Summary Background High quantities of tumour-infiltrating lymphocytes (TILs) in primary HER2-positive breast cancer are associated with improved prognosis and response to therapy. We aimed to ...investigate the prognostic role of host antitumour immunity as represented by baseline quantities of TILs in patients with advanced HER2-positive breast cancer treated with either pertuzumab or placebo in addition to trastuzumab and docetaxel. Methods CLEOPATRA was a randomised phase 3 study comparing the addition of either pertuzumab or placebo to first-line therapy with trastuzumab and docetaxel for patients with locally recurrent, unresectable, or metastatic HER2-positive breast cancer. We assessed the quantity of stromal TILs in prospectively collected tumour samples and investigated their association with progression-free survival, overall survival, clinicopathological characteristics, and pertuzumab treatment. We estimated hazard ratios (HR) and 95% CIs with multivariate Cox regression models fitting stromal TILs as a continuous variable (per 10% increment). The CLEOPATRA trial is registered with ClinicalTrials.gov , number NCT00567190. Findings Tumour samples from 678 (84%) of 808 participants were evaluable for TILs, including 519 (77%) archival samples, 155 (23%) freshly obtained samples (collected 45 days or fewer before randomisation), and four samples of unknown archival status. Median follow-up was 50 months (IQR 41–54) for progression-free survival and 51 months (IQR 46–57) for overall survival. 519 progression-free survival events occurred and 358 patients died. The median TIL value was 10% (IQR 5–30). Freshly obtained tumour samples had significantly lower TIL values than did archival samples (10·00% 95% CI 5·00–20·00 vs 15·00% 5·00–35·00; p=0·00036). We detected no significant association between TIL values and progression-free survival (adjusted HR 0·95, 95% CI 0·90–1·00, p=0·063). However, for overall survival, each 10% increase in stromal TILs was significantly associated with longer overall survival (adjusted HR 0·89, 95% CI 0·83–0·96, p=0·0014). The treatment effect of pertuzumab did not differ significantly by stromal TIL value for either progression-free survival (pinteraction =0·23) or overall survival (pinteraction =0·21). Interpretation In patients with advanced HER2-positive breast cancer treated with docetaxel, trastuzumab, and pertuzumab or placebo, higher TIL values are significantly associated with improved overall survival, suggesting that the effect of antitumour immunity extends to the advanced setting. Future clinical studies in this cancer subtype should consider TILs as a stratification factor and investigate whether therapies that can augment immunity could potentially further improve survival. Funding F Hoffmann-La Roche–Genentech and the Breast Cancer Research Foundation.
There is now accumulating evidence that the host immune system plays an important role in influencing response to treatment and prognosis in breast cancer. Immunotherapy with immune checkpoint ...inhibitors is a promising and rapidly growing field of interest in many solid tumours, including breast cancer. Trials to date have largely focused on metastatic triple-negative disease, a genomically unstable subtype of breast cancer that is believed to be the most immunogenic and following the development of treatment resistance, has limited treatment options and a particularly poor prognosis. Both checkpoint inhibitor monotherapy and combinations with chemotherapy are being investigated. In this review, we discuss the current evidence for PD-1/PD-L1 blockade in metastatic triple-negative breast cancer (TNBC), HER2+ breast cancer and ER+ disease, as well as the emerging evidence for use in the early-stage (neoadjuvant) setting. We also propose potential ways of improving responses to checkpoint blockade in breast cancer.
The presence of tumour-infiltrating lymphocytes (TILs) is associated with favourable outcomes in patients with breast cancer as well as in those with other solid tumours. T cells make up a ...considerable proportion of TILs and current evidence suggests that CD8
T cells are a crucial determinant of favourable clinical outcomes. Studies involving tumour material from numerous solid tumour types, including breast cancer, demonstrate that the CD8
TILs include a subpopulation of tissue-resident memory T (T
) cells. This subpopulation has features consistent with those of T
cells, which have been described as having a role in peripheral immune surveillance and viral immunity in both humans and mice. Patients with early-stage triple-negative breast cancers harbouring greater numbers of T
cells have a substantially improved prognosis and longer overall survival. Furthermore, patients with advanced-stage breast cancers with higher levels of T
cells have increased response rates to anti-PD-1 antibodies. These findings have motivated efforts to explore whether CD8
T
cells include tumour-specific T cells, their functional responses to cognate antigens and their role in responses to immune checkpoint inhibition. In this Review, we focus on the clinical significance of CD8
T
cells and the potential ways that these cells can be targeted to improve the success of immunotherapeutic approaches in patients with breast cancer, as well as in those with other solid tumour types.
Breast cancer has not previously been considered a highly immunogenic cancer. Observations of tumour-infiltrating lymphocytes (TILs) in and around neoplastic cells in tumour samples, and associations ...with improved pathological complete response and clinical survival end points have changed our perspective on this. Lymphocytic infiltrates have long been observed in breast cancer; however, more recently, retrospective analysis of prospectively collected tissue samples from clinical trials has demonstrated the potential role of host immunosurveillance in influencing the biology of breast cancer. This association appears to be strongest in triple negative and HER2 positive breast cancer subtypes. Contrastingly, the association in luminal tumours is less clear, and is potentially limited by substantial tumoural heterogeneity. Several methodologies have been employed to quantify, and describe the composition of TILs, each with its own advantages and disadvantages. The results of these analyses have been generally consistent, and valuable efforts are currently underway to standardise the evaluation of TILs toward a universal approach. More technical methods of TIL characterisation remain important in the research setting. The evaluation of TILs becomes increasingly relevant with the emerging role of immunotherapy in breast cancer. Early phase trials of checkpoint blockade show promising results; however, it is likely that some patients will require combination treatments to maximise therapeutic benefits. Equally, some patients may not derive any benefit from immunotherapies. This underscores the importance of the development of relevant predictive biomarkers. As a key representative of the immune interaction between host and tumour, lymphocytic infiltrates are ideally placed for continued research into the determinants of immunogenicity, and response to immunotherapeutic approaches. In this review, we will discuss the current methodologies of evaluation, and the clinical relevance of TILs. Additionally, we discuss the emerging role of immunotherapy in breast cancer, and the future of TIL characterisation in this context.
The interest in tumor-infiltrating lymphocytes (TILs) as a prognostic biomarker in breast cancer has grown in recent years. Biomarkers must undergo comprehensive evaluation in terms of analytical ...validity, clinical validity and clinical utility before they can be accepted as part of clinical practice. The International Immuno-Oncology Biomarker Working Group has developed a practice guideline on scoring TILs in breast cancer in order to standardize TIL assessment. The prognostic value of TILs as a biomarker in early-stage breast cancer has been established by assessing tumor samples in thousands of patients from large prospective clinical trials of adjuvant therapy. There is a strong linear relationship between increase in TILs and improved disease-free survival for triple-negative and HER2-positive disease. Higher levels of TILs have also been associated with increased rates of pathological complete response to neoadjuvant therapy. TILs have potential clinical utility in breast cancer in a number of areas. These include prediction of responders to immune checkpoint blockade, identification of primary HER2-positive and triple-negative patients who have excellent prognoses and may thus be appropriate for treatment de-escalation, and potentially incorporation into a neoadjuvant endpoint which may be a better surrogate maker for drug development.
The presence of tumor-infiltrating lymphocytes in triple-negative breast cancers is correlated with improved outcomes. Ras/MAPK pathway activation is associated with significantly lower levels of ...tumor-infiltrating lymphocytes in triple-negative breast cancers and while MEK inhibition can promote recruitment of tumor-infiltrating lymphocytes to the tumor, here we show that MEK inhibition adversely affects early onset T-cell effector function. We show that α-4-1BB and α-OX-40 T-cell agonist antibodies can rescue the adverse effects of MEK inhibition on T cells in both mouse and human T cells, which results in augmented anti-tumor effects in vivo. This effect is dependent upon increased downstream p38/JNK pathway activation. Taken together, our data suggest that although Ras/MAPK pathway inhibition can increase tumor immunogenicity, the negative impact on T-cell activity is functionally important. This undesirable impact is effectively prevented by combination with T-cell immune agonist immunotherapies resulting in superior therapeutic efficacy.MEK inhibition in breast cancer is associated with increased tumour infiltrating lymphocytes (TILs), however, MAPK activity is required for T cells function. Here the authors show that TILs activity following MEK inhibition can be enhanced by agonist immunotherapy resulting in synergic therapeutic effects.
Metastatic breast cancer remains incurable. Next-generation sequencing (NGS) offers the ability to identify actionable genomic alterations in tumours which may then be matched with targeted ...therapies, but the implementation and utility of this approach is not well defined for patients with metastatic breast cancer.
We recruited patients with advanced breast cancer of any subtype for prospective targeted NGS of their most recent tumour samples, using a panel of 108 breast cancer-specific genes. Genes were classified as actionable or non-actionable using the European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT) guidelines.
Between February 2014 and May 2019, 322 patients were enrolled onto the study, with 72% (n = 234) of patients successfully sequenced (n = 357 samples). The majority (74%, n = 171) of sequenced patients were found to carry a potentially actionable alteration, the most common being a PIK3CA mutation. Forty-three percent (n = 74) of patients with actionable alterations were referred for a clinical trial or referred for confirmatory germline testing or had a change in therapy outside of clinical trials. We found alterations in AKT1, BRCA2, CHEK2, ESR1, FGFR1, KMT2C, NCOR1, PIK3CA and TSC2 to be significantly enriched in our metastatic population compared with primary breast cancers. Concordance between primary and metastatic samples for key driver genes (TP53, ERBB2 amplification) was > 75%. Additionally, we found that patients with a higher number of mutations had a significantly worse overall survival.
Genomic profiling of patients with metastatic breast cancer can have clinical implications and should be considered in all suitable patients.
New treatments for triple-negative breast cancer (TNBC) are urgently needed. Despite there being little evidence of clinical activity as single-agent therapies, we show that dual blockade of PI3Kα ...and CDK4/6 is synergistically effective against multiple
-wild-type TNBC models. Combined PI3Kα and CDK4/6 inhibition significantly increased apoptosis, cell-cycle arrest, and tumor immunogenicity and generated immunogenic cell death in human TNBC cell lines. Combination treatment also significantly improved disease control in human xenograft models compared with either monotherapy. Combined PI3Kα and CDK4/6 inhibition significantly increased tumor-infiltrating T-cell activation and cytotoxicity and decreased the frequency of immunosuppressive myeloid-derived suppressor cells in a syngeneic TNBC mouse model. Notably, combined PI3Kα and CDK4/6 inhibition, along with inhibition of immune checkpoints PD-1 and CTLA-4, induced complete and durable regressions (>1 year) of established TNBC tumors
Overall, our results illustrate convergent mechanisms of PI3Kα and CDK4/6 blockade on cell-cycle progression, DNA damage response, and immune-modulation and may provide a novel therapeutic approach for TNBC.
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CD8+ tumor-infiltrating lymphocytes with a tissue-resident memory T (TRM) cell phenotype are associated with favorable prognosis in patients with triple-negative breast cancer (TNBC). However, the ...relative contribution of CD8+ TRM cells to anti-tumor immunity and immune checkpoint blockade efficacy in breast cancer remains unknown. Here, we show that intratumoral CD8+ T cells in murine mammary tumors transcriptionally resemble those from TNBC patients. Phenotypic and transcriptional studies established two intratumoral sub-populations: one more enriched in markers of terminal exhaustion (TEX-like) and the other with a bona fide resident phenotype (TRM-like). Treatment with anti-PD-1 and anti-CTLA-4 therapy resulted in expansion of these intratumoral populations, with the TRM-like subset displaying significantly enhanced cytotoxic capacity. TRM-like CD8+ T cells could also provide local immune protection against tumor rechallenge and a TRM gene signature extracted from tumor-free tissue was significantly associated with improved clinical outcomes in TNBC patients treated with checkpoint inhibitors.
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•Intratumoral CD8+ T cells in murine TNBC consist of both TEX-like and TRM-like cells•Dual-ICB therapy augments and enhances the killing capacity of TRM-like cells•CD8+ TRM-like cells provide local tissue protection from TNBC tumor rechallenge•CD8+ TRM signature is associated with better treatment outcomes in TNBC patients
Virassamy et al. characterize the qualitative features of intratumoral CD8+ T cells and the critical role of T cells displaying residency properties (TRM) in mouse models of triple-negative breast cancer (TNBC). TRM cells expand in response to anti-PD-1 and anti-CTLA-4 immune checkpoint inhibition and confer ongoing tissue protective immunity against TNBC.
Overall survival (OS) results from randomized control trials (RCT) provide the strongest evidence for efficacy of anti-cancer treatments but can take a considerable amount of time to mature. ...Progression free survival (PFS) and objective response rate (ORR) are used as an early surrogate of OS treatment effect however their validity remains unclear. Our study aims to comprehensively evaluate ORR and PFS as surrogates for OS treatment effect across tumor groups and treatment types.
Phase 3 RCTs in solid malignancies that reported OS/PFS and ORR published between 1st of January 2010 and 30th of June 2022 were evaluated. The relationship of surrogate endpoints and OS treatment effect was assessed via weighted linear regression. The coefficient of determination (R2) quantified the fit of the regression model.
675 phase 3 RCT comprising of 350 112 patients were analysed. ORR (R2 of 0.10) and PFS (R2 of 0.38) were poor surrogate markers of OS treatment effect. The strength of surrogacy differed within treatment and tumour groups. PFS had the highest R2 for chemotherapy (0.56) and lowest for targeted therapy (0.40). PFS had the highest level of surrogacy for melanoma (R2 = 0.72) and pancreatic cancer (R2 = 0.70) compared to other tumour groups. Importantly ORR and PFS were also poorly correlated to each other (R2 = 0.33).
ORR and PFS were poor trial-level surrogate markers of OS. The surrogacy performance of ORR and PFS differed by treatment and malignancy sub-type.
•ORR and PFS are not strong surrogates of OS treatment effect.•Surrogacy of ORR and PFS for OS differs based on treatment and tumor.•surrogacy of ORR and PFS for OS treatment effect was highest for chemotherapy.•PFS was a better surrogate of OS treatment for melanoma and pancreatic cancer.
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