Cancer remains one of the most significant health challenges facing women worldwide, with several types particularly prevalent in the female population. Understanding the complexity of these malignancies requires a comprehensive examination of their molecular characteristics, diagnostic approaches, and treatment methodologies. The landscape of women’s cancer care has evolved dramatically over the past two decades, driven by advances in genomic medicine, targeted therapies, and precision oncology. From the most common breast cancers to the more challenging ovarian malignancies, each cancer type presents unique clinical considerations that demand specialised knowledge and multidisciplinary approaches.
The epidemiological data reveals concerning trends, with breast cancer affecting approximately 1 in 8 women during their lifetime, whilst ovarian cancer continues to challenge clinicians with its silent progression and late-stage presentation. These statistics underscore the critical importance of early detection, risk stratification, and personalised treatment strategies. Modern oncology has transformed from a one-size-fits-all approach to a sophisticated understanding of tumour biology, genetic predisposition, and individual patient factors that influence both prognosis and therapeutic response.
Breast cancer: invasive ductal carcinoma and Triple-Negative subtypes
Invasive ductal carcinoma represents approximately 75% of all breast cancer cases, originating from the milk ducts and spreading into surrounding breast tissue. This heterogeneous group of tumours exhibits varying degrees of aggressiveness and response to treatment, making molecular classification essential for optimal patient management. The pathological assessment involves examining cellular architecture, nuclear grade, and proliferation markers to determine the most appropriate therapeutic approach.
Triple-negative breast cancer (TNBC) presents unique clinical challenges, characterised by the absence of oestrogen receptors, progesterone receptors, and HER2 amplification. This subtype disproportionately affects younger women and those of African descent, often presenting as rapidly growing, high-grade tumours. The lack of targetable hormone receptors means that patients cannot benefit from endocrine therapy or HER2-directed treatments, making chemotherapy the primary systemic treatment option.
Recent advances in immunotherapy have shown promising results for TNBC patients, particularly those with PD-L1 positive tumours. The integration of immune checkpoint inhibitors with chemotherapy has demonstrated improved pathological complete response rates in the neoadjuvant setting. Additionally, PARP inhibitors have emerged as valuable treatment options for patients with germline BRCA mutations, exploiting the concept of synthetic lethality to selectively target cancer cells with defective DNA repair mechanisms.
Human epidermal growth factor receptor 2 (HER2) overexpression mechanisms
HER2 overexpression occurs in approximately 15-20% of breast cancers, resulting from gene amplification that leads to excessive protein production on the cell surface. This oncogenic driver promotes uncontrolled cell proliferation, invasion, and metastasis through activation of downstream signalling pathways including PI3K/AKT and MAPK cascades. The development of HER2-targeted therapies has revolutionised treatment outcomes for this historically aggressive subtype.
Trastuzumab, the first approved HER2-targeted therapy, demonstrated remarkable efficacy in reducing recurrence rates and improving overall survival. Subsequent innovations including pertuzumab, T-DM1 (ado-trastuzumab emtansine), and more recently, T-DXd (trastuzumab deruxtecan) have expanded treatment options across different disease settings. The dual HER2 blockade strategy, combining trastuzumab and pertuzumab, has become standard care in both neoadjuvant and metastatic settings.
Oestrogen Receptor-Positive luminal A subtype characteristics
Luminal A breast cancers constitute the largest subgroup, representing approximately 60% of all breast malignancies. These tumours are characterised by high expression of oestrogen and progesterone receptors, low proliferation indices, and generally favourable prognosis. The molecular signature includes activation of oestrogen-responsive genes and dependence on hormonal stimulation for growth and survival.
Endocrine therapy forms the cornerstone of treatment for luminal A cancers, with options including selective oestrogen receptor modulators (SERMs), aromatase inhibitors, and selective oestrogen receptor degraders (SERDs). The duration of endocrine therapy has evolved from the traditional five years to extended regimens of up to ten years for high-risk patients. Multigene assays such as Oncotype DX and MammaPrint have enhanced our ability to identify patients who may benefit from chemotherapy in addition to endocrine therapy.
BRCA1 and BRCA2 genetic mutation screening protocols
Hereditary breast and ovarian cancer syndrome, primarily caused by germline mutations in BRCA1 and BRCA2 genes, accounts for 5-10% of all breast cancers. These tumour suppressor genes play crucial roles in DNA repair through homologous recombination, and their loss predisposes individuals to early-onset breast and ovarian cancers. BRCA1 mutations typically associate with triple-negative phenotypes, whilst BRCA2 mutations often present as hormone receptor-positive tumours.
Current screening guidelines recommend genetic counselling and testing for individuals with strong family histories, early-onset disease, or specific ethnic backgrounds with founder mutations. The identification of pathogenic variants has profound implications for treatment decisions, including the use of PARP inhibitors and platinum-based chemotherapy, which exploit the defective DNA repair mechanisms in BRCA-mutated tumours.
Mammographic density assessment using BI-RADS classification
The Breast Imaging Reporting and Data System (BI-RADS) provides standardised terminology for mammographic density assessment, categorising breast tissue into four density groups from almost entirely fatty to extremely dense. Dense breast tissue not only masks potential malignancies on mammography but also represents an independent risk factor for breast cancer development. Women with extremely dense breasts have a four to six-fold increased risk compared to those with fatty breasts.
Supplemental screening modalities, including digital breast tomosynthesis, ultrasonography, and magnetic resonance imaging, have been developed to address the limitations of conventional mammography in dense breast tissue. Legislative requirements in many regions now mandate density notification, empowering women to make informed decisions about additional screening options based on their individual risk profiles.
Sentinel lymph node biopsy techniques in Early-Stage detection
Sentinel lymph node biopsy has revolutionised axillary staging in early-stage breast cancer, significantly reducing morbidity compared to complete axillary lymph node dissection. The technique involves injecting radioactive tracer and/or blue dye near the primary tumour to identify the first lymph nodes that drain the breast tissue. This minimally invasive procedure accurately predicts the status of the entire axillary basin in the majority of cases.
Recent clinical trials have challenged traditional paradigms regarding the necessity of completion axillary dissection in patients with limited sentinel node involvement. The Z0011 and AMAROS trials demonstrated that women with one to two positive sentinel nodes who receive breast-conserving therapy and radiation can safely omit further axillary surgery without compromising survival outcomes.
Cervical cancer: HPV-Associated squamous cell carcinoma pathogenesis
Human papillomavirus (HPV) infection represents the primary aetiological factor in cervical cancer development, with high-risk subtypes 16 and 18 responsible for approximately 70% of cases. The viral oncoproteins E6 and E7 disrupt normal cellular regulatory mechanisms by inactivating tumour suppressor proteins p53 and Rb, respectively. This molecular disruption leads to uncontrolled cell proliferation and genomic instability, facilitating malignant transformation over a period of years to decades.
The natural history of cervical cancer involves a well-characterised progression from normal epithelium through various grades of cervical intraepithelial neoplasia (CIN) to invasive carcinoma. This predictable sequence provides multiple opportunities for intervention through screening programmes and treatment of precancerous lesions. The integration of HPV DNA into the host genome represents a critical step in carcinogenesis, often occurring at sites that disrupt cellular growth control mechanisms.
Squamous cell carcinoma accounts for approximately 85% of cervical cancers, typically arising in the transformation zone where columnar and squamous epithelia meet. The remaining cases primarily consist of adenocarcinomas, which tend to be more challenging to detect through conventional cytological screening due to their endocervical location. Understanding these pathological distinctions is crucial for developing effective screening strategies and treatment approaches.
Prevention strategies have evolved significantly with the introduction of prophylactic HPV vaccines targeting the most oncogenic viral subtypes. These vaccines have demonstrated remarkable efficacy in preventing persistent HPV infections and associated precancerous lesions, particularly when administered before sexual debut. The implementation of gender-neutral vaccination programmes promises to achieve population-level immunity and dramatically reduce cervical cancer incidence in the coming decades.
The success of HPV vaccination programmes represents one of the most significant cancer prevention achievements in modern medicine, offering the realistic possibility of cervical cancer elimination in many countries.
Ovarian cancer: epithelial tumour classifications and CA-125 biomarker analysis
Epithelial ovarian cancer encompasses several distinct histological subtypes, each with unique molecular characteristics and clinical behaviours. The traditional classification system has undergone significant revision with advances in molecular pathology, leading to a more nuanced understanding of ovarian carcinogenesis. Serous carcinomas represent the most common subtype, while clear cell, endometrioid, and mucinous carcinomas each present distinct therapeutic challenges and prognostic implications.
The dualistic model of ovarian cancer pathogenesis distinguishes between Type I and Type II tumours, providing crucial insights into tumour biology and treatment approaches. Type I tumours, including low-grade serous, mucinous, clear cell, and endometrioid carcinomas, typically develop slowly from precursor lesions and often present at earlier stages. Conversely, Type II tumours, predominantly high-grade serous carcinomas, are characterised by aggressive behaviour, widespread dissemination at diagnosis, and p53 mutations.
CA-125 remains the most widely utilised biomarker in ovarian cancer management, despite its limitations in specificity and sensitivity. Elevated levels can indicate various benign conditions, particularly in premenopausal women, whilst approximately 20% of ovarian cancers do not produce elevated CA-125 levels. The biomarker proves most valuable in monitoring treatment response and detecting recurrence in patients with known disease, rather than as a primary screening tool.
Novel biomarker approaches, including HE4 (human epididymis protein 4) and multi-marker panels, have been developed to improve diagnostic accuracy. The ROMA (Risk of Ovarian Malignancy Algorithm) combines CA-125 and HE4 levels with menopausal status to enhance discrimination between benign and malignant pelvic masses. Despite these advances, the development of effective screening strategies for the general population remains elusive due to the relative rarity of ovarian cancer and the high specificity required to avoid false-positive results.
High-grade serous carcinoma (HGSC) molecular profiling
High-grade serous carcinoma represents the most lethal subtype of ovarian cancer, accounting for approximately 70% of cases and the majority of ovarian cancer deaths. Recent genomic analyses have revealed that HGSC is characterised by universal p53 mutations, extensive chromosomal instability, and defective DNA repair mechanisms. Approximately 50% of HGSC cases exhibit homologous recombination deficiency (HRD), either through germline or somatic BRCA mutations or other HRD-associated genetic alterations.
The molecular landscape of HGSC has informed the development of targeted therapies, particularly PARP inhibitors, which exploit synthetic lethality in tumours with defective DNA repair. Comprehensive genomic profiling has identified additional molecular vulnerabilities, including alterations in genes involved in the PI3K/AKT pathway, RAS signalling, and cell cycle regulation. These discoveries have opened new avenues for therapeutic intervention and combination treatment strategies.
Peritoneal carcinomatosis staging using FIGO criteria
The International Federation of Gynecology and Obstetrics (FIGO) staging system provides the globally accepted framework for ovarian cancer classification, with recent revisions incorporating advances in surgical technique and imaging technology. The staging system emphasises the pattern of disease spread, with particular attention to peritoneal implants, lymph node involvement, and distant metastases. Accurate staging is crucial for treatment planning and prognostic assessment.
Peritoneal carcinomatosis, characterised by widespread intraperitoneal tumour dissemination, represents a hallmark of advanced ovarian cancer. The assessment of peritoneal disease burden influences surgical decisions regarding optimal debulking feasibility and the timing of chemotherapy administration. Sophisticated imaging techniques and minimally invasive staging procedures have enhanced our ability to accurately assess disease extent and guide treatment decisions.
Germline BRCA testing for hereditary ovarian cancer syndrome
Germline BRCA testing has become standard care for all patients diagnosed with epithelial ovarian cancer, regardless of family history or age at diagnosis. The identification of pathogenic BRCA mutations has profound implications for both the patient and their family members, influencing treatment decisions and risk management strategies. BRCA-mutated tumours demonstrate enhanced sensitivity to platinum-based chemotherapy and PARP inhibitors, often achieving higher response rates and improved survival outcomes.
The concept of cascade testing has gained prominence, involving the systematic evaluation of at-risk family members once a pathogenic variant is identified in the proband. This approach enables the implementation of enhanced surveillance, risk-reducing surgeries, and chemoprevention strategies for mutation carriers before cancer development. The psychological and social implications of genetic testing require careful consideration and appropriate counselling support throughout the process.
Platinum-based chemotherapy resistance mechanisms
Platinum resistance represents the primary obstacle to long-term survival in ovarian cancer patients, with most initially responsive tumours eventually developing resistance to platinum-based agents. The mechanisms underlying platinum resistance are multifaceted, involving enhanced DNA repair capacity, increased drug efflux, altered drug metabolism, and activation of alternative survival pathways. Understanding these resistance mechanisms is crucial for developing strategies to overcome or prevent treatment failure.
Emerging therapeutic approaches target specific resistance pathways, including combinations of platinum agents with DNA repair inhibitors, cell cycle checkpoint modulators, and anti-angiogenic agents. The timing of treatment interventions, including the concept of platinum-free intervals and maintenance therapy strategies, has evolved to optimise treatment efficacy whilst minimising cumulative toxicity and resistance development.
Endometrial cancer: type I endometrioid adenocarcinoma risk factors
Type I endometrial cancer, predominantly consisting of endometrioid adenocarcinomas, represents approximately 80% of uterine malignancies and is strongly associated with oestrogen exposure. The pathogenesis involves prolonged oestrogenic stimulation of the endometrium in the absence of adequate progesterone opposition, leading to endometrial hyperplasia and subsequent malignant transformation. This hormone-driven pathway explains the association with various risk factors including obesity, diabetes, nulliparity, and late menopause.
Obesity represents the most significant modifiable risk factor for endometrial cancer, with mechanisms involving increased peripheral conversion of androgens to oestrogens in adipose tissue, elevated insulin levels, and chronic inflammatory states. The relationship demonstrates a dose-response pattern, with severely obese women facing up to ten-fold increased risk compared to those with normal body mass index. The rising global prevalence of obesity has contributed to increasing endometrial cancer incidence rates, particularly in developed countries.
Diabetes mellitus confers independent risk for endometrial cancer development through multiple mechanisms, including hyperinsulinaemia, insulin resistance, and associated metabolic dysfunction. The relationship persists even after adjusting for obesity, suggesting direct effects of altered glucose metabolism on endometrial tissue. Metformin therapy has shown potential protective effects against endometrial cancer in some observational studies, though causality remains to be definitively established through randomised trials.
Polycystic ovary syndrome (PCOS) increases endometrial cancer risk through chronic anovulation and prolonged oestrogen exposure without cyclical progesterone production. The syndrome’s association with insulin resistance and obesity compounds the risk profile. Young women with PCOS may benefit from progestin therapy or hormonal contraceptives to provide endometrial protection and regulate menstrual cycles.
The strong association between metabolic factors and endometrial cancer highlights the importance of lifestyle interventions in both prevention and management of this increasingly common malignancy.
Lung cancer in women: adenocarcinoma predominance and EGFR mutations
Lung cancer in women exhibits distinct epidemiological and molecular characteristics that differentiate it from the disease patterns observed in men. Adenocarcinoma has emerged as the predominant histological subtype in female patients, accounting for approximately 60-65% of cases compared to the historically more common squamous cell carcinoma. This shift reflects changing smoking patterns and increased recognition of lung cancer in never-smokers, a demographic that predominantly consists of women and demonstrates unique molecular profiles.
The incidence of lung cancer in never-smoking women has garnered significant attention from the oncology community, as these patients often present with distinct clinical characteristics and therapeutic responses. Environmental factors such as secondhand smoke exposure, radon gas, air pollution, and occupational carcinogens contribute to lung cancer development in this population. Additionally, hormonal influences may play a role, with some studies suggesting associations between oestrogen exposure and lung cancer risk, though the mechanisms remain incompletely understood.
EGFR (epidermal growth factor receptor) mutations represent the most clinically significant molecular alteration in lung adenocarcinoma, occurring in approximately 40-50% of Asian women and 10-15% of Caucasian women with the disease. These activating mutations, predominantly involving exons 19 and 21, result in constitutive receptor signalling and tumour cell proliferation. The discovery of EGFR mutations has revolutionised treatment approaches, enabling the development of targeted therapies that demonstrate superior efficacy compared to traditional chemotherapy regimens.
The molecular landscape of lung adenocarcinoma in women reveals additional targetable alterations, including ALK rearrangements, ROS1 fusions, and BRAF mutations. These genetic drivers occur predominantly in never-smokers and younger patients, offering opportunities for precision medicine approaches. The mutually exclusive nature of these alterations suggests distinct pathogenetic pathways and underscores the importance of comprehensive molecular profiling in treatment planning.
Non-small cell lung cancer (NSCLC) targeted therapy options
The therapeutic landscape for non-small cell lung cancer has been transformed by the development of targeted agents directed against specific molecular drivers. First-generation EGFR tyrosine kinase inhibitors (TKIs), including erlotinib and gefitinib, demonstrated remarkable efficacy in patients with EGFR-mutated tumours, achieving response rates exceeding 70% and progression-free survival times of 10-14 months. However, the inevitable development of acquired resistance, most commonly through the T790M resistance mutation, necessitated the development of newer therapeutic strategies.
Second-generation EGFR TKIs such as afatinib and dacomitinib offered improved activity against certain resistance mutations but failed to overcome T790M-mediated resistance effectively. The development of osimertinib, a third-generation EGFR TKI specifically designed to target the T790M mutation while sparing wild-type EGFR, represented a significant advancement. Clinical trials demonstrated osimertinib’s superiority over first-generation TKIs in both treatment-naive and T790M-positive resistant settings, leading to its current status as first-line therapy for EGFR-mutated NSCLC.
Beyond EGFR-targeted therapy, the identification of additional molecular drivers has expanded treatment options significantly. ALK inhibitors, beginning with crizotinib and progressing through alectinib, ceritinib, and lorlatinib, have demonstrated sequential improvements in efficacy and central nervous system penetration. Similarly, targeted agents for ROS1 fusions, RET rearrangements, and NTRK fusions have provided therapeutic options for these rare but highly targetable molecular subsets.
ALK rearrangement testing in Never-Smoker female patients
Anaplastic lymphoma kinase (ALK) rearrangements occur in approximately 3-5% of NSCLC cases, with a strong predilection for younger patients, never-smokers, and women. The EML4-ALK fusion represents the most common variant, though multiple fusion partners have been identified, each potentially conferring distinct clinical characteristics and therapeutic responses. The testing for ALK rearrangements has become standard practice in the molecular workup of lung adenocarcinoma, particularly in non-smoking patients.
Immunohistochemistry using the D5F3 clone has emerged as a reliable screening method for ALK rearrangements, offering rapid results and widespread availability. Positive immunohistochemical staining correlates highly with the presence of ALK rearrangements detected by fluorescence in situ hybridisation (FISH) or next-generation sequencing. The clinical significance of ALK testing extends beyond initial diagnosis, as resistance mechanisms and optimal sequencing of ALK inhibitors require ongoing molecular monitoring.
The sequential use of ALK inhibitors has become increasingly sophisticated, with each generation designed to overcome specific resistance mutations. Alectinib has demonstrated superior efficacy compared to crizotinib in treatment-naive patients, whilst lorlatinib shows activity against multiple resistance mechanisms including the challenging G1202R mutation. Understanding the resistance profiles of different ALK inhibitors enables rational treatment sequencing and optimal long-term disease management.
PD-L1 expression levels for immunotherapy eligibility
Programmed death-ligand 1 (PD-L1) expression has emerged as the primary biomarker for predicting immunotherapy response in NSCLC, though its utility remains context-dependent and imperfect. The assessment of PD-L1 expression requires careful attention to technical factors, including antibody selection, scoring methodology, and specimen adequacy. The 22C3 pharmDx assay has gained widespread acceptance for pembrolizumab eligibility determination, whilst other companion diagnostics have been developed for specific immunotherapy agents.
PD-L1 expression levels are categorised into different thresholds, with tumour proportion scores (TPS) of ≥50% indicating high expression and potential eligibility for single-agent immunotherapy. Patients with TPS 1-49% may benefit from combination immunotherapy and chemotherapy, whilst those with <1% expression typically receive chemotherapy alone in the absence of targetable mutations. However, the dynamic nature of PD-L1 expression and tumour heterogeneity can complicate interpretation and treatment decisions.
The integration of additional biomarkers, including tumour mutational burden (TMB) and microsatellite instability, may enhance patient selection for immunotherapy. High TMB (≥10 mutations per megabase) has shown correlation with immunotherapy response independent of PD-L1 expression, though the optimal cut-off values and testing methodologies continue to evolve. Women with lung cancer often demonstrate different immune microenvironments compared to men, potentially influencing immunotherapy efficacy and toxicity profiles.
Low-dose CT screening guidelines for High-Risk women
Low-dose computed tomography (LDCT) screening has demonstrated significant mortality reduction in high-risk populations, leading to widespread guideline adoption and implementation programmes. The current eligibility criteria typically include individuals aged 50-80 years with ≥20 pack-year smoking history who currently smoke or quit within the past 15 years. However, these criteria may inadequately capture lung cancer risk in women, particularly never-smokers who develop the disease due to alternative risk factors.
The application of LDCT screening in women requires consideration of sex-specific factors, including differential radiation sensitivity and the potential for increased false-positive rates due to hormonal influences on breast tissue density. Shared decision-making becomes particularly important in women with borderline risk factors, where the benefits of screening must be weighed against potential harms including radiation exposure, false-positive results, and psychological distress from screening participation.
Emerging risk prediction models incorporate additional factors beyond smoking history, including family history, personal history of cancer, and environmental exposures. The PLCOm2012 and LCRAT models have shown promise in identifying high-risk individuals who fall outside traditional screening criteria. For women with strong family histories of lung cancer or known genetic predispositions, individualised screening approaches may be warranted despite not meeting standard eligibility requirements.
Colorectal cancer: microsatellite instability and lynch syndrome associations
Colorectal cancer represents the third most common malignancy in women worldwide, with distinct molecular subtypes that influence both prognosis and treatment approaches. Microsatellite instability (MSI) occurs in approximately 15% of colorectal cancers, resulting from defective DNA mismatch repair (MMR) mechanisms. The MSI phenotype can arise through sporadic hypermethylation of the MLH1 promoter or germline mutations in MMR genes associated with Lynch syndrome, the most common hereditary colorectal cancer syndrome.
Lynch syndrome affects approximately 1 in 300 individuals and accounts for 3-5% of all colorectal cancers, with women facing additional risks for endometrial, ovarian, and other gynaecological malignancies. The syndrome results from germline mutations in MMR genes including MLH1, MSH2, MSH6, PMS2, and EPCAM, each conferring different cancer risks and age distributions. Women with Lynch syndrome have lifetime risks of 40-60% for colorectal cancer and 40-60% for endometrial cancer, necessitating enhanced surveillance and risk-reducing interventions.
The identification of MSI tumours has gained significant clinical importance due to their distinct biological behaviour and therapeutic implications. MSI colorectal cancers demonstrate better prognosis when diagnosed at early stages, often exhibiting less aggressive behaviour and reduced propensity for distant metastasis. However, these tumours show poor response to 5-fluorouracil-based chemotherapy, requiring alternative treatment strategies in the adjuvant setting.
Universal screening for Lynch syndrome has become standard practice in many institutions, involving MSI testing and/or immunohistochemistry for MMR proteins in all newly diagnosed colorectal cancers. This approach has significantly increased the detection of Lynch syndrome families, enabling cascade genetic testing and implementation of appropriate surveillance measures for at-risk relatives. The identification of Lynch syndrome has profound implications for women, as it necessitates gynaecological screening and consideration of prophylactic hysterectomy and bilateral salpingo-oophorectomy after completion of childbearing.
The recognition of microsatellite instability as both a prognostic marker and therapeutic target has fundamentally changed our approach to colorectal cancer management, particularly in women with Lynch syndrome who face multiple cancer risks throughout their lives.
Immunotherapy has emerged as a revolutionary treatment option for patients with MSI-high colorectal cancers, with pembrolizumab and nivolumab demonstrating remarkable efficacy in both treatment-refractory and first-line settings. The high mutational burden characteristic of MSI tumours creates abundant neoantigens that trigger robust immune responses when checkpoint inhibition is employed. Response rates exceeding 40% have been observed in heavily pretreated patients, with many achieving durable complete responses.
The integration of genetic counselling services has become essential in the management of women diagnosed with colorectal cancer, particularly those with MSI tumours or early-onset disease. The identification of Lynch syndrome enables personalised screening recommendations, including annual colonoscopy beginning 20-25 years of age and annual endometrial sampling starting at age 30-35 years. Additionally, the knowledge of Lynch syndrome status influences reproductive counselling and family planning decisions, as affected individuals have a 50% chance of transmitting the mutation to their offspring.