Sex and Gender Influences on Cancer Immunotherapy Response

The global burden of cancer is growing and a wide disparity in the incidence, malignancy and mortality of different types of cancer between each sex has been demonstrated. The sex specificity of cancer appears to be a relevant issue in the management of the disease, and studies investigating the role of sex and gender are becoming extremely urgent. Sex hormones are presumably the leading actors of sex differences in cancer, especially estrogens. They modulate gene expression, alter molecules and generate disparities in effectiveness and side effects of anticancer therapies. Recently immunotherapy aims to improve anticancer treatment strategies reducing off-target effects of chemotherapy and direct cancer cells killing. It is recognized as a fruitful strategy to treat and possible to cure cancer. Immunotherapeutic agents are used to activate or boost the activation of the immune system to fight cancer cells through physiological mechanisms often evaded in the offensive march of the disease. These therapeutic strategies have allowed new successes, but also have serious adverse effects including non-specific inflammation and autoimmunity. Sex and gender issues are of primary importance in this field, due to their recognized role in inflammation, immunity and cancer, and the clarification and understanding of these aspects is a necessary step to increase the responses and to diminish the adverse effects of immunotherapy. This review describes the available knowledge on the role of sex and gender in cancer immunotherapy, and will offer insights to stimulate the attention and practice of clinicians and researchers in a gender perspective of new cancer treatment strategies

Safe Administration of Ipilimumab, Pembrolizumab, and Nivolumab in a Patient with Metastatic Melanoma, Psoriasis, and a Previous Guillain–Barré Syndrome

Background. Patients with autoimmune diseases were not evaluated in clinical trials with immune checkpoint inhibitors (ICIs), since a history of immune disorders, such as Guillain–Barré syndrome (GBS) and psoriasis, is one of the major risk factors for the development of immune-related adverse events (irAEs). This risk cannot be defined; therefore, physicians are called to manage these patients in clinical practice. Case Report. We report the case of a 62-year-old male patient affected by metastatic melanoma, with a history of GBS and psoriasis, and treated with sequential ipilimumab, pembrolizumab, and nivolumab, without significant toxicities. Conclusion. This case report supports that although a history of immune disorders is one of the major risk factors for development of irAEs, in some patients, it could be possible to safely administer sequential treatments with ICIs. A proper decision should be made, considering therapeutic options, disease-related risks, and those related to a recurrence of preexisting autoimmune disorders

Invasive Ductal Breast Cancer with Osteoclast-Like Giant Cells: A Case Report Based on the Gene Expression Profile for Changes in Management

We report the case of a 49-year-old woman diagnosed with a rare histotype of early breast cancer (BC), invasive ductal carcinoma with osteoclast-like giant cells (OGCs), from the perspective of gene profile analysis tests. The patient underwent a quadrantectomy of the right breast with removal of 2 cm neoplastic nodule and three ipsilateral sentinel lymph nodes. The Oncotype Dx gave a recurrence score (RS) of 23, and taking into account the patient’s age, an RS of 23 corresponds to a chemotherapy benefit of 6.5%. After a multidisciplinary collegial discussion, and in consideration of the patient’s age, the absence of comorbidity, the premenopausal state, the rare histotype and the Oncotype Dx report, the patient was offered adjuvant chemotherapy treatment followed by hormone therapy. This case may be an example of the utility of integrating gene expression profiling tests into clinical practice in the adjuvant treatment decision of a rare histotype BC. The Oncotype Dx test required to supplement the histological examination made us opt for the proposal of a combined treatment of adjuvant chemotherapy followed by adjuvant hormone therapy. It demonstrates the importance of considering molecular tests and, in particular, the Oncotype Dx, in estimating the risk of disease recovery at 10 years in order to identify patients who benefit from hormone therapy alone versus those who benefit from the addition of chemotherapy, all with a view toward patient-centered oncology. Here, we discuss the possible validity and limitations of the Oncotype Dx in a rare luminal A-like histotype with high infiltrate of stromal/inflammatory cells

Anthracycline-Free Neoadjuvant Treatment in Patients with HER2-Positive Breast Cancer: Real-Life Use of Pertuzumab, Trastuzumab and Taxanes Association with an Exploratory Analysis of PIK3CA Mutational Status

HER2 is considered one of the most traditional prognostic and predictive biomarkers in breast cancer. Literature data confirmed that the addition of pertuzumab to a standard neoadjuvant chemotherapy backbone (either with or without anthracyclines), in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC), leads to a higher pathological complete response (pCR) rate, which is known to correlate with a better prognosis. In this retrospective analysis, 47 consecutive patients with HER2-positive EBC received sequential anthracyclines and taxanes plus trastuzumab (ATH) or pertuzumab, trastuzumab and docetaxel (THP). Despite the limited sample size, this monocentric experience highlights the efficacy (in terms of pCR) and safety of THP in the neoadjuvant setting of HER2-positive EBC as an anthracycline-free approach. Given the role of PIK3CA as a prognostic and therapeutic target in breast cancer, tumors were also analyzed to assess the PIK3CA mutational status. Thirty-eight out of forty-seven patients were evaluated, and PIK3CA variants were identified in 21% of tumor samples: overall, one mutation was detected in exon 4 (2.6%), two in exon 9 (5.3%) and four in exon 20 (10.5%). Of note, one sample showed concurrent mutations in exons 9 (codon 545) and 20 (codon 1047). Among patients reaching pCR (n = 13), 38.5% were PIK3CA mutants; on the other hand, among those lacking pCR (n = 25), just 12% showed PIK3CA variants. Regarding THP-treated mutant patients (n = 5), 80% reached pCR (three hormone-receptor-negative, one hormone-receptor-positive). Interestingly, the only patient not achieving pCR had a tumor with two co-occurring PIK3CA mutations. In conclusion, this study provides new evidence about the efficacy and good safety profile of THP, compared to the ATH regimen, as an anthracycline-free neoadjuvant treatment of HER2-positive EBC. Further studies on larger/multicentric cohorts are planned for more in-depth analysis to confirm our molecular and clinical results