Incorporating weekly carboplatin in anthracycline and paclitaxel-containing neoadjuvant chemotherapy for triple-negative breast cancer: propensity-score matching analysis and TIL evaluation.

BACKGROUND: The generation of data capturing the risk-benefit ratio of incorporating carboplatin (Cb) to neoadjuvant chemotherapy (NACT) for triple-negative breast cancer (TNBC) in a clinical practice setting is urgently needed. Tumour-infiltrating lymphocytes (TILs) have an established role in TNBC receiving NACT, however, the role of TIL dynamics under NACT exposure in patients receiving the current standard of care is largely uncharted. METHODS: Consecutive TNBC patients receiving anthracycline-taxane [A-T] +/- Cb NACT at three Institutions were enrolled. Stromal-TILs were evaluated on pre-NACT and residual disease (RD) specimens. In the clinical cohort, propensity-score-matching was used to control selection bias. RESULTS: In total, 247 patients were included (A-T = 40.5%, A-TCb = 59.5%). After propensity-score-matching, pCR was significantly higher for A-TCb vs A-T (51.9% vs 34.2%, multivariate: OR = 2.40, P = 0.01). No differences in grade ≥3 haematological toxicities were observed. TILs increased from baseline to RD in the overall population and across A-T/A-TCb subgroups. TIL increase from baseline to RD was positively and independently associated with distant disease-free survival (multivariate: HR = 0.43, P = 0.05). CONCLUSIONS: We confirmed in a clinical practice setting of TNBC patients receiving A-T NACT that the incorporation of weekly Cb significantly improved pCR. In addition, A-T +/- Cb enhanced immune infiltration from baseline to RD. Finally, we reported a positive independent prognostic role of TIL increase after NACT exposure.

Epidemiology trends and progress in breast cancer survival: earlier diagnosis, new therapeutics.

PURPOSE OF REVIEW: In this review we will critically appraise the latest evidence on breast cancer (BC) survival trends and discuss how these may reflect breakthroughs in early diagnosis and treatment approaches. We will address the wide global inequalities in BC survival and review the ongoing initiatives aimed at improving cancer control worldwide. RECENT FINDINGS: BC outcomes have improved in high-income countries during the last decades, following the implementation of strategies for early detection and optimal multimodality treatment. Novel therapeutics, such as anti-HER2 targeted treatments, have also contributed to the progress in BC survival. However, BC mortality is still high in low-income countries, due to the lack of optimal healthcare infrastructures. In the context of marked inequities in BC management across world regions, international collaborations such as the Global Breast Cancer Initiative and the Global Initiative for Cancer Registry Development work to foster capacity-building in developing countries, tackle the burden of BC and deliver the Sustainable Development Goals by 2030. SUMMARY: Collection of robust, high-quality data from population-based cancer registries is crucial to drive and refine public health interventions. Population-based data are also the litmus paper to evaluate the real-world impact of clinical advances and monitor progress.

To Transplant or Not to Transplant During the SARS-CoV-2 Pandemic? That Is the Question.

The novel coronavirus disease 2019 has grown to be a global public health emergency. The rapid spread of the infection has raised many questions in the oncohematological scientific community regarding the appropriateness of high-dose chemotherapy with autologous stem cell transplantation (ASCT). We here report two cases of patients who received ASCT at our Institute during the epidemic in Italy, affected with Hodgkin lymphoma and germ cell tumor, respectively. The two patients underwent a nasopharyngeal swab for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on hospital admittance and during the period of bone marrow aplasia. They were attended to exclusively by dedicated health care staff who followed specifically implemented protocols for bedside nursing and care. They completed the procedure without unexpected side effect. Our experience demonstrates how ASCT can be performed safely if procedures are reorganized ad hoc to reduce the risk of SARS-CoV-2 infection.

Circulating tumor DNA validity and potential uses in metastatic breast cancer.

Following the first characterization of circulating tumor DNA (ctDNA) in the 1990s, recent advances led to its introduction in the clinics. At present, the European Society Of Medical Oncology (ESMO) recommendations endorse ctDNA testing in routine clinical practice for tumor genotyping to direct molecularly targeted therapies in patients with metastatic cancer. In studies on metastatic breast cancer, ctDNA has been utilized for treatment tailoring, tracking mechanisms of drug resistance, and for predicting disease response before imaging. We review the available evidence regarding ctDNA applications in metastatic breast cancer.

PIK3CA copy-number gain and inhibitors of the PI3K/AKT/mTOR pathway in triple-negative breast cancer.

As wider insights are gained on the molecular landscape of triple-negative breast cancer (TNBC), novel targeted therapeutic strategies might become an option in this setting as well. Activating mutations of PIK3CA represent the second most common alteration in TNBC after the TP53 mutation, with a prevalence of ∼10%-15%. Considering the well-established predictive role of PIK3CA mutations for response to agents targeting the PI3K/AKT/mTOR pathway, several clinical trials are currently evaluating these drugs in patients with advanced TNBC. However, much less is known regarding the actionability of PIK3CA copy-number gains, which represent a thoroughly common molecular alteration in TNBC, with a prevalence estimated at 6%-20%, and are listed as "likely gain-of-function" alterations in the OncoKB database. In the present paper, we describe two clinical cases in which patients harboring PIK3CA-amplified TNBC received a targeted treatment with the mTOR-inhibitor everolimus and the PI3K-inhibitor alpelisib, respectively, with evidence of disease response on 18F-FDG positron-emission tomography (PET) imaging. Hence, we discuss the evidence presently available regarding a possible predictive value of PIK3CA amplification for response to targeted treatment strategies, suggesting that this molecular alteration might represent an intriguing biomarker in this sense. Considering that few of the currently active clinical trials assessing agents targeting the PI3K/AKT/mTOR pathway in TNBC select patients based on tumor molecular characterization, and none of these based on PIK3CA copy-number status, we urge for the introduction of PIK3CA amplification as a criterion for patient selection in future clinical trials in this setting.

PI3K/PTEN/mTOR pathway dynamic tracking and prognostic value in HR+/HER2- BC patients with residual disease after neoadjuvant chemotherapy: a cohort study.

AIMS: Hormone receptor-positive (HR)+/HER2- breast cancer (BC) is highly heterogeneous, with PI3K/PTEN/mTOR pathway alterations emerging as possible players within this complexity. We longitudinally tracked PI3K/PTEN/mTOR pathway dynamics from baseline biopsy to residual disease (RD)-and to metastases in case of relapse-in HR+/HER2- BC patients receiving neoadjuvant chemotherapy (NACT). METHODS: HR+/HER2- BC patients with RD after NACT were identified. We assessed PIK3CA mutational, Pten-loss and phosphorylation levels of mTOR and its substrates (p70S6K and 4EBP1) on baseline biopsies and matched RD samples; in case of disease relapse, we also assessed PIK3CA mutational status on metastatic samples. Recurrence-free survival (RFS) was adopted as endpoint. RESULTS: 92 patient were included. The conversion rate of PIK3CA mutational status was 12.8%; 1 patient acquired PIK3CA mutation at relapse; the rate of Pten conversion was 33.3%; mTOR phosphorylation levels significantly increased from baseline biopsy to RD, while its substrates significantly decreased. Baseline phosphorylated-mTOR significantly predicted poorer RFS in patients with PIK3CA wild-type status; baseline phosphorylated-70S6K was positively associated with RFS. CONCLUSIONS: We observed that PI3K/PTEN/mTOR pathway is highly dynamic under NACT exposure and the assessment of PIK3CA mutations may capture only a small fraction of such complexity. In this context, mTOR activation trough alternative pathways with respect to PIK3CA signalling may have a crucial role in shaping the molecular landscape of HR+/HER2- BC with RD after NACT. It is imperative to further elucidate the role of PIK3CA and mTOR-dependent pathways in shaping chemoresistance and endocrine resistance in high-risk HR+/HER2- early/locally advanced BC patients.

Association of body mass index with clinicopathological features and survival in patients with primary invasive lobular breast cancer.

PURPOSE: Invasive lobular carcinoma (ILC) represents up to 15% of all breast carcinomas. While the proportion of women with overweight and obesity increases globally, the impact of body mass index (BMI) at primary diagnosis on clinicopathological features of ILC and the prognosis of the patients has not been investigated yet. PATIENTS AND METHODS: We performed a multicentric retrospective study including patients diagnosed with non-metastatic pure ILC. The association of BMI at diagnosis with clinicopathological variables was assessed using linear or multinomial logistic regression. Univariable and multivariable survival analyses were performed to evaluate the association of BMI with disease-free survival (DFS), distant recurrence-free survival (DRFS), and overall survival (OS). RESULTS: The data of 2856 patients with ILC and available BMI at diagnosis were collected, of which 2570/2856 (90.0%) had oestrogen receptor (ER)-positive and human epidermal growth factor receptor (HER2) not amplified/overexpressed (ER+/HER2-) ILC. Of these 2570 patients, 80 were underweight (3.1%), 1410 were lean (54.9%), 712 were overweight (27.7%), and 368 were obese (14.3%). Older age at diagnosis, a higher tumour grade, a larger tumour size, a nodal involvement, and multifocality were associated with a higher BMI. In univariable models, higher BMI was associated with worse outcomes for all end-points (DFS: hazard ratio (HR) 1.21, 95CI 1.12-1.31, p value<0.01; DRFS: HR 1.25, 95CI 1.12-1.40, p value<0.01; OS: HR 1.25, 95CI 1.13-1.37, p value<0.01). This association was not statistically significant in multivariable analyses (DFS: HR 1.09, 95CI 0.99-1.20, p value 0.08; DRFS: HR 1.03, 95CI 0.89-1.20, p value 0.67; OS: HR 1.11, 95CI 0.99-1.24, p value 0.08), whereas grade, tumour size, and nodal involvement were still prognostic for all end-points. CONCLUSION: Worse prognostic factors such as higher grade, larger tumour size, and nodal involvement are associated with higher BMI in ER+/HER2- ILC, while there was no statistical evidence for an independent prognostic role for BMI. Therefore, we hypothesise that the effect of BMI on survival could be mediated through its association with these clinicopathological variables.

HER2-low-positive breast cancer: evolution from primary tumor to residual disease after neoadjuvant treatment.

Approximately a half of breast tumors classified as HER2-negative exhibit HER2-low-positive expression. We recently described a high instability of HER2-low-positive expression from primary breast cancer (BC) to relapse. Previous studies reporting discordance in HER2 status between baseline biopsy and residual disease (RD) in patients undergoing neoadjuvant treatment did not include the HER2-low-positive category. The aim of this study is to track the evolution of HER2-low-positive expression from primary BC to RD after neoadjuvant treatment. Patients undergoing neoadjuvant treatment with available baseline tumor tissue and matched samples of RD (in case of no pCR) were included. HER2-negative cases were sub-classified as HER2-0 or HER2-low-positive (IHC 1+ or 2+ and ISH negative). Four-hundred forty-six patients were included. Primary BC phenotype was: HR-positive/HER2-negative 23.5%, triple-negative (TN) 35%, HER2-positive 41.5%. HER2-low-positive cases were 55.6% of the HER2-negative cohort and were significantly enriched in the HR-positive/HER2-negative vs. TN subgroup (68.6% vs. 46.8%, p = 0.001 χ2 test). In all, 35.3% of non-pCR patients (n = 291) had a HER2-low-positive expression on RD. The overall rate of HER2 expression discordance was 26.4%, mostly driven by HER2-negative cases converting either from (14.8%) or to (8.9%) HER2-low-positive phenotype. Among HR-positive/HER2-negative patients with HER2-low-positive expression on RD, 32.0% and 57.1% had an estimated high risk of relapse according to the residual proliferative cancer burden and CPS-EG score, respectively. In conclusion, HER2-low-positive expression showed high instability from primary BC to RD after neoadjuvant treatment. HER2-low-positive expression on RD may guide personalized adjuvant treatment for high-risk patients in the context of clinical trials with novel anti-HER2 antibody-drug conjugates.

Evolution of HER2-low expression from primary to recurrent breast cancer.

About a half of HER2-negative breast cancer (BC) show HER2-low expression that can be targeted by new antibody-drug conjugates. The main aim of this study is to describe the evolution of HER2 expression from primary BC to relapse by including HER2-low category in both primary and recurrent BC samples. Patients with matched primary and relapse BC samples were included. HER2 was evaluated according to ASCO/CAP recommendations in place at the time of diagnosis. A cutoff of >10% cells staining for HER2-positivity was applied. HER2-negative cases were sub-classified as HER2-low (IHC = 1 + /2+ and ISH not amplified), or HER2-0 (IHC-0). 547 patients were included. The proportion of HER2-low cases was 34.2% on the primary tumor and 37.3% on the relapse samples. Among HER2-negative cases, HER2-low status was more frequent in HR-positive vs triple-negative tumors (47.3% vs 35.4% on primary tumor samples, 53.8% vs 36.2% on relapse samples). The overall rate of HER2 discordance was 38.0%, mostly represented by HER2-0 switching to HER2-low (15%) and HER2-low switching to HER2-0 (14%). Among patients with a primary HER2-negative tumor, the rate of HER2 discordance was higher in HR-positive/HER2-negative vs triple-negative cases (45.5% vs 36.7% p = 0.170). This difference was mostly driven by cases switching from HER2-0 to HER2-low. HER2-low expression is highly unstable during disease evolution. Relapse biopsy in case of a primary HER2-0 tumor may open new therapeutic opportunities in a relevant proportion of patients.

Exertional rhabdomyolysis leading to acute kidney injury: when genetic defects are diagnosed in adult life.

Rhabdomyolysis is a common cause of acute kidney injury (AKI) that is usually triggered by trauma. However, less common causes of rhabdomyolysis may precipitate AKI as well, possibly representing a diagnostic challenge even for the experienced nephrologist. Genetic defects of muscle metabolism represent one of these causes and can be overlooked in adults, since these diseases usually become apparent in childhood. We present here a case in which an adult patient with severe exertional rhabdomyolysis leading to AKI was finally diagnosed with a genetic defect of lipid metabolism. A 41-year-old patient was brought to our attention because of AKI and pigmenturia after strenuous physical effort. At admission, the patient was over-hydrated with a weight increase of 3 kg in few days. Laboratory examination showed creatinine of 8.7 mg/dl, along with increased myoglobin and CPK. Urinalysis was positive for haemoglobin and proteins, while urinary sediment analysis did not demonstrate any red blood cell but rather "muddy-brown" casts and tubular cells. Urine output was forced and the patient completely recovered renal function. Genetic analysis later demonstrated the presence of a common mutation of Carnitine Palmitoyl-Transferase II (CPTII). When facing rhabdomyolysis of obscure origin, nephrologists must keep in mind the possibility that even adult patients may have a genetic defect of energy metabolism. In these cases, patients usually experience rhabdomyolysis during exertion, fasting, or infection. CPTII deficiency often has a subtle presentation and might be unrecognized until AKI develops. Therefore, it is important to consider a genetic defect of muscle metabolism even in adult patients when a history of rhabdomyolysis of unclear origin is present.