Clinical implications of prospective genomic profiling of metastatic breast cancer patients.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Genomic profiling of patients with metastatic breast cancer can have clinical implications and should be considered in all suitable patients.

Checkpoint blockade in the treatment of breast cancer: current status and future directions.

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.

Tumour-infiltrating lymphocytes in advanced HER2-positive breast cancer treated with pertuzumab or placebo in addition to trastuzumab and docetaxel: a retrospective analysis of the CLEOPATRA study.

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.

Advancing Immunotherapy in Metastatic Breast Cancer.

OPINION STATEMENT: Despite many advances in the treatment of breast cancer, the development of metastatic disease remains an incurable and frequent cause of cancer death for women worldwide. An improved understanding of the role of host immunosurveillance in modulating breast cancer disease biology, as well as impressive survival benefits seen to checkpoint blockade in other malignancies have provided great hope for an expanding role of immunotherapies in breast cancer management. While these novel therapies are currently being investigated in clinical trials, signals of efficacy, and tolerability in early phase studies suggest these will eventually make their way into standard practice algorithms. Ongoing research has highlighted a high degree of intertumoural heterogeneity in tumour lymphocytic infiltrates, suggesting some tumours or subtypes are more immunogenic than others. Furthermore, tumour intrinsic mechanisms of immune evasion are beginning to be uncovered, potentially representing key therapeutic targets to use in combination with checkpoint blockade, exemplifying the emerging concept of personalised medicine approaches to immune therapies. Subsequently, different immunotherapeutic strategies may be required based on stratification by these factors-for the minority of tumours with a high level of pre-existing immunity, immune checkpoint blockade monotherapy may be sufficient. However, for the majority of tumours with lower levels of pre-existing immunity, combination approaches will likely be required to achieve maximal therapeutic effect. Results of ongoing clinical trials including combinations with chemotherapy, radiation therapy, and targeted therapies are eagerly awaited.

Objective response rate and progression-free survival as surrogates for overall survival treatment effect: A meta-analysis across diverse tumour groups and contemporary therapies.

BACKGROUND: 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. MATERIAL AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Trends in phase 1 oncology clinical trials across Australia; Analysis of ClinicalTrials.gov 2012-2022.

BACKGROUND: Phase 1 oncology trials provide access to new therapies and may improve cancer outcomes. Phase 1 trials conducted in the Asian-Pacific region are increasing at a faster rate than the global trend. This study aimed to describe the changing landscape of phase 1 oncology trials in Australia in the last decade. METHODS: This cross-sectional study reviewed phase 1 oncology trials registered on ClinicalTrials.gov conducted in Australia. Phase 1 trials were included for analysis if they enrolled adults with solid organ malignancies, used at least one systemic agent, and were first registered between January 1, 2012, and December 31, 2022. The number of trials, site locations, sponsor type, and drug class were analyzed using descriptive statistics. RESULTS: Over the 10-year period, ClinicalTrials.gov included 493 phase 1 clinical trials across 71 Australian sites. Most sites were in metropolitan locations; in Melbourne, trials were concentrated within selected sites, while in Sydney, trials were spread across a larger number of sites. The number of phase 1 trials per annum increased from 18 in 2012 to 75 in 2022. Since 2020, emerging biopharmaceutical companies have become the predominant sponsor type, a trend that is also seen globally. While most trial sponsors were North American (42%), there was increasing representation from Asian sponsors over the 10-year period (6% in 2012 to 39% in 2022). Immunomodulatory (45%) and targeted approaches (44%) accounted for most drug classes used alone or in combination. CONCLUSIONS: There are an increasing number of phase 1 trials conducted within Australia. Sponsors of phase 1 trials are increasingly from Asian countries and are more likely to be emerging biopharmaceutical companies.

Clinical Impact of Comprehensive Molecular Profiling in Adolescents and Young Adults with Sarcoma.

Sarcomas are a heterogenous group of tumours that commonly carry poor prognosis with limited therapeutic options. Adolescents and young adults (AYAs) with sarcoma are a unique and understudied patient population that have only achieved modest survival gains compared to other groups. We present our institutional experience of AYAs with sarcoma who underwent comprehensive molecular profiling (CMP) via either large-panel targeted DNA sequencing or whole genome and transcriptome sequencing and evaluated the feasibility and clinical impact of this approach. Genomic variants detected were determined to be clinically relevant and actionable following evaluation by the Molecular Tumour Board. Clinicians provided feedback regarding the utility of testing three months after reporting. Twenty-five patients who were recruited for CMP are included in this analysis. The median time from consent to final molecular report was 45 days (interquartile range: 37-57). Potentially actionable variants were detected for 14 patients (56%), and new treatment recommendations were identified for 12 patients (48%). Pathogenic germline variants were identified in three patients (12%), and one patient had a change in diagnosis. The implementation of CMP for AYAs with sarcoma is clinically valuable, feasible, and should be increasingly integrated into routine clinical practice as technologies and turnaround times continue to improve.

Tucatinib promotes immune activation and synergizes with programmed cell death-1 and programmed cell death-ligand 1 inhibition in HER2-positive breast cancer.

BACKGROUND: Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors have poor efficacy in patients with trastuzumab-resistant advanced HER2-positive breast cancer. Tucatinib is a potent, selective anti-HER2 tyrosine kinase inhibitor with proven clinical benefit in the advanced setting in patients with trastuzumab resistance. We investigated if tucatinib can alter the tumor microenvironment and if this could be harnessed for therapeutic efficacy. METHODS: We investigated the antitumor efficacy and contribution of the immune response of tucatinib using 2 immunocompetent, HER2-positive murine breast cancer models (trastuzumab-sensitive H2N113; trastuzumab-resistant Fo5) and the efficacy of tucatinib with trastuzumab and PD-1 or PD-L1 checkpoint inhibitors. RESULTS: In both models, tucatinib statistically significantly inhibited tumor growth and demonstrated dose-dependent efficacy. Ex vivo analysis by flow cytometry of tumor-infiltrating lymphocytes in mice treated with tucatinib showed increased frequency, higher proliferation, and enhanced effector function of CD8+ effector memory T cells. Tucatinib treatment also increased frequency of CD8+PD-1+ and CD8+TIM3+ T cells, CD49+ natural killer cells, monocytes, and major histocompatibility complex II expression on dendritic cells and macrophages and a decrease in myeloid-derived suppressor cells. Gene expression analysis revealed statistically significant enrichment in pathways associated with immune activation, type I and II interferon response, adaptive immune response, and antigen receptor signaling. In vivo, tucatinib and α-PD-L1 or α-PD-1 demonstrated statistically significantly increased efficacy and improved survival of mice compared with tucatinib alone. CONCLUSION: Tucatinib modulates the immune microenvironment favorably, and combination treatment with α-PD-L1 or α-PD-1 demonstrated increased efficacy in preclinical HER2-positive tumor models. These findings provide a rationale for investigation of tucatinib and immune checkpoint inhibition in the clinic.

Combined PARP and WEE1 inhibition triggers anti-tumor immune response in BRCA1/2 wildtype triple-negative breast cancer.

Novel therapeutic strategies that can effectively combine with immunotherapies are needed in the treatment of triple-negative breast cancer (TNBC). We demonstrate that combined PARP and WEE1 inhibition are synergistic in controlling tumour growth in BRCA1/2 wild-type TNBC preclinical models. The PARP inhibitor (PARPi) olaparib combined with the WEE1 inhibitor (WEE1i) adavosertib triggered increases in anti-tumour immune responses, including STING pathway activation. Combinations with a STING agonist resulted in further improved durable tumour regression and significant improvements in survival outcomes in murine tumour models of BRCA1/2 wild-type TNBC. In addition, we have identified baseline tumour-infiltrating lymphocyte (TIL) levels as a potential predictive biomarker of response to PARPi, WEE1i and immunotherapies in BRCA1/2 wild-type TNBC.

Intratumoral CD8+ T cells with a tissue-resident memory phenotype mediate local immunity and immune checkpoint responses in breast cancer.

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.

BRAF-mediated brain tumors in adults and children: A review and the Australian and New Zealand experience.

The mitogen-activated protein kinase (MAPK) pathway signaling pathway is one of the most commonly mutated pathways in human cancers. In particular, BRAF alterations result in constitutive activation of the rapidly accelerating fibrosarcoma-extracellular signal-regulated kinase-MAPK significant pathway, leading to cellular proliferation, survival, and dedifferentiation. The role of BRAF mutations in oncogenesis and tumorigenesis has spurred the development of targeted agents, which have been successful in treating many adult cancers. Despite advances in other cancer types, the morbidity and survival outcomes of patients with glioma have remained relatively stagnant. Recently, there has been recognition that MAPK dysregulation is almost universally present in paediatric and adult gliomas. These findings, accompanying broad molecular characterization of gliomas, has aided prognostication and offered opportunities for clinical trials testing targeted agents. The use of targeted therapies in this disease represents a paradigm shift, although the biochemical complexities has resulted in unexpected challenges in the development of effective BRAF inhibitors. Despite these challenges, there are promising data to support the use of BRAF inhibitors alone and in combination with MEK inhibitors for patients with both low-grade and high-grade glioma across age groups. Safety and efficacy data demonstrate that many of the toxicities of these targeted agents are tolerable while offering objective responses. Newer clinical trials will examine the use of these therapies in the upfront setting. Appropriate duration of therapy and durability of response remains unclear in the glioma patient cohort. Longitudinal efficacy and toxicity data are needed. Furthermore, access to these medications remains challenging outside of clinical trials in Australia and New Zealand. Compassionate access is limited, and advocacy for mechanism of action-based drug approval is ongoing.

Pitfalls and progress in adrenocortical carcinoma diagnosis: the utility of a multidisciplinary approach, immunohistochemistry and genomics.

SUMMARY: Adrenocortical carcinoma is a rare disease with poor prognosis whose clinical heterogeneity can at times present a challenge to accurate and timely diagnosis. We present the case of a patient who presented with extensive pulmonary lesions, mediastinal and hilar lymphadenopathy and an adrenal mass in whom the oncological diagnosis was initially uncertain. Through the use of immunohistochemistry, biochemistry and genomic testing, an accurate diagnosis of adrenocortical carcinoma was ultimately made which resulted in more directed treatment being administered. The use of multidisciplinary input and genomics to aid in diagnosis and prognosis of adrenocortical carcinoma is discussed. LEARNING POINTS: Adrenocortical carcinomas can present a diagnostic challenge to clinicians given it is a rare malignancy with significant clinical heterogeneity. Specialist multidisciplinary team input is vital in the diagnosis and management of adrenocortical carcinomas. Hormonal testing is recommended in the diagnostic workup of adrenal masses, even in the absence of overt clinical signs/symptoms of hormone excess. Immunostaining for the highly sensitive and specific steroidogenic factor-1 is vital for accurate diagnosis. Genomics can provide prognostic utility in management of adrenocortical carcinoma.

Comparing Survival Outcomes for Advanced Cancer Patients Who Received Complex Genomic Profiling Using a Synthetic Control Arm.

BACKGROUND: Complex genomic profiling (CGP) has transformed cancer treatment decision making, yet there is a lack of robust and quantifiable evidence for how utilisation of CGP improves patient outcomes. OBJECTIVE: This study evaluated cohort level clinical effectiveness of CGP to improve overall survival (OS) in real-world advanced cancer patients using a registry-based matched control population. PATIENTS AND METHODS: Two cohorts of advanced and refractory cancer patients were seen in consecutive series for early phase trial enrolment consideration. The first cohort (CGP group) accessed tumour profiling via a research study; while the second cohort that followed was not profiled. Overall survival between cohorts was compared using Kaplan-Meier curves and Cox proportional hazard models. Potential confounding was analysed and adjusted for using stabilised weights based on propensity scores. RESULTS: Within the CGP group, 25 (17.6%) patients received treatment informed by CGP results and this subgroup had significantly improved survival compared with CGP patients in whom results did not impact their treatment (unadjusted HR = 0.44, (0.22-0.88), p = 0.02). However, when comparing the entire CGP cohort with the No CGP cohort, no significant survival benefit was evident with adjusted median OS for CGP of 13.5 months (9.2-17.0) compared with 11.0 (9.2-17.4) for No CGP (adjusted HR = 0.92, (0.65-1.30), p = 0.63). CONCLUSIONS: This study utilised real-world data to simulate a control arm and quantify the clinical effectiveness of genomic testing. The magnitude of survival benefit for patients who had CGP result-led treatments was insufficient to drive an overall survival gain for the entire tested population. Translation of CGP into clinics requires strategies to ensure higher rates of tested patients obtain clinical benefit to deliver on the value proposition of CGP in an advanced cancer population.

Tumor Cellularity and Infiltrating Lymphocytes as a Survival Surrogate in HER2-Positive Breast Cancer.

In early-stage HER2-positive breast cancer, biomarkers that guide deescalation and/or escalation of systemic therapy are needed. CelTIL score is a novel, combined biomarker based on stromal tumor-infiltrating lymphocytes and tumor cellularity and is determined in tumor biopsies at week 2 of anti-HER2 therapy only. We evaluated the prognostic value of CelTIL in 196 patients with early-stage HER2-positive disease treated with standard trastuzumab-based chemotherapy in the NeoALTTO phase III trial. Using a prespecified CelTIL cutoff, a better 5-year event-free survival and overall survival was observed between CelTIL-high and CelTIL-low score with a 76.4% (95% confidence interval [CI] = 68.0% to 85.0%) vs 59.7% (95% CI = 50.0% to 72.0%) (hazard ratio = 0.40, 95% CI = 0.17 to 0.94) and 86.4% (95% CI = 80.0% to 94.0%) vs 73.5% (95% CI = 64.0% to 84.0%) (hazard ratio = 0.43, 95% CI = 0.20 to 0.92), respectively. Statistical significance was maintained after adjusting for baseline tumor-infiltrating lymphocytes, hormone receptor status, pretreatment tumor size and nodal status, type of surgery, treatment arm, and pathological complete response. Further studies to support CelTIL as an early readout biomarker to help deescalate or escalate systemic therapy in HER2-positive breast cancer seem warranted.

Alpelisib Monotherapy for PI3K-Altered, Pretreated Advanced Breast Cancer: A Phase II Study.

There is limited knowledge on the benefit of the α-subunit-specific PI3K inhibitor alpelisib in later lines of therapy for advanced estrogen receptor-positive (ER+) HER2- and triple-negative breast cancer (TNBC). We conducted a phase II multicohort study of alpelisib monotherapy in patients with advanced PI3K pathway mutant ER+HER2- and TNBC. In the intention-to-treat ER+ cohort, the overall response rate was 30% and the clinical benefit rate was 36%. A decline in PI3K pathway mutant circulating tumor DNA (ctDNA) levels from baseline to week 8 while on therapy was significantly associated with a partial response, clinical benefit, and improved progression-free-survival [HR 0.24; 95% confidence interval (CI), 0.083-0.67, P = 0.0065]. Detection of ESR1 mutations at baseline in plasma was also associated with clinical benefit and improved progression-free survival (HR 0.22; 95% CI, 0.078-0.60, P = 0.003). SIGNIFICANCE: Alpelisib monotherapy displayed efficacy in heavily pretreated ER+ breast cancer with PIK3CA mutations. PIK3CA mutation dynamics in plasma during treatment and ESR1 mutations detected in plasma at baseline were candidate biomarkers predictive of benefit from alpelisib, highlighting the utility of ctDNA assays in this setting. This article is highlighted in the In This Issue feature, p. 2007.

Extended adjuvant aromatase inhibitor therapy: less is more.

Adjuvant endocrine therapy has transformed outcomes for patients with early-stage, hormone receptor-positive, HER2-negative breast cancer; however, the optimal duration remains undefined. In a recent issue of The New England Journal of Medicine, Gnant et al. report the results of the ABCSG-16/SALSA trial that investigated the optimal duration of extended adjuvant aromatase inhibition and found that 5 years was not more beneficial than a 2-year extension.1.

Tumor-Infiltrating Lymphocyctes in Triple-Negative Breast Cancer: Update for 2020.

ABSTRACT: Triple-negative breast cancer (TNBC) continues to represent an unmet need because of its significantly poorer outcomes, including higher relapse rates following early-stage disease and dismal survival times in the advanced setting, when compared with other breast cancer subtypes (Cancer 2012;118:5463-5472). Furthermore, there remains a lack of established systemic treatment options beyond conventional cytotoxic chemotherapy, with the exception of PARP inhibitors in the small subset of patients who harbor a BRCA mutation (N Engl J Med 2018;379:753; Lancet Oncol 2020;21:1269-1282; Ann Oncol 2019;30:558-566) and recently the use of immunotherapy in the first-line metastatic setting in those who are programmed death ligand 1-positive (Lancet Oncol 2020;21(1):44-59; N Engl J Med 2018;379(22):2108-2121). Suitable biomarkers for improving prognostication and directing therapy in both the early and advanced TNBC settings are required in order for improvements in survival outcomes to be continued to be attained. Tumor-infiltrating lymphocytes are gaining increasing relevance as an immunological biomarker in this arena.

A pituitary metastasis, an adenoma and potential hypophysitis: A case report of tumour to tumour metastasis in the pituitary.

Tumour to tumour metastasis is a rare event, especially in the pituitary. Metastases to pituitary adenomas most commonly occurs in late stage disease, commonly presenting with visual field defects and adenohypophyseal dysfunction. The most frequent primary cancers are lung, breast and renal carcinoma which deposit most commonly in prolactinomas, somatotropinomas, gonadotropinomas. In nearly 40% of cases, sellar symptoms are the harbinger to the diagnosis of primary malignancy. The abnormal vascularity and growth promoting microenvironment of pituitary adenomas may encourage metastatic seeding and proliferation of these "collision tumours". Here, we present a case of a breast carcinoma metastasis to a pituitary null-cell adenoma in the setting of immunotherapy. Infundibular thickening in the setting of immunotherapy is often ascribed to hypophysitis, but our case highlights that metastatic spread should be part of the differential diagnosis.

Tissue-resident memory T cells in breast cancer control and immunotherapy responses.

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 (TRM) cells. This subpopulation has features consistent with those of TRM 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 TRM cells have a substantially improved prognosis and longer overall survival. Furthermore, patients with advanced-stage breast cancers with higher levels of TRM cells have increased response rates to anti-PD-1 antibodies. These findings have motivated efforts to explore whether CD8+ TRM 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+ TRM 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.