Evaluation of the Geographical Accessibility of Genome-Matched Clinical Trials on a National Experience.

BACKGROUND: Molecular-driven oncology allows oncologists to identify treatments that match a cancer's genomic profile. Clinical trials are promoted as an effective modality to deliver a molecularly matched treatment. We explore the role of geographical accessibility in Italy, and its impact on patient access to clinical trials. MATERIAL AND METHODS: We retrospectively reviewed molecular data from a single-institutional case series of patients receiving next-generation sequencing testing between March 2019 and July 2020. Actionable alterations were defined as the ones with at least one matched treatment on Clinicaltrials.gov at the time of genomic report signature. We then calculated the hypothetical distance to travel to reach the nearest assigned clinical trial. RESULTS: We identified 159 patients eligible for analysis. One hundred and one could be potentially assigned to a clinical trial in Italy, and the median distance that patients needed to travel to reach the closest location with a suitable clinical trial was 76 km (interquartile range = 127.46 km). Geographical distribution of clinical trials in Italy found to be heterogeneous, with Milan and Naples being the areas with a higher concentration. We then found that the probability of having a clinical trial close to a patient's hometown increased over time, according to registered studies between 2015 and 2020. CONCLUSIONS: The median distance to be travelled to the nearest trial was generally acceptable for patients, and trials availability is increasing. Nevertheless, many areas are still lacking trials, so efforts are required to increase and homogenize the possibilities to be enrolled in clinical trials for Italian patients with cancer.

Deleterious alterations in homologous recombination repair genes and efficacy of platinum-based chemotherapy in biliary tract cancers.

BACKGROUND: Platinum-based chemotherapy represents the standard first-line treatment for biliary tract cancers (BTC). Deficits in genes involved in the homologous recombination (HR) and DNA damage response (DDR) may confer higher sensitivity to platinum agents. METHODS: We retrospectively included patients affected by BTC from 2 Italian institutions. Inclusion criteria consist of the receipt of platinum-based chemotherapy in the metastatic setting and the availability of comprehensive genomic profiling using next-generation sequencing (NGS). Patients were included in the HRD-like group if demonstrated oncogenic or likely oncogenic alterations in HR-/DDR-genes. Clinical endpoints were compared between the HRD-like group and the non-HRD-like group. RESULTS: Seventy-four patients were included, of whom 25 (33%) in the HRD-like group and 49 (66%) in the non-HRD group. With a median follow-up of 26.04 months (interquartile-range [IQR] 9.41-29.27) in the HRD-like group and of 22.48 months (IQR 16.86-40.53) in the non-HRD group, no PFS difference emerged, with a mPFS of 5.18 months in the HRD-like group compared to 6.04 months in the non-HRD group (hazard ratio [HR], 1.017, 95% CI 0.58-1.78; P = .95). No differences were observed in DCR (64% [95 CI 45%-83%] vs 73% [95 CI 61%-86%]; P = .4), and CBR (45% [95% CI 28%-73%] vs 50% [95% CI, 37%-68%]; P = .9) between the HRD-like group and non-HRD groups, respectively. Median OS did not statistically differ between the HRD-like group and non-HRD group (26.7 vs 18.0 months, respectively; HR, 0.670, 0.33 to 1.37, P = .27). CONCLUSION: HR-/DDR-genes, when assessed with regular tumor-only NGS panels, provide limited clinical validity to identify patients with BTC more likely to benefit from platinum-based chemotherapy.

Cancers of Unknown Primary Origin: Real-World Clinical Outcomes and Genomic Analysis at the European Institute of Oncology.

BACKGROUND: Cancer of unknown primary origin (CUP) poses a significant challenge due to poor clinical outcomes and limited treatment options. As such, further definition of clinicopathological factors and genomic profile to better adapt treatment strategies is required. METHODS: Medical records were interrogated to retrospectively include CUP with available clinical and genomics data at the European Institute of Oncology. Next-generation sequencing (NGS) included targeted panels. Statistical analyses were conducted with R Software 4.2.2. RESULTS: A total of 44 patients were included. With a median follow-up of 39.46 months (interquartile range [IQR] 35.98-47.41 months), median PFS (mPFS) to first-line regimen was 3.98 months (95% CI 3.22-5.98), with a clinical benefit rate of 26% (95% CI 14%-49%), and disease control rate (DCR) limited to 48.28%. Most patients (26 of 31, 83.87%) received platinum-doublet chemotherapy, with no statistically significant difference between first-line treatment regimens. Median OS (mOS) was 18.8 months (95% CI 12.3-39.9), with a 12-month OS rate of 66% (95% CI 50%-85%). All patients received comprehensive genomic profiling (CGP). For 11 patients, NGS was unsuccessful due to low sample quantity and/or quality. For the remaining, TP53 (n = 16, 48%) and KRAS (n = 10, 30%) represented the most altered (alt) genes. No microsatellite instability was observed (0 of 28), while 6 of 28 (21.43%) tumors carried high TMB (≥10 mutation per megabase). Eight of 33 tumors (24.2%) displayed at least one actionable alteration with potential clinical benefit according to ESCAT. Only 2 of them received targeted therapy matched to genomic alterations, with a combined mPFS of 2.63 months (95% CI 1.84-not evaluable) as third-line regimens. Six patients received anti-PD1/PD-L1 therapy, showing a meaningful mPFS of 13 months (95% CI 2.04-not evaluable). CONCLUSION: CUP exhibits poor prognosis with limited benefits from standard treatment regimens. A significant proportion of CUPs carry actionable alterations, underscoring the importance of genomic profiling to gather additional treatment opportunities. In addition, immunotherapy might represent a valuable treatment option for a subset of CUP. Finally, accurate definition of sequencing methods and platforms is crucial to overcome NGS failures.

Immune-Related Adverse Event Likelihood Score Identifies "Pure" IRAEs Strongly Associated With Outcome in a Phase I-II Trial Population.

BACKGROUND: Immune-related adverse events (IRAE) pose a significant diagnostic and therapeutic challenge in patients treated with immune-oncology (IO) drugs. IRAEs have been suggested to correlate with better outcome, but studies are conflicting. Estimating the true incidence of IRAEs is particularly difficult in the early phase I/II trial setting. A key issue is the lack of IRAE diagnostic criteria, necessary to discriminate "pure" IRAEs from other treatment-related adverse events not sustained by an autoimmune process. METHODS: In patients treated with immune-oncology (IO) drugs in phases I-II trials at our institute, we identified high confidence (HC) or low confidence (LC) IRAEs by clinical consensus. We empirically developed an IRAE likelihood score (ILS) based on commonly available clinical data. Correlation with outcome was explored by multivariate Cox analysis. To mitigate immortal time-bias, analyses were conducted (1) at 2-month landmark and (2) modeling IRAEs as time-dependent covariate. RESULTS: Among 202 IO-treated patients, 29.2% developed >1 treatment-related adverse events (TRAE). Based on ILS >5, we classified patients in no IRAE (n = 143), HC IRAE (n = 24), or LC IRAE (n = 35). hazard ratios (HR) for HC were significantly lower than LC patients (HR for PFS ranging 0.24-0.44, for OS 0.18-0.23, all P < .01). CONCLUSION: ILS provides a simple system to identify bona fide IRAEs, pruning for other treatment-related events likely due to different pathophysiology. Applying stringent criteria leads to lower and more reliable estimates of IRAE incidence and identifies events with significant impact on survival.

Endocrine therapy for early breast cancer in the era of oral selective estrogen receptor degraders: challenges and future perspectives.

PURPOSE OF REVIEW: Growth and survival of hormone receptor positive breast cancer cells are dependent on circulating hormones (e.g., estrogen and progesterone). Endocrine therapy improved outcomes in both early and advanced hormone receptor positive breast cancer. These treatments include drugs with different mechanisms of action, namely selective estrogen receptor modulators (SERM), aromatase inhibitors, and selective estrogen receptor degraders (SERDs). SERDs represent estrogen receptor antagonists, favoring its degradation and thus interfering with proliferation genes transcription and activation. Fulvestrant is the first approved SERD, administered intramuscularly for treating advanced breast cancer. RECENT FINDINGS: Oral SERDs have been tested to overcome the limitation of the intramuscular administration, and to increase SERD bioavailability. Recently, an oral SERD, Elacestrant, has been approved by the Food and Drug Administration (FDA) for patients carrying an ESR1 mutation. In fact, oral SERDs seem to be effective in tumors harboring ESR1 mutations, a well known mechanism of resistance to endocrine therapy (especially aromatase inhibitors). SUMMARY: More recently, oral SERDs have been tested in patients with early hormone receptor positive breast cancer, although their impact on survival and in this curative setting compared to standard endocrine therapy still needs to be elucidated. The best timing and duration of SERD administration and specific biomarkers in (neo)adjuvant setting remain largely unknown.

Predicting Response to Antibody Drug Conjugates: A Focus on Antigens' Targetability.

Antibody-drug conjugates (ADCs) represent a cornerstone in the treatment of many cancers nowadays. ADCs fulfill their function by binding a target on tumor cell membrane to deliver a cytotoxic payload; in addition, those moieties capable of crossing cancer cell membranes can achieve near-by cells that do not express the target antigen, exerting the so-called "bystander" cytotoxic effect. The presence of a specific target antigen expressed on cancer cells has been for long considered crucial for ADCs and commonly required for the inclusion of patients in clinical trials with ADCs. To date, only ado-trastuzumab-emtansine, fam-trastuzumab deruxtecan-nxki, and mirvetuximab soravtansine-gynx are approved according to the expression of a target antigen in solid tumors, while the clinical use of other ADCs (eg, sacituzumab govitecan) is not conditioned by the presence of a specific biomarker. Given the ever-growing number of approved ADCs and those under investigation, it is essential to find new biomarkers to guide their use, especially in those settings for which different ADCs are approved to establish the best therapeutic sequence based on robust biomarkers. Hence, this work addresses the role of target antigens in predicting response to ADCs, focusing on examples of antigens' targetability according to their expression on cancer cells' surface or to the presence of specific target aberrations (eg, mutation or over-expression). New methods for the assessment and quantification of targets' expression, like molecular imaging and in vitro assays, might be key tools to improve biomarker analysis and eventually deliver better outcomes by refined patient selection.

Screening Programs for Breast Cancer: Toward Individualized, Risk-Adapted Strategies of Early Detection.

Early detection of breast cancer (BC) comprises two approaches: screening of asymptomatic women in a specified target population at risk (usually a target age range for women at average risk), and early diagnosis for women with BC signs and symptoms. Screening for BC is a key health intervention for early detection. While population-based screening programs have been implemented for age-selected women, the pivotal clinical trials have not addressed the global utility nor the improvement of screening performance by utilizing more refined parameters for patient eligibility, such as individualized risk stratification. In addition, with the exception of the subset of women known to carry germline pathogenetic mutations in (high- or moderately-penetrant) cancer predisposition genes, such as BRCA1 and BRCA2, there has been less success in outreach and service provision for the unaffected relatives of women found to carry a high-risk mutation (i.e., "cascade testing") as it is in these individuals for whom such actionable information can result in cancers (and/or cancer deaths) being averted. Moreover, even in the absence of clinical cancer genetics services, as is the case for the immediate and at least near-term in most countries globally, the capacity to stratify the risk of an individual to develop BC has existed for many years, is available for free online at various sites/platforms, and is increasingly being validated for non-Caucasian populations. Ultimately, a precision approach to BC screening is largely missing. In the present chapter, we aim to address the concept of risk-adapted screening of BC, in multiple facets, and understand if there is a value in the implementation of adapted screening strategies in selected women, outside the established screening prescriptions, in the terms of age-range, screening modality and schedules of imaging.

The return of RET GateKeeper mutations? an in-silico exploratory analysis of potential resistance mechanisms to novel RET macrocyclic inhibitor TPX-0046.

TPX-0046 is designed to overcome resistance to FDA approved RET inhibitors Selpercatinib and Pralsetinib. Early prediction of resistance mechanisms to investigational drugs may facilitate subsequent drug and trial designs. This study aims to predict potential mutations inducing resistance to TPX-0046. We conducted an in-silico analysis of TPX-0046 macrocyclic structure and predicted the binding mode on RET. We used as reference literary examples of resistance mechanisms to other macrocyclic inhibitors (Lorlatinib on ALK/ROS1) to construct RET secondary resistance mutations. We conducted docking simulations to evaluate impact of mutations on TPX-0046 binding. TPX-0046 binding mode on RET appears to not be influenced by Solventfront G810X mutation presence. Bulky Gatekeeper V804X mutations affect predicted TPX-0046 binding mode. Mutations in Beta 7 strand region L881F and xDFG S891L impair TPX-0046 docking. Our findings suggest that development of second generation RET inhibitors focused mainly on Solventfront G810X mutations granting resistance to selective RET inhibitors Selpercatinib and Pralsetinib. If these findings are confirmed by identification of Gatekeeper V804X mutations in patients progressing to TPX-0046, explanation of acquired resistance and loss of benefit will be easier These findings might accelerate development of third generation RET inhibitors, as well as clinical trial design in precision oncology settings.

Use of Antibody-Drug Conjugates in the Early Setting of Breast Cancer.

Antibody-drug conjugates (ADCs) are anticancer agents with the capacity to selectively deliver their payloads to cancer cells. Antibody-drug conjugates consist of a monoclonal antibody backbone connected by a linker to cytotoxic payloads. Antibody-drug conjugate effect occurs either by directly targeting cancer cells via membrane antigen or through "bystander effect." Antibody-drug conjugates have demonstrated efficacy against various types of tumors, including breast cancer. Ado-trastuzumab emtansine is presently the only approved ADC for the treatment of breast cancer in the early setting, while several ADCs are now approved for metastatic breast cancer. Due to the transformative impact that several ADCs have reported in the setting of advanced breast cancer, researchers are now testing more of such compounds in the early setting, to portend benefits to patients through highly potent anticancer drugs. Ongoing trials hold the potential to transform treatment protocols for early breast cancer in the near future. These trials are aiming at evaluating different treatment modulation approaches, as informed by breast cancer risk of recurrence, including toward treatment de-escalation. Efforts are provided in ongoing clinical trials to identify the patients who will benefit most, to pursue paradigms of precision medicine with the novel ADCs. This review focuses on the potential role of ADCs in early breast cancer, providing an overview of the latest progress in their development and how they are implemented in ongoing clinical trials.

Unlocking the Potential: Biomarkers of Response to Antibody-Drug Conjugates.

Antibody-drug conjugates (ADCs) have reshaped the cancer treatment landscape across a variety of different tumor types. ADCs' peculiar pharmacologic design combines the cytotoxic properties of chemotherapeutic agents with the selectivity of targeted therapies. At present, the approval of many ADCs used in clinical practice has not always been biomarker-driven. Indeed, predicting ADCs' activity and toxicity through the demonstration of specific biomarkers is still a great unmet need, and the identification of patients who can derive significant benefit from treatment with ADCs may often be uncertain. With the lack of robust predictive biomarkers to anticipate primary, intrinsic resistance to ADCs and no consolidated biomarkers to aid in the early identification of treatment resistance (ie, acquired resistance), the determination of precise biologic mechanisms of ADC activity and safety becomes priority in the quest for better patient-centric outcomes. Of great relevance, whether the target antigen expression is a determinant of ADCs' primary activity is still to be clarified, and available data remain quite controversial. Antigen expression assessment is typically performed on tissue biopsy, hence only providing information on a specific tumor site, therefore unable to capture heterogeneous patterns of tumor antigen expression. Quantifying the expression of the target antigen across all tumor sites would help better understand tumor heterogeneity, whereas molecularly characterizing tumor-intrinsic features over time might provide information on resistance mechanisms. In addition, toxicity can represent a critical concern, since most ADCs have a safety profile that resembles that of chemotherapies, with often unique adverse events requiring special management, possibly because of the differential in pharmacokinetics between the small-molecule agent versus payload of a similar class (eg, deruxtecan conjugate-related interstitial lung disease). As such, the identification of robust predictive biomarkers of safety and activity of ADCs has the potential to improve patient selection and enrich the population of patients most likely to derive a substantial clinical benefit, especially in those disease settings where different ADCs happen to be approved in competing clinical indications, with undefined biomarkers to make precise decision making and unclear data on how to sequence ADCs. At this point, the identification of clinically actionable biomarkers in the space of ADCs remains a top research priority.

Circulating tumor DNA in patients with locally advanced rectal cancer treated with multimodal treatment.

Background: The management of locally advanced rectal cancer (LARC) relies on a multimodal approach. Neither instrumental work-up nor molecular biomarkers are currently available to identify a risk-adapted strategy. Objectives: We aim to investigate the role of circulating tumor DNA (ctDNA) and its clearance at different timepoints during chemo-radiotherapy (CRT) and correlate them with clinical outcomes. Design: Between November 2014 and November 2019, we conducted a monocentric prospective observational study enrolling consecutive patients with LARC managed with neoadjuvant standard CRT (capecitabine and concomitant pelvic long-course radiotherapy), followed by consolidation capecitabine in selected cases and surgery. Methods: Blood samples for ctDNA were obtained at pre-planned timepoints. We evaluated the correlation of baseline variant allele frequency (VAF) with pathologic complete response (pCR) down-staging, node regression (pN0), event-free survival (EFS), and overall survival (OS). Results: Among 112 screened patients, 61 were enrolled. In all, 38 (62%) had a positive ctDNA at baseline with VAF > 0 and 23 had negative ctDNA (VAF = 0). Among patients with negative ctDNA, 30% had a complete response, while only 13% of positive ctDNA patients had pCR [odds ratio (OR) 0.35 (95% confidence interval (CI): 0.10-1.26), p = 0.11]. Similarly, 96% and 74% of pN0 were observed among negative and positive ctDNA patients, respectively [OR 0.13 (95% CI: 0.02-1.07), p = 0.058]. The presence of a baseline VAF > 0 was associated with a trend toward a lower EFS compared with VAF = 0 patients [hazard ratio (HR) = 2.30, 95% CI: 0.63-8.36, p = 0.21]. Within the limitations of small sample size, no difference in OS was observed according to the baseline ctDNA status (HR = 1.18, 95% CI: 0.35-4.06, p = 0.79). Conclusion: Within the limitations of a reduced number of patients, patients with baseline negative ctDNA seem to show a higher probability of pN0 status and a trend toward improved EFS. Prospective translational studies are required to define the role of ctDNA analysis in the multimodal treatment of LARC.

A demand-offer critical analysis of current drug development. Phase I drugs versus TCGA sequencing data.

BACKGROUND: Phase I clinical trials have become increasingly critical to regulatory approvals of novel agents. In phase I drug development, a global problem of unknown magnitude is the multiplicity of similar drugs being investigated against the same target, colloquially known as the 'me too' phenomenon. METHODS: Ranging from December 2020 to December 2022 we annotated phase I clinical trials present on clinicaltrials.gov. Public databases were queried for annotation of investigational agents (IAs). Extensive literature research and data mining were performed to annotate agents not present in public databases. The Cancer Genome Atlas (TCGA) pan-cancer sequencing cohort was used to perform second-level analyses to evaluate tumour types with a higher number of IA matches. RESULTS: A total of 1054 unique drug targets were identified. The most frequent IA classes were: cell products (1223), small-molecule inhibitors (1110), antibodies (733), and vaccines (346). Only a minority (8.9%) of phase I IAs were explored against a target without a competitive agent; 7% of agents shared targets with 2-3 other agents. Unfortunately, the majority (84%) shared targets with at least four other agents. Using data from the TCGA pan-cancer sequencing potentially underserved histologies were identified. Analysis of alteration-IA matches revealed potentially frequent and unexplored alterations in many tumour types. CONCLUSIONS: The majority of IAs (86%) shared targets with at least three other agents. We argue that these duplicative efforts could be redirected toward unmet needs instead.

Evolution of biological features of invasive lobular breast cancer: Comparison between primary tumour and metastases.

BACKGROUND: Invasive lobular carcinoma (ILC) has unique clinical-biological features. Phenotypical differences between primary tumours (PTs) and metastases (M) have been described for invasive ductal carcinoma, but data on ILC are limited. METHODS: We retrospectively analysed patients with recurrent ILC from our institution from 2013 to 2020. We evaluated the discordance of the oestrogen receptor (ER), progesterone receptor (PgR) and HER2 between PT and M, to understand prognostic and therapeutic implications. RESULTS: Thirteen percent (n = 91) of all patients had ILC. We observed 15%, 44% and 5% of ER, PgR and HER2 status discordance between PT and M. ER/PgR discordance was related to receptor loss and HER2 mainly due to gain. PT presented a luminal-like phenotype (93%); 6% and 1% were triple-negative (TNBC) and HER2-positive. In M, there was an increase in TNBC (16%) and HER2-positive (5%). Metastasis-free survival and overall survival (OS) were different according to clinical phenotype, with poorer prognosis for HER2+ and TNBC (p < 0.001); OS after metastatic progression did not differ across phenotypes (p = 0.079). In luminal-like ILC (n = 85) at diagnosis, we found that OS after relapse was poorer in patients experiencing a phenotype switch to TNBC but improved in patients with HER2 gain (p = 0.0028). Poorer survival was reported in patients with a PgR and/or ER expression loss of ≥25%. There was HER2-low enrichment in M1 (from 37% to 58%): this change was not associated with OS (p > 0.05). CONCLUSION: Our results suggest that phenotype switch after metastatic progression may be associated with patients' outcomes. Tumour biopsy in recurrent ILC could drive treatment decision-making, with prognostic implications.

Molecular tumour board at European Institute of Oncology: Report of the first three year activity of an Italian precision oncology experience.

BACKGROUND: Precision oncology aims to improve clinical outcomes by personalising treatment options for patients with cancer. Exploiting vulnerabilities identified in a patient's cancer genome requires reliable interpretation of a huge mole of alterations and heterogeneous biomarkers. ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) allows evidence-based evaluation of genomic findings. Molecular tumour boards (MTBs) convey the required multi-disciplinary expertise to enable ESCAT evaluation and strategical treatment choice. MATERIALS AND METHOD: We retrospectively reviewed the records of 251 consecutive patients discussed by European Institute of Oncology MTB between June 2019 and June 2022. RESULTS: One-hundred eighty-eight (74.6%) patients had at least one actionable alteration. After MTB discussion, 76 patients received molecularly matched therapies (MMTs) while 76 patients received standard of care. Patients receiving MMT displayed higher overall response rate (37.3% versus 12.9%), median progression-free survival (mPFS 5.8 months, 95% confidence interval [CI] 4.1-7.5 versus 3.6 months, 95% CI 2.5-4.8, p = 0.041; hazard ratio 0.679, 95% CI 0.467-0.987) and median overall survival (mOS 35.1 months, 95% CI not evaluable versus 8.5 months, 95% CI 3.8-13.2; hazard ratio 0.431, 95% CI 0.250-0.744, p = 0.002). Superiority in OS and PFS persisted in multivariable models. Among 61 pretreated patients receiving MMT, 37.5% of patients had PFS2/PFS1 ratio ≥1.3. Patients with higher actionable targets (ESCAT tier I) had better OS (p = 0.001) and PFS (p = 0.049), while no difference was observed in lower evidence levels. CONCLUSIONS: Our experience shows that MTBs can yield valuable clinical benefit. Higher actionability ESCAT level appears to be associated with better outcomes for patients receiving MMT.

Clinicopathological features and survival outcomes of luminal-like breast tumors with estrogen receptor loss at metastatic recurrence: A case-control study.

INTRODUCTION: Estrogen receptor (ER) loss at metastatic relapse occurs in up to 20% of luminal-like primary breast tumors. Data about clinicopathological features associated with ER loss and its prognostic significance are limited. METHODS: In a nested-case-control study, we compared clinicopathological characteristics and clinical outcomes between a cohort of 51 patients with primary ER+ /HER2- and paired triple-negative metastasis (LUM-TN) and two control cohorts of paired early-metastatic ER+ /HER2- (LUM-LUM, n = 50) and triple-negative (TN-TN, n = 49) breast cancers. Stromal tumor-infiltrating lymphocytes (TILs) were assessed according to the TILs Working Group recommendations as continuous and discrete variables with cutoffs (20%, 40%). RESULTS: LUM-TN tumors had lower ER expression than LUM-LUM tumors, but lower grade and Ki67 than TN-TN cases. Median distant-metastasis free survival was similar for LUM-TN and LUM-LUM cohorts, but significantly longer than in TN-TN cases (log-rank P < 0.001). LUM-TN and TN-TN cohorts had a comparable survival from the time of metastatic recurrence, which was significantly shorter than in patients with LUM-LUM tumors (log-rank P < 0.001). High TILs were associated with worse outcomes in patients with ER loss (P < 0.001). CONCLUSIONS: Breast tumors with ER loss at metastatic relapse have intermediate features and outcomes compared with metastatic luminal-like and ab initio triple-negative tumors. Further investigation on the biological mechanisms underpinning the loss of ER expression is ongoing.

Investigational immunomodulatory drugs for enhancement of triple negative breast cancer (TNBC) immunotherapy: early phase development.

INTRODUCTION: Immunotherapy through the blockade of PD1-PDL1 axis has shown to improve outcomes in advanced and early triple negative breast cancer (TNBC). To further enhance immune-stimulation, and ultimately improve patient outcomes, a wide variety of next-generation immunotherapies (NGIO) is being developed for this disease. AREAS COVERED: In the present article, we discuss the immune landscape of TNBC and recapitulate the rationale and available clinical evidence of NGIO under early phase development for TNBC, highlighting challenges and opportunities in this emerging field of research. EXPERT OPINION: Multiple immunotherapeutic strategies beyond PD-(L)1 blockade have been tested for TNBC, including the targeting of further inhibitory checkpoints, the agonism of costimulatory molecules, the intratumoral administration of immunotherapies and cancer vaccines. Most of these strategies have demonstrated to be safe in early clinical trials, with some exhibiting early signs of antitumor activity. To optimally harness the potential of NGIO, a refined patient selection based on emerging immune biomarkers will be required, through an adaptation of immunotherapeutic strategies based on patient and tumor characteristics. More mature data from ongoing clinical trials, added to the progressively increasing knowledge on breast cancer immune landscape, will hopefully clarify the role of NGIO for the treatment of TNBC.

PIK3CAMutations in Breast Cancer Subtypes Other Than HR-Positive/HER2-Negative.

The phosphoinositide 3-kinase (PI3K) pathway plays a key role in cancer, influencing growth, proliferation, and survival of tumor cells. PIK3CA mutations are generally oncogenic and responsible for uncontrolled cellular growth. PI3K inhibitors (PI3Ki) can inhibit the PI3K/AKT/mTOR pathway, although burdened by not easily manageable toxicity. Among PI3Ki, alpelisib, a selective p110α inhibitor, is approved for the treatment of hormone receptor (HR)+/HER2- PIK3CA mutant metastatic breast cancer (BC) that has progressed to a first line endocrine therapy. PIK3CA mutations are also present in triple negative BC (TNBC) and HER2+ BC, although the role of PI3K inhibition is not well established in these subtypes. In this review, we go through the PI3K/AKT/mTOR pathway, describing most common mutations found in PI3K genes and how they can be detected. We describe the available biological and clinical evidence of PIK3CA mutations in breast cancers other than HR+/HER2-, summarizing clinical trials investigating PI3Ki in these subtypes.

Loss of HER2 in breast cancer: biological mechanisms and technical pitfalls.

Loss of HER2 in previously HER2-positive breast tumors is not rare, occurring in up to 50% of breast cancers; however, clinical research and practice underestimate this issue. Many studies have reported the loss of HER2 after neoadjuvant therapy and at metastatic relapse and identified clinicopathological variables more frequently associated with this event. Nevertheless, the biological mechanisms underlying HER2 loss are still poorly understood. HER2 downregulation, intratumoral heterogeneity, clonal selection, and true subtype switch have been suggested as potential causes of HER2 loss, but translational studies specifically investigating the biology behind HER2 loss are virtually absent. On the other side, technical pitfalls may justify HER2 loss in some of these samples. The best treatment strategy for patients with HER2 loss is currently unknown. Considering the prevalence of this phenomenon and its apparent correlation with worse outcomes, we believe that correlative studies specifically addressing HER2 loss are warranted.

Challenges and Obstacles in Applying Therapeutical Indications Formulated in Molecular Tumor Boards.

Considering the rapid improvement of cancer drugs' efficacy and the discovery of new molecular targets, the formulation of therapeutical indications based on the multidisciplinary approach of MTB is becoming increasingly important for attributing the correct salience to the targets identified in a single patient. Nevertheless, one of the biggest stumbling blocks faced by MTBs is not the bare indication, but its implementation in the clinical practice. Indeed, administering the drug suggested by MTB deals with some relevant difficulties: the economical affordability and geographical accessibility represent some of the major limits in the patient's view, while bureaucracy and regulatory procedures are often a disincentive for the physicians. In this review, we explore the current literature reporting MTB experiences and precision medicine clinical trials, focusing on the challenges that authors face in applying their therapeutical indications. Furthermore, we analyze and discuss some of the solutions devised to overcome these difficulties to support the MTBs in finding the most suitable solution for their specific situation. In conclusion, we strongly encourage regulatory agencies and pharmaceutical companies to develop effective strategies with medical centers implementing MTBs to facilitate access to innovative drugs and thereby allow broader therapeutical opportunities to patients.

Combining antibody-drug conjugates with immunotherapy in solid tumors: current landscape and future perspectives.

Antibody-drug conjugates (ADCs) and immunotherapy have prompted a revolution in the treatment of cancer. However, only a limited fraction of patients obtained a long-term benefit; consequently, combination studies have become a central focus of the current preclinical and clinical research in oncology. A strong biological rationale supports the investigation of combining ADCs with immunotherapy to overcome the occurrence of resistance and improve patient outcomes. ADCs interact with cancer and immune cells by eliciting mechanisms such as immunogenic cell death, antibody-dependent cell-mediated cytotoxicity and dendritic cell activation, ultimately providing potential synergism with immunotherapy. Indeed, ADCs induce tumor-specific adaptive immunity, increasing the infiltration of T cells into the tumor microenvironment, whereas immune-checkpoint inhibitors reinvigorate exhausted T cells, enhancing antitumor immune responses. In light of the promising preclinical data, several clinical trials are currently underway in multiple tumor types to evaluate the safety and activity of combination regimens. Initial evidence from early phase clinical trials has already reported encouraging signals. This review focuses on the combination of ADCs and immunotherapy, highlighting the key mechanisms underlying the synergistic effect and providing an overview of the available clinical evidence in solid tumors. In addition, opportunities to optimize the combination are explored, such as defining the optimal dose, balancing the risks and benefits of dose modifications, and the possibility of developing novel immunoconjugates.