically viable and effective alternative to current chemoimmunotherapy regimens, and merits further investigation.

Neoadjuvant therapy with immune checkpoint inhibitors in operable nonsmall cell lung cancer.

In localized nonsmall cell lung cancer (NSCLC) systemic recurrences after surgery are common. Therefore, adjuvant or neoadjuvant chemotherapy is used. With the advent of immune checkpoint inhibitors (ICIs) in metastatic disease the question is whether ICIs can further improve the outcome. In several phase I/II trials, major pathological response (MPR) rates with several ICIs between 7% and 50% were seen. No major additional side effects occurred. In combination with chemotherapy CheckMate-816 randomized additional neoadjuvant nivolumab and achieved a high pathological complete response (pCR) rate and a better event-free survival (EFS) - without negatively influencing surgery. More randomized trials are performed with neoadjuvant immunochemotherapy and adjuvant treatment after surgery. In Keynote-671, pembrolizumab is used pre and postoperatively with a significantly higher EFS rate at 2 years (62.4% vs. 40.6%). Similar preliminary results are reported in the AEGEAN (durvalumab) and Neotorch (toripalimab) trials. Higher tumour stage and MPR, partly programmed cell death 1 ligand 1 (PD-L1) expression, tumour mutational burden (TMB) and circulating tumour DNA (ctDNA) are correlated with efficacy. Neoadjuvant immunochemotherapy improves MPR and EFS rates, especially in more advanced tumours and tumours expressing PD-L1 - without relevantly increasing toxicities. But further and longer evaluation is needed.

Complete pathological response in patients with HER2 positive breast cancer treated with neoadjuvant therapy in Colombia

Breast cancer is the most common type of cancer and the leading cause of death by cancer in women in Colombia. Approximately 15 to 20% of breast cancers overexpress HER2. To analyze the relationship between multiple clinical and histological variables and pathological complete response in patients with HER2-positive breast cancer undergoing neoadjuvant therapy in a specialized cancer center in Colombia. We performed a retrospective analysis of non-metastatic HER2-positive breast cancer patients who received neoadjuvant therapy between 2007 and 2020 at the Instituto de Cancerología Las Americas Auna (Medellín, Colombia). Assessed parameters were tumor grade, proliferation index, estrogen receptor, progesterone receptor, HER2 status, type of neoadjuvant therapy, pathologic complete response rates, and overall survival. Variables associated with low pathologic complete response rates were tumor grades 1-2 (OR = 0.55; 95% CI = 0.37-0.81; p = 0.03), estrogen receptor positivity (OR =0.65; 95%; CI = 0.43-0.97; p=0.04), and progesterone receptor positivity (OR = 0.44; 95% CI = 0.29-0.65; p = 0.0001). HER2 strong positivity (score 3+) was associated with high pathological complete response rates (OR = 3.3; 95% CI = 1.3-8.35; p=0.013). Five-year overall survival was 91.5% (95% CI = 82.6-95.9) in patients with pathological complete response and 73.6% (95% CI = 66.4-79.6) in patients who did not achieve pathological complete response (p = 0.001). Additionally, the pathological complete response rate was three times higher in patients receiving combined neoadjuvant chemotherapy with anti-HER2 therapy than in those with chemotherapy alone (48% versus 16%). In patients with HER2-positive breast cancer, tumor grade 3, estrogen receptor negativity, progesterone receptor negativity, strong HER2 positivity (score 3+), and the use of the neoadjuvant trastuzumab are associated with higher pathological complete response rates.

Long-course chemoradiation plus concurrent/sequential PD-1 blockade as neoadjuvant treatment for MMR-status-unscreened locally advanced rectal cancer: protocol of a multicentre, phase 2, randomised controlled trial (the POLAR-STAR trial)

IntroductionRecent preclinical studies have discovered unique synergism between radiotherapy and immune checkpoint inhibitors, which has already brought significant survival benefit in lung cancer. In locally advanced rectal cancer (LARC), neoadjuvant...

Metformin: A Promising Radiosensitizer in Neoadjuvant Rectal Cancer Treatment.

Neoadjuvant chemoradiotherapy (nCRT) decreases the risk of local recurrence after surgery in patients with locally advanced rectal cancer (LARC) and metformin is constantly gaining scientific interest due to its potentially radiosensitizing effect. This review article aims to better clarify the role of metformin as a radiosensitizer in patients with LARC undergoing neoadjuvant concurrent chemoradiotherapy. We used the PubMed database to retrieve journal articles and the inclusion criteria were all human studies that illustrated the effective role of metformin in the neoadjuvant setting of locally advanced rectal cancer. Our search resulted in 17 citations, of which 10 eventually fulfilled the inclusion criteria of our study. Promising results (improved tumor and nodal regression as well as higher pathologic complete response rate) have been occasionally documented with metformin use in some of the included studies. However, regarding survival and all-cause mortality, no significant difference has been found. Metformin might constitute a highly promising radiosensitizer in neoadjuvant LARC treatment attracting much scientific interest. Due to the lack of studies with high evidence, further advanced research is required to enhance the existing knowledge about its potential value in this field.