Frequency of Radiation Therapy-Induced Malignancies in Patients With Li-Fraumeni Syndrome and Early-Stage Breast Cancer and the Influence of Radiation Therapy Technique.

PURPOSE: Breast cancer (BC) is the most common malignancy in female patients with Li-Fraumeni syndrome (LFS), a condition associated with an increased risk of various malignancies, including radiation therapy (RT)-induced malignancies (RIM) within previously irradiated areas. Our study aimed to assess the incidence of RIM in patients with LFS and early-stage BC treated with adjuvant RT, including the effect of RT dose and technique. METHODS AND MATERIALS: We examined patients with a germline pathogenic/likely pathogenic TP53 variant diagnosed with early-stage BC and monitored by a hereditary cancer team at a single cancer center. The study endpoints included RIM frequency, the association of RIM with the dose and type of RT (2-dimensional [2D] RT, 3-dimensional [3D] RT, and intensity modulated RT [IMRT]), and BC recurrence. RESULTS: We analyzed 48 patients with a median age of 39 years (range, 21-62). The majority (71%) had the TP53 R337H variant, and 87% were unaware of their LFS diagnosis at the time of BC treatment. Treatment modalities included mastectomy (62%), (neo)adjuvant chemotherapy (66%), and RT (62%), with RT being more common after breast-conserving surgery (87% vs 46% with mastectomy, P = .010). Among the 30 patients treated with RT, 10% developed RIM in the irradiated field, consisting of 3 soft tissue malignancies. RT dose (≤40.8 or >40.8 Gy) did not influence RIM occurrence, but the type of RT did. RIM was observed in 100% of cases with 2D RT (2/2), 50% with IMRT (1/2), and 0% with 3D RT (0/16) (P = .004). CONCLUSIONS: Our study underscores a concerning rate of RIM after adjuvant RT, emphasizing the importance of a thorough risk-benefit evaluation before recommending RT, with preference for its avoidance if possible. Although subgroup sizes were limited, the risk of RIM appeared to be influenced by the RT technique, with higher rates observed with 2D RT and IMRT compared with 3D RT. Early TP53 testing is essential to guide the BC treatment plan.

Borderline ovarian tumors: a review of its biology, molecular profile, and management / Tumores borderline de ovário: uma revisão de sua biologia, perfil molecular e manejo

Borderline ovarian tumors typically exhibit indolent behavior and boast a favorable prognosis; however, a subset of patients experiences disease recurrence and progression to low-grade ovarian carcinoma. The complex biology underlying these phenomena has been illuminated through molecular analyses. KRAS and BRAF mutations have emerged as recurrent ?ndings in borderline ovarian tumors. Speci?cally, KRAS mutations have been linked to a higher risk of recurrence and progression to low-grade ovarian carcinoma, while BRAF mutations seem to confer a protective e?ect, inducing a senescent state that mitigates the likelihood of progression. In this comprehensive review, we explore the biology and the molecular pro?le of borderline ovarian tumors, shedding light on recent discoveries that have enriched our comprehension. Additionally, we discuss the current state of borderline ovarian tumors management. Surgery remains the cornerstone of treatment. While cytotoxic therapies role is limited so far, molecular characterization emphasizes the imminent potential for personalized therapeutic approaches.

Os tumores borderline de ovário geralmente exibem comportamento indolente e apresentam prognóstico favorável; no entanto, um subconjunto de pacientes apresenta recorrência da doença e progressão para carcinoma de ovário de baixo grau. A biologia complexa subjacente a estes fenômenos foi iluminada através de análises moleculares. Mutações KRAS e BRAF surgiram como achados recorrentes em tumores borderline de ovário. Especificamente, as mutações KRAS têm sido associadas a um maior risco de recorrência e progressão para carcinoma de ovário de baixo grau, enquanto as mutações BRAF parecem conferir um efeito protetor, induzindo um estado senescente que mitiga a probabilidade de progressão. Nesta revisão abrangente, exploramos a biologia e o perfil molecular dos tumores borderline de ovário, lançando luz sobre descobertas recentes que enriqueceram nossa compreensão. Além disso, discutimos o estado atual do manejo de tumores borderline de ovário. A cirurgia continua sendo o pilar de tratamento. Embora o papel das terapias citotóxicas seja limitado até o momento, a caracterização molecular enfatiza o potencial iminente para abordagens terapêuticas personalizadas.

Long-term outcomes of neoadjuvant immunotherapy plus chemotherapy in patients with early-stage triple-negative breast cancer: an extracted individual patient data and trial-level meta-analysis.

BACKGROUND: Neoadjuvant immunotherapy (nIO) has emerged as a treatment option for stage II-III triple-negative breast cancer (TNBC). While randomised clinical trials (RCTs) demonstrated pathological complete response rate benefit to nIO added to chemotherapy, additional data on long-term outcomes is warranted. We performed this analysis to evaluate long-term efficacy outcomes of nIO in TNBC. METHODS: We searched databases for RCTs evaluating nIO in early-stage TNBC. A meta-analysis of extracted individual patient data (EIPD) was performed to evaluate EFS and OS, with data from reported Kaplan-Meier plots. Additionally, we conducted a trial-level meta-analysis using fixed and random effects models. RESULTS: The literature search resulted in four included RCTs with available EFS or OS (KEYNOTE-522, IMpassion031, I-SPY2 and GeparNuevo). EIPD showed that the addition of nIO to chemotherapy provides statistically significant benefits in EFS (HR 0.62, 0.50-0.76; p < 0.001) and OS (HR 0.62, 0.46-0.82, p < 0.001). Number needed to treat to avoid one EFS or OS event in 4 years was 9 and 14, respectively. Trial-level meta-analysis yielded similar results (EFS: HR 0.64, 0.51-0.79; OS: 0.57, 0.37-0.89). CONCLUSIONS: Results show that nIO combined with chemotherapy can provide significant EFS and OS benefits, supporting its use as standard treatment for early-stage TNBC.

A matched case-control study of the prognosis of early breast cancer in patients with Li-Fraumeni syndrome (BREAST TP53).

INTRODUCTION: Breast cancer (BC) is the most common type of cancer in premenopausal women with germline TP53 pathogenic variants (mTP53) (Li Fraumeni syndrome - LFS). However, little is known about the BC prognosis in these patients. This study analyzed the BC-related oncologic outcomes of patients with LFS. METHODS: We evaluated a cohort of LFS patients with BC in comparison with a control cohort of BC patients with no pathogenic variant in a hereditary cancer panel. The primary endpoint was recurrence-free survival (RFS). Due to the risk of second malignancies in LFS, only locoregional and distant recurrences were considered events for RFS. Secondary endpoints included rates of contralateral BC, overall survival (OS), and breast cancer-specific survival (BCSS). RESULTS: Forty-one patients were evaluated in the mTP53 group and 82 in the control group. Median age at BC diagnosis was 40 and 41 years, respectively. The mTP53 group received less adjuvant radiotherapy than the control group (63.4% vs 93.9%, P < 0.001). Other relevant baseline characteristics and treatment received were similar between groups. 5y-RFS rates were 79.4% in the mTP53 versus 93.6% in the control group (HR 2.43, 95%CI 0.74-8.01, P = 0.143); and were not impacted by the use of adjuvant radiotherapy. 5y-BCSS rates were 92.2% and 98.6%, respectively (HR 1.87, IC95% 0.25-13.48, P = 0.534). CONCLUSIONS: Our results showed no statistically significant difference in BC-related RFS and BCSS between patients with mTP53 and a control group with no pathogenic variant. Larger multicentric studies are warranted to confirm these results.

Activity of capecitabine for central nervous system metastases from breast cancer.

Purpose: Central nervous system (CNS) metastases are a significant burden in breast cancer (BC). Capecitabine is a frequent choice in this scenario, but data supporting its single-agent activity are scarce. We aimed to evaluate the intracranial efficacy of capecitabine in CNS metastases from BC. Methods: This retrospective cohort included patients with CNS metastases from BC treated with capecitabine at a single centre. Study endpoints were intracranial CNS objective response rate (CNS-ORR), intracranial CNS disease control rate (CNS-DCR), intracranial CNS progression-free survival (CNS-PFS) and overall survival (OS). Results: 209 patients were included; 41.6% hormone receptor-positive HER2-negative (HR + HER2-), 33.9% human epidermal growth factor receptor 2 positive (HER2+), and 26.4% triple-negative breast cancer (TNBC). Radiotherapy was performed in 90.4% and CNS surgery in 27.5%. Among patients accessible for intracranial response, 3-month CNS-ORR and CNS-DCR were 41.6% and 81.2%. CNS-ORR was numerically higher among TNBC (61% versus 38% in HR + HER2-BC and 35% in HER2 + BC) (p = 0.194). When considering patients who were not evaluable at 3-month as non-responders, the 3-month CNS-ORR was 19.1% (18.4% in HR + HER2-, 18.3% in HER2+, and 21.6% in TNBC). Nevertheless, TNBC was associated with lower CNS-PFS (p < 0.001) and OS (p < 0.001). Median PFS was 8.3 months in HR + HER2-, 5.0 months in HER2+, and 3.0 months in TNBC. Median OS was 8.7, 9.1 and 4.5 months, respectively. Conclusion: Among patients with BC and CNS metastases accessible for intracranial response at 3 months, intracranial activity was observed with capecitabine. These patients have a poor prognosis regardless of the BC subtype, especially in scenarios where newer therapeutic options are unavailable.

Disease Behavior and Treatment Response of Special Histological Types of Triple-Negative Breast Cancer.

BACKGROUND: Special histological types (SHT) of triple-negative breast cancer (TNBC) are a heterogeneous group of rare poorly understood diseases. We aimed to evaluate the clinical features, treatment, and outcomes of patients with SHT of TNBC. METHODS: We evaluated patients with a SHT of TNBC treated in a cancer center between 2009 and 2020. The endpoints were characterization of clinical and pathological features, pathologic complete response (PCR) rate after neoadjuvant chemotherapy, disease-free survival (DFS), progression-free survival, and overall survival (OS). RESULTS: The 132 patients included had the following histologies: metaplastic (n=71), medullary pattern (n=14), lobular (n=12), adenoid cystic (n=12), apocrine (n=10), and others (n=13). Metaplastic, lobular, and medullary pattern tumors had higher grade (66.6-85.7% grade 3); adenoid cystic and apocrine had mainly grade 1-2 (70-83.3%). Metaplastic and lobular carcinomas had higher disease stages (47.8% and 58.2% stages III-IV). PCR rates were 10.3% for metaplastic and 33.3% for lobular carcinomas, with 5-year DFS rates of 56% and 51.4%. Medullary pattern carcinomas had a great response to treatment, with PCR rate of 100%, and 5-year DFS rate of 92.8%. Apocrine carcinomas also had favorable prognosis, with no recurrence after early disease treatment, and 5-year DFS rate of 83.3%. Adenoid cystic carcinomas had intermediate prognosis, with 5-year DFS rate of 66.6%. CONCLUSION: SHT of TNBC encompasses heterogeneous malignancies with distinct behaviors. Lobular and metaplastic carcinomas showed high aggressiveness and poor treatment response, while medullary pattern and apocrine carcinomas had favorable outcomes. Treatment strategies focus on molecular features of each of these diseases are warranted.

Management of patients with early-stage triple-negative breast cancer following pembrolizumab-based neoadjuvant therapy: What are the evidences?

New therapy options have changed the treatment landscape of early-stage triple-negative breast cancer (TNBC) in recent years. Most patients are candidates for neoadjuvant chemotherapy, which helps to downstage the tumor and tailor adjuvant systemic therapy based on pathologic response. Capecitabine, pembrolizumab, and olaparib have been incorporated into the armamentarium of adjuvant treatment for selected patients. The KEYNOTE-522 trial, that demonstrated the benefit of pembrolizumab, given in addition to neoadjuvant chemotherapy and adjuvantly after surgery, represented a paradigm shift for early-stage TNBC treatment. Pembrolizumab was continued in the adjuvant setting irrespective of response to neoadjuvant therapy, and other adjuvant therapies were not administered in the trial. Many questions were then raised on the selection of adjuvant therapy regimens for patients with residual disease (RD). Prior to the routine use of immune-checkpoint inhibitors (ICI), the value of adjuvant capecitabine for patients with RD after neoadjuvant polychemotherapy was demonstrated. Given the poor prognosis of some patients with RD after neoadjuvant chemo-immunotherapy, while the survival advantage of adding capecitabine during the adjuvant phase of pembrolizumab is unknown, it does appear safe and can be considered. Regarding patients harboring germline BRCA mutations with RD after neoadjuvant ICI-containing regimens, the combination of olaparib with pembrolizumab can be an option based on existing safety data.

Breast cancer trends in women younger than 40 years in Brazil.

BACKGROUND: A recent Brazilian populational database analysis showed a concerning increase in breast cancer mortality rates among patients under 40 years. We aimed to evaluate the trends in the proportion of new breast cancer cases and deaths occurring in patients younger than 40 years over the last decade in Brazil. METHODS: We evaluated all consecutive breast cancer patients treated from 2009 to 2020 in a Brazilian tertiary cancer center. The proportions of new cases and deaths in patients younger than 40 years was compared between two time periods (2015-2020 versus 2009-2014) using Chi-squared test. Linear regression was used to evaluate the trends in the proportion of new cases and deaths in young patients over the years. RESULTS: From 2009 to 2020, a total of 12,569 breast cancer patients started treatment at our institution; 1441 were younger than 40 years. From 2009 to 2014, 9.9% (95% CI 9.2-10.7%) were patients younger than 40 years compared to 12.9% (95% CI 12.1-13.8%) from 2015 to 2020. Similarly, the proportion of deaths among breast cancer patients younger than 40 years increased during the period (2009-2014: 9.6%, 95% CI 7.8-11.6%; 2015-2020: 12.4%, 95% CI 10.9-14%). The linear regression model showed a trend for an increasing proportion of new breast cancer cases occurring in patients under 40 years (P = 0.005). Proportion increased from 7.9% (95% CI 6.2-9.8%) in 2009 to 21.8% (95% CI 19.1-24.8%) in 2020. The trend for the increase in the proportion of deaths in this young population was also observed in the linear regression model (P = 0.01). CONCLUSIONS: The proportion of new breast cancer cases and deaths among patients younger than 40 years has increased in a public Brazilian cancer center over the past decade. These results raise the concern for the need to reconsider primary and secondary prevention strategies for young women.

A Prospective Cohort Study of Biomarkers in Squamous Cell Carcinoma of the Anal Canal (SCCAC) and their Influence on Treatment Outcomes.

Background: Although Chemoradiation (CRT) is the curative treatment for SCCAC, many patients present primary resistance. Since it is a rare tumor, response predictors remain unknown. Methods: We performed a prospective cohort study to evaluate biomarkers associated with CRT response, progression-free survival (PFS), and overall survival (OS). The primary endpoint was response at 6 months (m). Tumor DNA and HPV were analyzed by next-generation sequencing, while KI-67 and PD-L1 by immunohistochemistry in tumor tissue. Results: Seventy-eight patients were recruited between October/2011 and December/2015, and 75 were response evaluable. The median age was 57 years, 65% (n=49) were stage III and 12% (n=9) were HIV positive (HIV+). At 6m, 62.7% (n=47) presented CR. On multivariate analyses, stage II patients were 4.7 more likely to achieve response than stage III (OR, 4.70; 95%CI, 1.36-16.30; p=0.015). HIV+ was associated with a worse response (OR, 5.72; 95%CI, 2.5-13.0; p<0.001). 5-year PFS and OS rates were 63.3% and 76.4%, respectively, with a median follow up of 66m. On multivariate analyses, older age (HR 1.06, p=0.022, 95%IC 1.01-1.11) and absence of CR at 6m (HR 3.36, p=0.007, 95%IC 1.39-8.09) were associated with inferior OS. The 5-year OS rate was 62.5% in HIV+ group compared to 78% among HIV- pts, although this difference was not statistically significant (p=0.4). PIK3CA, MET and TP53 mutations, HPV, Ki-67 expression, and PD-L1 expression, were not associated with PFS and OS. Conclusions: Clinical stage III and HIV+ were associated with worse response to CRT at 6m. The absence of CR was the main factor associated with poor 5-year OS.

Impact of the COVID-19 pandemic on breast and cervical cancer stage at diagnosis in Brazil.

BACKGROUND: The COVID-19 pandemic has led to the need for health services adjustments, which may have compromised management of other diseases. For cancer patients, delays may significantly impair outcomes in some situations. We aimed to assess the impact of the COVID-19 pandemic in breast and cervical cancer diagnosis and treatment compared to the same period prior to the pandemic. METHODS: Data were collected from patients attending their first visit to a Brazilian cancer centre from 1 September 2020 to 31 January 2021 and from 1 September 2019 to 31 January 2020. The pandemic started in February 2020 in Brazil and is still ongoing. We considered this period (September/20-January/21) to be representative of the pandemic impact on cancer management. The primary endpoint was breast and cervical cancer stages at diagnosis. RESULTS: A total of 268 breast cancer patients and 44 cervical cancer patients had their first consult in our cancer centre from September/20 to January/21; 457 and 60, respectively, occurred from September/19 to January/20. Patients who attended their first visit during the pandemic (September/20-January/21) presented with more advanced-stage breast cancer (p < 0.001) and cervical cancer (p = 0.328) than those in the period prior to the pandemic (September/19-January/20), although the difference was not statistically significant for cervical cancer. The proportion of cervical cancer patients diagnosed with locally advanced disease (stages III-IVA) was 56.8% (N = 25) in September/20-January/21 compared to 43.3% (N = 26) in September/19-January/20. Similarly, 37.3% (N = 100) of breast cancer patients had stage III disease in September/20-January/21 compared to 23.2% (N = 106) in September/19-January/20. Fewer breast cancer patients (13.7%) were diagnosed due to screening tests during the pandemic than before it (25.5%) (p < 0.001). CONCLUSIONS: Breast and cervical cancer patients had more advanced-stage diseases in their first visit to a cancer centre during the COVID-19 pandemic compared to a similar period prior to the pandemic. Efforts should be made not to compromise essential cancer services since this results in long-term negative impacts for oncologic patients.

Phase II trial of humanized anti-Lewis Y monoclonal antibody for advanced hormone receptor-positive breast cancer that progressed following endocrine therapy.

OBJECTIVES: The Lewis-Y antigen is expressed in 44%-90% of breast cancers (BCs). The expression of the antigen in carcinoma tissue differs from that in normal tissues. This study aimed to evaluate the clinical benefit of the humanized anti-Lewis Y monoclonal antibody, hu3S193, in advanced hormone receptor-positive and Lewis Y-positive BC after administration of endocrine therapy (ET). METHODS: A single-arm phase II study was conducted in seven centers. Patients with advanced hormone receptor-positive BC who failed first-line ET were included. The inclusion criterion was the observation of tumoral expression of the Lewis Y antigen during immunohistochemistry. The treatment comprised hu3S193 antibody administration at weekly intravenous doses of 20 mg/m2 for 8-week cycles. The primary endpoint was the clinical benefit rate. ClinicalTrials.gov NCT01370239. RESULTS: The study stopped accrual following an unplanned interim analysis as the hu3S193 antibody lacked sufficient activity to justify continuation of the study. Twenty-two patients were enrolled, of whom 21 were included in the efficacy analysis. The clinical benefit rate was 19%, with four patients presenting with stable disease after 24 weeks. One patient with prolonged stable disease received medication for over 2 years. No partial or complete responses were observed. The median time to progression and overall survival was 5.4 and 37.5 months, respectively. CONCLUSIONS: The humanized anti-Lewis Y monoclonal antibody, hu3S193, exhibited insufficient activity in this cohort. However, the possibility of activity in a more strictly selected subgroup of patients with higher levels of Lewis Y tumoral expression cannot be overlooked.

Everolimus plus anastrozole for female adnexal tumor of probable Wolffian origin (FATWO) with STK11 mutation.

Female adnexal tumor of probable Wolffian origin (FATWO) are a rare type of cancer that originates from Wolffian duct remnants. Due to its rarity, no standard systemic treatment is established for cases of recurrent or metastatic disease. Previous literature reported the use of platinum-based chemotherapy and c-Kit tyrosine kinase inhibitors for FATWO cases with c-Kit positive expression. Currently, however, the broader availability of next-generation sequencing (NGS) tests allows a better molecular characterization of rare cancer such as FATWO and a possibility for the use of personalized, targeted therapy. Previous case series that performed NGS for FATWO patients described the presence of STK11 mutations in a considerable number of cases, representing a potential target in this population. To our knowledge, we describe here the first case report of a patient with FATWO and STK11 mutation exhibiting a considerable and durable response after treatment with an mTOR inhibitor plus endocrine therapy.

Epidemiology and Outcomes of Patients With Brain Metastases From Colorectal Cancer-Who Are These Patients?

BACKGROUND: Brain metastases (BMs) from colorectal cancer (CRC) are unusual; however, an increase in incidence has been reported. The evidence available on the subject is scarce, and a better understanding is warranted. We aimed to characterize the epidemiology and the outcomes of patients with BMs from CRC. PATIENTS AND METHODS: A cohort of patients with BMs from CRC was retrospectively evaluated. Patients were treated in a single center between May 2008 and April 2019. BMs were confirmed by brain computed tomography or magnetic resonance imaging. RESULTS: A total of 247 consecutive patients were evaluated. Most patients had a left-sided primary tumor (193, 78%) and at least two extra-cranial metastatic sites (194, 78%). Ninety-six patients (39%) were RAS wild-type; 68 patients (27%) were RAS mutated; and 83 patients (34%) were not characterized. Median time from the initial diagnosis to BMs was 27.6 months (interquartile range, 13.1-46.9). Regarding local therapy, 43 patients (17.4%) were treated with BM surgery alone, 76 patients (30.8%) with radiotherapy (RT) alone, and 58 patients (23.5%) with both surgery and RT. Median overall survival (OS) was 2.9 months (95% confidence interval [CI], 2.2-3.5). Six-month and 1-year OS rates were 29% (95% CI, 23-25) and 13.5% (95% CI, 9.2-18.6), respectively. In a multivariable analysis, BM surgery alone (hazard ratio [HR], 0.56; P = .018), RT alone (HR, 0.51; P = .001), and surgery plus RT (HR, 0.27; P < .001) were associated with superior OS, whereas Eastern Cooperative Oncology Group Performance Status 3 or 4 (HR, 2.01; P = .009) and male gender (HR, 1.46; P = .012) were negative prognostic factors. RAS status was not associated with OS. CONCLUSION: BMs occur late during the course of colorectal cancer and are more common in patients with a left-sided primary tumor and a high volume of metastatic disease. BMs from colorectal cancer are still associated with an extremely poor prognosis; however, selected patients may benefit from treatment with surgical resection and radiotherapy.

Effectiveness and toxicity of adjuvant chemotherapy in patients with non-small cell lung cancer.

OBJECTIVE: Adjuvant chemotherapy (AC) improves survival of patients with resected non-small cell lung cancer (NSCLC). However, the cisplatin-vinorelbine regimen has been associated with a significant risk of clinically relevant toxicity. We sought to evaluate the effectiveness, safety, and feasibility of AC for NSCLC patients in a real-world setting. METHODS: This was a single-center, retrospective cohort study of patients with stage I-III NSCLC undergoing surgery with curative intent between 2009 and 2018. AC was administered at the discretion of physicians. The patients were divided into two groups: AC group and no AC (control) group. Study outcomes included overall survival (OS) and recurrence-free survival (RFS), as well as the safety profile and feasibility of the cisplatin-vinorelbine regimen in a real-world setting. RESULTS: The study involved 231 patients, 80 of whom received AC. Of those, 55 patients received the cisplatin-vinorelbine regimen. Survival analyses stratified by tumor stage showed that patients with stage II NSCLC in the AC group had better RFS (p = 0.036) and OS (p = 0.017) than did those in the no AC group. Among patients with stage III NSCLC in the AC group, RFS was better (p < 0.001) and there was a trend toward improved OS (p = 0.060) in comparison with controls. Of those who received the cisplatin-vinorelbine regimen, 29% had grade 3-4 febrile neutropenia, and 9% died of toxicity. CONCLUSIONS: These results support the benefit of AC for NSCLC patients in a real-world setting. However, because the cisplatin-vinorelbine regimen was associated with alarming rates of toxicity, more effective and less toxic alternatives should be investigated.

Perspectives on PARP Inhibitor Combinations for Ovarian Cancer.

Poly (ADP-ribose) polymerase (PARP) inhibitors constitute an important treatment option for ovarian cancer nowadays. The magnitude of benefit from PARP inhibitors is influenced by the homologous recombination status, with greater benefit observed in patients with BRCA mutated or BRCA wild-type homologous recombination deficient (HRD) tumors. Although some PARP inhibitor activity has been shown in homologous recombination proficient (HRP) ovarian tumors, its clinical relevance as a single agent is unsatisfactory in this population. Furthermore, even HRD tumors present primary or secondary resistance to PARP inhibitors. Strategies to overcome treatment resistance, as well as to enhance PARP inhibitors' efficacy in HRP tumors, are highly warranted. Diverse combinations are being studied with this aim, including combinations with antiangiogenics, immunotherapy, and other targeted therapies. This review discusses the rationale for developing therapy combinations with PARP inhibitors, the current knowledge, and the future perspectives on this issue.

Effectiveness and toxicity of adjuvant chemotherapy in patients with non-small cell lung cancer / Eficácia e toxicidade da quimioterapia adjuvante em pacientes com câncer de pulmão de células não pequenas

ABSTRACT Objective: Adjuvant chemotherapy (AC) improves survival of patients with resected non-small cell lung cancer (NSCLC). However, the cisplatin-vinorelbine regimen has been associated with a significant risk of clinically relevant toxicity. We sought to evaluate the effectiveness, safety, and feasibility of AC for NSCLC patients in a real-world setting. Methods: This was a single-center, retrospective cohort study of patients with stage I-III NSCLC undergoing surgery with curative intent between 2009 and 2018. AC was administered at the discretion of physicians. The patients were divided into two groups: AC group and no AC (control) group. Study outcomes included overall survival (OS) and recurrence-free survival (RFS), as well as the safety profile and feasibility of the cisplatin-vinorelbine regimen in a real-world setting. Results: The study involved 231 patients, 80 of whom received AC. Of those, 55 patients received the cisplatin-vinorelbine regimen. Survival analyses stratified by tumor stage showed that patients with stage II NSCLC in the AC group had better RFS (p = 0.036) and OS (p = 0.017) than did those in the no AC group. Among patients with stage III NSCLC in the AC group, RFS was better (p < 0.001) and there was a trend toward improved OS (p = 0.060) in comparison with controls. Of those who received the cisplatin-vinorelbine regimen, 29% had grade 3-4 febrile neutropenia, and 9% died of toxicity. Conclusions: These results support the benefit of AC for NSCLC patients in a real-world setting. However, because the cisplatin-vinorelbine regimen was associated with alarming rates of toxicity, more effective and less toxic alternatives should be investigated.

RESUMO Objetivo: A quimioterapia adjuvante melhora a sobrevida de pacientes com câncer pulmonar de células não pequenas (CPCNP) ressecado. No entanto, o esquema cisplatina-vinorelbina está relacionado com risco significativo de toxicidade clinicamente relevante. Nosso objetivo foi avaliar a eficácia, segurança e viabilidade da quimioterapia adjuvante para pacientes com CPCNP em um cenário de mundo real. Métodos: Estudo retrospectivo de coorte realizado em um único centro com pacientes com CPCNP em estágio I-III submetidos a cirurgia com intuito curativo entre 2009 e 2018. A quimioterapia adjuvante foi administrada a critério dos médicos. Os pacientes foram divididos em dois grupos: quimioterapia adjuvante e sem quimioterapia adjuvante (grupo controle). Os desfechos estudados foram sobrevida global (SG) e sobrevida livre de recidiva (SLR), bem como o perfil de segurança e viabilidade do esquema cisplatina-vinorelbina em um cenário de mundo real. Resultados: O estudo envolveu 231 pacientes, 80 dos quais receberam quimioterapia adjuvante. Destes, 55 receberam o esquema cisplatina-vinorelbina. As análises de sobrevida estratificadas pelo estágio do tumor mostraram que os pacientes com CPCNP em estágio II que receberam quimioterapia adjuvante apresentaram melhor SLR (p = 0,036) e SG (p = 0,017) do que os do grupo controle. Entre os pacientes com CPCNP em estágio III que receberam quimioterapia adjuvante, a SLR foi melhor (p < 0,001) e houve uma tendência a melhor SG do que no grupo controle (p = 0,060). Dos que receberam o esquema cisplatina-vinorelbina, 29% apresentaram neutropenia febril de grau 3-4, e 9% morreram em virtude de toxicidade. Conclusões: Os resultados confirmam o efeito benéfico da quimioterapia adjuvante em pacientes com CPCNP em um contexto real. No entanto, o esquema cisplatina-vinorelbina relacionou-se com taxas alarmantes de toxicidade e alternativas mais eficazes e menos tóxicas devem ser investigadas.

Phase II trial of humanized anti-Lewis Y monoclonal antibody for advanced hormone receptor-positive breast cancer that progressed following endocrine therapy

OBJECTIVES: The Lewis-Y antigen is expressed in 44%-90% of breast cancers (BCs). The expression of the antigen in carcinoma tissue differs from that in normal tissues. This study aimed to evaluate the clinical benefit of the humanized anti-Lewis Y monoclonal antibody, hu3S193, in advanced hormone receptor-positive and Lewis Y-positive BC after administration of endocrine therapy (ET). METHODS: A single-arm phase II study was conducted in seven centers. Patients with advanced hormone receptor-positive BC who failed first-line ET were included. The inclusion criterion was the observation of tumoral expression of the Lewis Y antigen during immunohistochemistry. The treatment comprised hu3S193 antibody administration at weekly intravenous doses of 20 mg/m2 for 8-week cycles. The primary endpoint was the clinical benefit rate. ClinicalTrials.gov NCT01370239. RESULTS: The study stopped accrual following an unplanned interim analysis as the hu3S193 antibody lacked sufficient activity to justify continuation of the study. Twenty-two patients were enrolled, of whom 21 were included in the efficacy analysis. The clinical benefit rate was 19%, with four patients presenting with stable disease after 24 weeks. One patient with prolonged stable disease received medication for over 2 years. No partial or complete responses were observed. The median time to progression and overall survival was 5.4 and 37.5 months, respectively. CONCLUSIONS: The humanized anti-Lewis Y monoclonal antibody, hu3S193, exhibited insufficient activity in this cohort. However, the possibility of activity in a more strictly selected subgroup of patients with higher levels of Lewis Y tumoral expression cannot be overlooked.

Management of cervical cancer patients during the COVID-19 pandemic: a challenge for developing countries.

During the COVID-19 pandemic, health services worldwide are going through important adaptations to assist patients infected with COVID-19, at the same time as continuing to provide assistance to other potentially life-threatening diseases. Although patients with cancer may be at increased risk for severe events related to COVID-19 infection, their oncologic treatments frequently cannot be delayed for long periods without jeopardising oncologic outcomes. Considering this, a careful consideration for treatment management of different malignancies is required. Cervical cancer is concentrated mainly in low-middle income countries (LMICs), which face particular challenges during the COVID-19 pandemic due to the scarcity of health resources in many places. Although cervical cancer is the fourth cause of cancer death among women, it receives little attention from international Oncology societies and scientific research studies. In this review paper, we discuss the cervical cancer landscape and provide specialists recommendations for its management during the COVID-19 pandemic, particularly focused on LMICs' reality.

Ovarian cancer risk assessment in the era of next-generation sequencing.

Ovarian cancer is one of the cancers most influenced by hereditary factors. Testing for hereditary susceptibility genes is recommended for every woman with epithelial ovarian cancer (EOC). Pathogenic germline variants in BRCA1 and BRCA2 genes are responsible for a substantial fraction of hereditary ovarian cancer. However, alterations in other genes, such as BRIP1, RAD51C, RAD51D, and mismatch repair genes, also enhance ovarian cancer risk. Other genes may also participate in ovarian carcinogenesis, but their role as ovarian cancer susceptibility genes still needs to be clarified. With several genes involved, the complexity of genetic testing increases. In this context, next-generation sequencing (NGS) allows testing for multiple genes simultaneously, with rapid turn-around time. However, the incorporation of this technology into clinical practice faces some challenges. In this review, we will discuss the ovarian cancer risk assessment in the era of NGS.

Radiotherapy-induced malignancies in breast cancer patients with TP53 pathogenic germline variants (Li-Fraumeni syndrome).

The risk of radiotherapy-induced malignancies (RIMs) is a concern when treating Li-Fraumeni syndrome (LFS) or Li-Fraumeni Like (LFL) patients. However, the type of TP53 pathogenic germline variant may possibly influence this risk. TP53 p.R337H mutation is particularly prevalent in Brazil. We aimed to evaluate the outcomes of patients with pathogenic TP53 variants treated for localized breast cancer in a Brazilian cohort. We evaluated retrospectively a cohort of patients with germline TP53 pathogenic variants treated for localized breast cancer between December 1999 and October 2017. All patients were followed by the Hereditary Cancer Group of an academic cancer center. Our primary objective was to evaluate the occurrence of RIMs after adjuvant radiotherapy. Sixteen patients were evaluated; 10 (62.5%) had a germline TP53 p.R337H pathogenic variant. Median age was 39.8 years. Thirteen patients had invasive ductal carcinoma: 8 (61.5%) were hormone receptor-positive; 6 (46.1%), human epithelial growth factor receptor 2 (HER2)-amplified. Three patients had ductal carcinoma in situ. Most patients (N = 12/16, 75%) received adjuvant radiotherapy. After a median follow-up of 52.5 months, 2 patients (2/12, 16.6%) had RIMs. One had a fibrosarcoma and the other, a low-grade leiomyosarcoma. In the group treated with radiotherapy, one distant recurrence was diagnosed (1/12), and no loco-regional recurrence occurred. Among 4 patients who did not receive radiotherapy, 2 presented with loco-regional recurrence. In this cohort of patients with LFS enriched in TP53 p.R337H pathogenic variant, the incidence of RIMs after treatment of localized breast cancer was lower than previous literature. Nevertheless, rates of RIMs were still alarming. Early molecular diagnosis and careful evaluation of treatment risks and benefits are essential for these patients.