Specific features of non-small cell lung cancer in women in northern Morocco between 2018 and 2023

¹Department of Medical Oncology, Ahmad Bin Zayed Al Nahyan Center of Cancer Treatment, Mohammed VI University Hospital of Tangier, Faculty of Medicine and Pharmacy Abdelmalek Essaadi University, Tangier, Morocco

^&Corresponding author
Houda Abrini, Department of Medical Oncology, Ahmad Bin Zayed Al Nahyan Center of Cancer Treatment, Mohammed VI University Hospital of Tangier, Faculty of Medicine and Pharmacy Abdelmalek Essaadi University, Tangier, Morocco

Introduction    

Lung cancer is a serious public health problem worldwide which represents the leading cause of cancer-related death [1]. In 2020, approximately 2.2 million new cases and 1.8 million deaths were recorded worldwide [2]. In Morocco, the incidence rate of lung cancer remains generally high (31.9/100,000) compared to other African countries [3]. This disease will continue to occupy the first place among cancers in 2040 with a mortality rate of 16/100,000 [4]. Lung cancers are histologically classified into non-small cell lung cancer (NSCLC) and small cell carcinoma (SCC). Approximately 85% of cases are non-small cell lung cancer [5]. After the onset of symptoms, the majority of lung cancers are at an advanced stage (stage IV) when diagnosed and cannot be surgically resected, which remains the fundamental element of treatment. This is why lung cancer must be diagnosed at an early stage (stage I) through screening. Indeed, the introduction of screening for this cancer should promote a change in stage to an early stage at the time of diagnosis, with an improvement in survival. Over the past decade, lung cancer has been considered a predominantly male disease. Currently, although lung cancer remains more common in men than in women, the gap between the two genders tends to disappear in many parts of the world, due to increasing incidence among women [6].

The main risk factor for lung cancer is smoking, with an exposure-effect correlation [7]. In the female population, while the impact of smoking was assessed as the main cause of lung cancer in most developed countries, researchers have highlighted the presence of other epidemiological contributors and hormonal, genetic, and molecular factors acting as independent risk factors or interacting with the effect of smoking [8]. The potential claim that women have an increased sensitivity to tobacco carcinogens remains controversial [9]. Lung cancer in women is a distinct and specific condition that requires several studies to define its epidemiological, clinical, molecular and therapeutic characteristics. In Morocco, very few studies have addressed lung cancer in women. These studies concerned the regions of Rabat, Casablanca, Fez and Marrakech. In this work, we present a retrospective study of a series of cases of non-small cell lung cancer in women treated at the Medical Oncology Department of the Mohamed VI University Hospital in Tangier. This study is the first conducted in northern Morocco; its aim was to evaluate the epidemiological, diagnostic, molecular, therapeutic, and prognostic characteristics of NSCLC in women.

Methods     

Study design: this study undertakes a descriptive retrospective analysis of a series of cases conducted within the Medical Oncology Department of the University Hospital of Tangier, covering a period of six years, from May 2018 to December 2023.

Study population and data collection: the subjects included in our analysis are female patients who have been treated for histologically confirmed non-small cell lung cancer. We excluded male patients, female patients diagnosed with small cell lung cancer, as well as all incomplete files deemed unusable. The medical records of patients in the Medical Oncology department of the University Hospital of Tangier were reviewed, and the data were extracted and entered into Microsoft Excel (2013) spreadsheets. The files were examined using a predefined data extraction form, filled retrospectively. This sheet allowed us to conduct an in-depth exploration of epidemiological, clinical, paraclinical, therapeutic and evolutionary data.

Statistical analyses: the collected data were analyzed using IBM SPSS Statistics 29 software (SPSS Inc., Chicago, IL, USA). Means, standard deviations, and percentages, relative to patient age, demographic data, clinical and histological characteristics, and therapeutic aspects, were calculated and detailed. Median overall survival (OS) and median progression-free survival (PFS) were determined using the Kaplan-Meier method. The p-value was obtained using the unstratified Log-Rank test, which is used to compare OS and PFS between two groups of patients. For example, this includes the comparison between the group treated with Anti-EGFR and that receiving platinum-based chemotherapy. A p-value of less than 0.05 was considered statistically significant.

Ethical considerations being a retrospective analysis of records, this study did not require patient consent; a formal submission to the ethics committee was approved. However, in order to preserve medical confidentiality, anonymity was rigorously preserved in the operating sheets. This study was approved by Tangier University Hospital Ethics Committee in 26 September 2024 (AC102ST/2024). Due to the retrospective nature of the study and in compliance with institutional and regulatory guidelines, a waiver of informed consent was granted by the same Ethics Committee.

Results     

Demographic characteristic: during a 6-year period (2018-2023), a total of 596 patients (86 women and 510 men) with lung cancer were treated in the Medical Oncology Department of the Tangier University Hospital. The frequency of female patients was 14.4%. Among the 596 patients, 315 (77 women and 238 men) were treated for NSCLC. This study focused on 77 women with NSCLC. The proportion of these patients compared to all patients with NSCLC was 24.4% and the proportion of women with NSCLC compared to all women with lung cancer was 89.5%. The average number of patients collected per year was 12.8. The average age of the 77 patients in our cohort was 60.5 ± 13.2 years with extremes ranging from 32 to 94 years. It is noted that the 2 age groups <55 years and 55-64 years were in the majority with a rate of 29.8% and 31.2%, respectively, followed by the 65-74 age group (24.7%) while the ≥75 age group was in the minority (14.3%) (Table 1). Analysis of patient records showed that 93.5% were non-smokers and 6.5% were exposed to passive smoking. 7.8% of patients were treated for pulmonary tuberculosis and 3.9% had chronic obstructive pulmonary disease (COPD). Lung cancer history was present in 2.6% of cases (Table 1).

Clinical characteristics: the time from clinical diagnosis to histological confirmation varied between 1 and 36 months, with a mean of 5.1 months. Dyspnea (42.8%) was the most frequent symptom, followed by cough (31.1%) and finally chest pain (25.9%) (Table 1). Furthermore, we observed that most patients (64.9%) had a preserved general condition (PS≤1). 28.6% had a PS 2 and 6.5% a PS 3 (Table 1).

Histological characteristics: the most frequently diagnosed histological type in patients was adenocarcinoma (87%), followed by squamous cell carcinoma (13%) (Table 1). Histological confirmation was obtained by CT-guided biopsy in 61% of cases, bronchoscopy in 18.2%, bone biopsy in 14.2%, supraclavicular lymph node biopsy in 3%, and brain, liver, or pericardial biopsy in 1.2% of cases.

Radiological data: based on thoraco-abdomino-pelvic computed tomography (TAP CT), tumors were locally advanced in the majority of cases. Thus, T4 tumors represented 40.4% and N2 lymph node invasion was found in 41.4% of tumors (Table 2). Based on the 8^th edition of the TNM classification, the most common radiological stage was stage IV in 90.9% of patients (62.3% IVA and 28.6% IVB). Stage III was present in 7.8% of patients (2.6% IIIA and 5.2% IIIB) and only one patient was diagnosed at stage I (1.3% IA-2). Moreover, 70% of patients had more than one metastatic site. The most common metastatic locations were pleural (55.7%), bone (44.3%), pulmonary (30%), hepatic (17.1%) and cerebral (14.3%).

Molecular profile: epithelial growth factor receptor (EGFR) mutation testing was performed in 27 patients (35% of cases), returning positive in 13 patients (48.1%) and negative in 14 patients (51.9%). Mutations were predominant in exon 19 (9 patients or 69.2%), followed by the L858 mutation in exon 21 (4 patients or 30.8%).

Therapeutic management: the time between histological confirmation and the start of treatment of patients was 2.1 months on average (varied between 6 days and 13.8 months). Among the 77 patients, 13 were lost to follow-up (16.8%), and 6 patients (7.8%) had received exclusive palliative supportive care (BSC: best supportive care). Only 1 patient (stage IA-2) was referred for surgery (1.3%) and then lost to follow-up, 3 stage IIIB patients (4%) had received neoadjuvant chemotherapy followed by concomitant chemoradiotherapy (CCR) and then placed under surveillance, and 54 stage IV patients (70.1%) had received first-line palliative systemic treatment. Among these, 46 had received platinum salt-based chemotherapy (including 5 EGFR mutated) (85.2%) and 8 EGFR mutated (14.8%) anti-EGFR treatment. In fact, Zoledronic acid was combined with palliative systemic treatment in 13 patients (16.9% of cases) and bevacizumab in 3 patients (4% of cases). The mean number of cycles of chemotherapy received was 3.8 (range: 1-7). For anti-EGFR therapy, the mean number of cycles was 15.9 (range: 6 -40). Among the 46 patients who received chemotherapy, 16 patients could not be evaluated for treatment response because they were lost to follow-up. Among the 30 patients with evaluable disease, 1 patient (3.3%) had a partial response, 6 patients (20%) had stability, and 23 patients (76.6%) had progression. Regarding anti-EGFR treatment (n=8), 1 patient was lost to follow-up (12.5%), 1 patient had a partial response (12.5%), 5 patients had stability (62.5%), and 1 patient had progression (12.5%).

After progression, 20 patients received second-line systemic treatment. 17 patients (85%) received chemotherapy, and 3 patients (15%) received anti-EGFR (Table 3). Palliative radiotherapy was performed in 23 patients, decompressive radiotherapy on the spine in 10 patients, cerebral radiotherapy in 9 patients, consolidation and analgesic radiotherapy on the femoral neck in 2 patients and on the humerus in 1 patient, and finally palliative pulmonary radiotherapy was performed in 1 patient. The median follow-up was 5 months (range: 0-56), and the median overall survival (OS) was 5 months 95% CI: (2.2-7.7). The median progression-free survival (PFS) was 5 months 95% CI [3.6-6.4]. Furthermore, the overall survival rates at 6 and 12 months were 44.4% and 28.7%, respectively and the PFS rates at 6 and 12 months were 38.5% and 7.7%, respectively (Figure 1,Figure 2). The median overall survival (OS) in the group of EGFR mutated patients treated with anti-EGFR was 20 months 95% CI [12.6-27.4] and in the EGFR-mutated group treated with platinum-based chemotherapy, it was 9 months 95% CI [4.7-13.3]. This median OS in the anti-EGFR therapy group was significantly longer than that in the platinum-based chemotherapy group with a p-value = 0.05 (Figure 3). Similarly, the median PFS in the group of EGFR mutated patients treated with anti-EGFR was 19 months 95% CI (8.3-29.7), while in the group of EGFR mutated patients treated with platinum-based chemotherapy, it was 5 months 95% CI, (0.7-9.3). The median PFS in the anti-EGFR therapy group was also significantly longer than that in the platinum-based chemotherapy group with a p-value of 0.028. It was also noted that the overall survival and PFS curves of chemotherapy treatment fell more rapidly compared to those of anti-EGFR treatment, meaning that patient death occurred very quickly under chemotherapy (Figure 4).

Discussion     

Epidemiological data: lung cancer is a leading cause of cancer worldwide, accounting for 11.4% of cases, and a major cause of cancer-related deaths in both men and women in developed and developing countries [2]. Among women, mortality is particularly high, with lung cancer deaths ranking second after breast cancer. In our cohort, women accounted for 14.4% of lung cancer cases. Similar frequencies were reported in Rabat (10.5% in 2005 - 2008) [10], in Marrakech (10.9% in 2015- 2021) [11]. In contrast, higher frequencies were observed in Guadeloupe (27.4%in 2008 - 2009) [12], Brazil (39.5% in 2006 - 2014) [13], and the USA (46.7% in 2001 - 2019) [14], confirming the greater prevalence of lung cancer among women in developed countries. Regarding the patients with NSCLC who were the subject of this study, the women with NSCLC represented 24.4%. This frequency is similar to those obtained in Rabat between 2014 and 2017 (23.3%) [15], close to those obtained in Turkey (20.6%) [16], Guadeloupe (26.9%) [12] and Indonesia (28%) [17], but it is much lower than those reported in Malaysia (42.3%) [18] and the USA (45.9%) [14], thus marking a significant variability in the frequency of NSCLC in women between countries.

In our series, the mean age of patients was 60.5 years. This average is similar to that reported in Italy (60 years) [19]. It is slightly higher than that reported in Morocco (58.3 years) [20] and in Indonesia (56.9 years) [17] and slightly lower than that observed in Switzerland (62 years) [21] in women with NSCLC. Furthermore, in this study the age extremes were between 32 and 94 years, indicating that NSCLC affects both young and old women. However, the majority of patients were younger than 55 years or between 55 and 64 years of age. The majority of patients (93.5%) were non-smokers and 6.5% were exposed to passive smoking. These results are in line with those of Zakkouri et al. [22], who reported that smoking does not explain all cases of lung cancer in women, because 75% of patients have never smoked and 14% have been exposed to passive smoking. Passive smoking is a risk factor for lung cancer in women that is often mentioned in the literature. According to Sisti and Boffetta [23], passive smoking is implicated in women in 14.2% of cases. However, the relative risk differs according to the type of exposure: family, professional or social, and according to the intensity and duration of passive smoking.Seven point eight percent (7.8%) of patients in this study were treated for pulmonary tuberculosis. Tuberculosis and other pulmonary infections increase the risk of lung cancer due to prolonged inflammation, pulmonary fibrosis, and lung tissue damage [24,25]. A history of lung cancer was present in 2.6% of cases in this study. A study by the International Lung Cancer Consortium showed that there is a 1.5-fold increased risk of lung cancer in people with a first-degree relative (mother, father, brother, or sister) with lung cancer, which would highlight the hereditary nature of the disease [26].

Clinical data: patients diagnosed at an early stage generally achieve high cure rates. However, lung cancer is often diagnosed late due to the late onset of symptoms, the inexpressive nature of the disease, and the lack of an early screening program. In this study, the diagnostic delay between the onset of symptoms and histological confirmation of the disease in the patients was 5.1 months on average. This delay in our context raises the issue of the delay in screening for bronchial cancer in women. The most frequently observed symptom in our study was dyspnea (42.8%), followed by cough (31.1%), then chest pain (25.9%). Weight loss was found in 27.2% of patients, which is consistent with the results of the study conducted in Mali which reported weight loss in 30% of cases [27]. The general condition can be quantified by the Performance Index (PI). In this study, only 35.5% of patients had an altered PI.

Pathological aspects: adenocarcinoma is the most predominant histological type in women with non-small cell lung cancer [28]. In our series, adenocarcinoma (87%) was also the most frequently diagnosed histological type in patients with NSCLC compared to squamous cell carcinoma. These results are similar to those reported in a study in the USA which showed that 71% of lung cancers in women were adenocarcinomas [29].

Radiological stage: in our series, the most frequent radiological stage was stage IV (90.9%). These results are consistent with those of other series in which the majority of bronchial cancers were diagnosed at a locally advanced or metastatic stage [30]. In European and American series, most cases of non-small cell lung cancer were diagnosed at a relatively advanced stage [31]. Similarly, in the study of Zakkouri et al. [22], the proportion of NSCLC diagnosed at stage IV was higher (82%) compared to those at stage III (16%) and stage II (2%). In this study, the high percentage of stage IV NSCLC may be explained by a delay in diagnosis.

Molecular profile: epithelial growth factor receptor mutation frequency varies by geographic area and ethnicity. In this study, the EGFR mutation frequency was high (48.1%). This frequency is similar to those obtained in other studies in women with NSCLC in Morocco [32], Turkey (48.4 %) [16] and Lebanon (44.4 %) [33]. However, the frequency of mutated EGFR obtained in a study conducted in Casablanca was significantly lower (24.3 %) [30]. In Europe and America, this frequency is generally lower (13.4%-37.8%) [19], [34]. Moreover, in China the EGFR mutation frequency is very high (70.5) [35]. In our study, the patients with EGFR mutation were characterized by a mean age of 58 years with the presence of young patients, by the histological subgroup adenocarcinoma and were non-smokers. Other studies also reported that EGFR mutated women were predominantly non-smokers and that their histological type was also dominated by adenocarcinoma as well as the presence of young patients [36]. It emerges from all these studies that the histological type adenocarcinoma, the high rate of EGFR mutation, and non-smoking are linked to NSCLC in women [36]. Furthermore, in this study, the most frequent EGFR mutation was in exon 19 (69.2%). The most common mutations associated with sensitivity to EGFR TKIs include the exon 19 mutation and the L858R point mutation in exon 21 [36]. In this study, these two mutations accounted for 100% of all EGFR mutations since mutations in exons 18 and 20 were absent.

Therapeutic management and survival: treatment of NSCLC includes various approaches, such as surgery, chemotherapy, radiotherapy, targeted therapies, and immunotherapy. These treatments are determined based on the staging of the cancer and the general condition of the patients. In this study, the stages observed included stage IA-2, stages IIIA and IIIB, and stages IVA and IVB. For stage I patients, surgery is the mainstay of treatment. After surgical resection, the 5-year disease-free survival rate is approximately 60% and the 5-year overall survival rate is approximately 80% [37]. In our series, only one patient was stage IA-2 and was referred for surgery. Stage IIIA and IIIB patients who are not eligible for surgery usually receive concomitant chemoradiotherapy (CRT), which is considered the standard of care [38]. In this study, three stage IIIB patients received neoadjuvant chemotherapy followed by CRT because they were unresectable despite a PS of 1. For stage IV, first-line chemotherapy consists of a combination of platinum salts and a third-generation drug (gemcitabine, paclitaxel, docetaxel, irinotecan, vinorelbine) for PS 0-1 patients. For those with PS 2, monotherapy or a non-platinum combination was recommended, while patients with PS 3 required palliative care [39]. In our series, 54 stage IV patients had received first-line systemic treatment, of whom 46 received platinum-based chemotherapy (5 EGFR mutated, 10 EGFR non-mutated, and 31 EGFR mutation undiagnosed) and 8 EGFR mutated were treated with EGFR TKIs (erlotinib or gefitinib). Among the 46 patients who received platinum-based chemotherapy, 28 had PS 0-1, 14 had PS 2, and 4 had PS 3. Among the 8 patients treated with EGFR TKIs, 7 had received erlotinib (of which 6 had PS 1 and 1 had PS 2) and 1 patient (PS 0) was treated with gefitinib.

The median OS and PFS of patients in our series were 5 months. The OS rate at 12 months was 28.7%. This rate is slightly lower than those obtained in studies conducted in Rabat (32.3%) [10] and Brazil (34.5%) [40]. To assess differences in response to chemotherapy, Albain et al. [41] found that women treated with platinum salts survived longer, with a 14% reduced risk of death, a notable difference in women aged 60 years and older. Similarly, Wakelee et al. [42] compared female and male patients in the Eastern Cooperative Oncology Group trial and found that median overall survival was significantly longer in women (9.2 months versus 7.3 months). Wheatley-Price et al. [43] pooled five phase III clinical trials and reported that women responded better to platinum-based chemotherapy with longer survival than men (9.6 months versus 8.6 months), this observation was specific to patients with adenocarcinoma. In second line, monotherapy (docetaxel, pemetrexed) or tyrosine kinase inhibitors (erlotinib) are used [39]. In our series, 20 patients had received second line systemic treatment. 85% had received chemotherapy (the majority of which monotherapy) and 15% erlotinib. Several studies have shown that female gender is predictive of a better response to EGFR TKIs (gefitinib or erlotinib), particularly in patients with NSCLC. Epithelial Growth Factor Receptor tyrosine kinase inhibitors have shown greater efficacy compared to chemotherapy, thus becoming the first-line treatment for EGFR-mutated non-small cell lung cancers, significantly improving patient management. In the ENSURE study of 217 patients, 61% of whom were women, with stage IIIB/IV EGFR-mutated NSCLC, comparing erlotinib to a cisplatin doublet, the median PFS was 11 months in the erlotinib group versus 5.5 months in the chemotherapy group [44].

The EURTAC trial [45] in Europe in patients with EGFR mutated NSCLC, 72.4% of whom were female, compared erlotinib with platinum-based chemotherapy in first-line metastatic disease. Results showed a PFS of 5.2 months in the platinum-based chemotherapy arm versus 9.7 months in the erlotinib arm. The response rate was 10.5% with chemotherapy versus 54.5% with erlotinib, and the median overall survival was 18.8 months for chemotherapy versus 22.9 months for erlotinib. In this study, the median PFS was significantly longer in the group of EGFR mutated patients who received anti-EGFR therapy (19 months) compared with the group of EGFR mutated patients receiving platinum-based chemotherapy (5 months). This PFS is close to those obtained in Korea in which the median PFS of female patients treated with EGFR TKIs was 15.8 [46]. But it is superior to those obtained in Asia, (14) [45], and this despite the small size of our patient series. Similarly, median OS was significantly longer for EGFR-mutated patients treated with anti-EGFR therapy (erlotinib or gefitinib) (20 months) compared with EGFR-mutated patients receiving platinum-based chemotherapy (9 months). This median OS is lower than that obtained in Korea (30.3 months) [46] but much higher than those reported in Asia (12 months) [47] and the Netherlands (12.4 months) [48].

Limitations: we acknowledge that the low rate of molecular testing represents an important limitation of our study. This was mainly attributable to financial constraints and the limited availability of molecular testing in our clinical setting during the study period. Moreover, this study is limited by its retrospective, single-center design and the small sample size, particularly in the treatment subgroup analyses, which reduced statistical power and resulted in wide confidence intervals. Therefore, the survival findings should be considered exploratory and interpreted with caution. Larger, multicenter studies are needed to validate these results.

Conclusion     

Lung cancer in women is a heterogeneous disease that remains poorly understood and has increased in recent years. In this study, NSCLC accounted for 24.4% of total NSCLC cases and 89.5% of lung cancer in women. Hormonal, genetic, and molecular factors likely contribute to NSCLC in these patients. Adenocarcinoma was the predominant histological type (87%), and nearly 91% of NSCLC in women were diagnosed at an advanced stage (stage IV). This underscores the need for effective prevention programs for early detection. Only one-third of the patients underwent molecular testing, revealing a high frequency of EGFR mutations (48.1%). All EGFR-mutated patients were non-smokers with adenocarcinoma, indicating that adenocarcinoma is a strong predictor of EGFR mutations. Targeted therapy with EGFR TKIs demonstrated high efficacy, improving median progression-free survival and overall survival, with a gain of 11 months compared to platinum-based chemotherapy. These findings strongly support performing EGFR mutation testing in all women with non-small cell lung adenocarcinoma to guide targeted therapy and improve survival outcomes.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

Houda Abrini: participated in study design, data collection, writing, analysis of data and drafted the manuscript. Fatima Zahra El’Mrabet: supervised the study and helped finalize this manuscript. All authors read and approved the final manuscript.

Tables and figures     

Table 1: demographic, clinical and histological characteristics of patients with confirmed NSCLC followed at the Medical Oncology Department of the Mohammed VI University Hospital Center in Tangier (Morocco) between May 2018 and December 2023 (N=77)

Table 2: distribution of tumors according to TNM classifications of patients with confirmed NSCLC followed at the Medical Oncology Department of the Mohammed VI University Hospital Center in Tangier (Morocco) between May 2018 and December 2023 (N=77)

Table 3: protocols used at Chemotherapy Day Unit, in second line for patients with confirmed NSCLC, followed at the Medical Oncology Department of the Mohammed VI University Hospital Center in Tangier (Morocco), between May 2018 and December 2023 (N=20)

Figure 1: kaplan-Meier curve representing overall survival of patients with confirmed NSCLC, treated at the Medical Oncology Department of the Mohammed VI University Hospital Center in Tangier (Morocco), between May 2018 and December 2023 (N=77)

Figure 2: kaplan-Meier curve representing progression-free survival of patients with confirmed NSCLC, followed at the Medical Oncology Department of the Mohammed VI University Hospital Center in Tangier (Morocco), between May 2018 and December 2023 (N=77)

Figure 3: kaplan-Meier curve representing overall survival of confirmed NSCLC-EGFR mutated patients, treated with anti-EGFR and platinum-based chemotherapy, at the Chemotherapy Day Unit, in the Medical Oncology Department of the Mohammed VI University Hospital Center in Tangier (Morocco), between May 2018 and December 2023 (N=77)

Figure 4: kaplan-Meier curve representing progression-free survival of confirmed NSCLC-EGFR mutated patients, treated with anti-EGFR and platinum-based chemotherapy, at the Chemotherapy Day Unit, in the Medical Oncology Department of the Mohammed VI University Hospital Center in Tangier (Morocco), between May 2018 and December 2023 (N=77)

References