Cancer Overview - Comprehensive Guide

Cancer encompasses a group of diseases characterized by uncontrolled cell proliferation, invasion of surrounding tissues, and potential spread to distant organs. It is the second leading cause of death globally, with approximately 19.3 million new cases and 10 million deaths annually. This article provides comprehensive coverage of cancer biology, classification, common malignancies, treatment approaches, and prevention strategies.

Carcinogenesis

Carcinogenesis is the multistep process by which normal cells transform into malignant cells through the accumulation of genetic and epigenetic alterations.

Hallmarks of Cancer (Hanahan and Weinberg)

Hallmark	Description
Sustaining proliferative signaling	Constitutive activation of growth factor pathways (RAS, MAPK, PI3K)
Evading growth suppressors	Loss of tumor suppressor function (RB, TP53)
Resisting cell death	Blocking apoptosis (BCL-2 overexpression, p53 loss)
Enabling replicative immortality	Telomerase reactivation, bypass of senescence
Inducing angiogenesis	VEGF upregulation, tumor vascularization
Activating invasion and metastasis	EMT, matrix metalloproteinases, intravasation
Reprogramming energy metabolism	Warburg effect (aerobic glycolysis)
Evading immune destruction	PD-L1 expression, Treg recruitment, MHC downregulation
Tumor-promoting inflammation	Macrophage polarization, cytokine production
Genome instability and mutation	Defective DNA repair, mutator phenotype

Stages of Carcinogenesis

Stage	Description	Duration
Initiation	Irreversible DNA damage in a single cell (mutagen exposure)	Seconds to days
Promotion	Clonal expansion of initiated cells by promoting agents (hormones, growth factors, inflammation)	Months to years
Progression	Accumulation of additional mutations, genomic instability, acquisition of invasive/metastatic phenotype	Years to decades
Metastasis	Dissemination of tumor cells to distant sites via lymphatics or bloodstream	Months to years

Oncogenes and Tumor Suppressor Genes

Key Oncogenes

Gene	Protein Function	Cancer Associations	Mechanism of Activation
KRAS	Small GTPase, MAPK signaling	Pancreatic (90%), colorectal (40%), lung (30%)	Point mutation (G12C, G12D, G12V)
EGFR	Receptor tyrosine kinase	Lung adenocarcinoma (10-15%), glioblastoma (40%)	Mutation, amplification, overexpression
HER2/ERBB2	Receptor tyrosine kinase	Breast cancer (20%), gastric cancer (15%)	Amplification, overexpression
BRAF	Serine/threonine kinase, MAPK pathway	Melanoma (50%), thyroid (45%), colorectal (10%)	Point mutation (V600E)
PI3CA	PI3K catalytic subunit	Breast, colorectal, endometrial	Activating mutation
MYC	Transcription factor	Burkitt lymphoma, many others	Translocation (t(8;14)), amplification
BCR-ABL	Tyrosine kinase (fusion protein)	CML (100%), ALL (5-20%)	Translocation t(9;22) (Philadelphia chromosome)
ALK	Receptor tyrosine kinase	Lung adenocarcinoma (3-7%)	Fusion (EML4-ALK)

Key Tumor Suppressor Genes

Gene	Protein Function	Cancer Associations	Mechanism of Inactivation
TP53	Transcription factor, apoptosis, cell cycle arrest (Guardian of the Genome)	>50% of all cancers	Mutation (missense, loss of function), loss of heterozygosity
RB1	Cell cycle regulation (G1/S checkpoint)	Retinoblastoma, osteosarcoma, SCLC, breast	Mutation, deletion, HPV E7 inactivation
APC	WNT pathway regulation, beta-catenin degradation	Colorectal (80-90%)	Mutation, loss of heterozygosity
BRCA1	DNA double-strand break repair (HRR)	Breast, ovarian, pancreatic, prostate	Mutation (germline/familial)
BRCA2	DNA double-strand break repair (HRR)	Breast, ovarian, pancreatic, prostate	Mutation (germline/familial)
PTEN	PI3K/AKT pathway phosphatase	Endometrial (40-50%), breast, prostate	Mutation, deletion
CDKN2A (p16)	Cyclin-dependent kinase inhibitor	Melanoma, pancreatic, head/neck	Mutation, deletion, methylation
VHL	E3 ubiquitin ligase (HIF regulation)	Renal cell carcinoma (clear cell)	Mutation, methylation
NF1	RAS-GAP (negative regulator of RAS)	Neurofibromatosis type 1, astrocytoma	Mutation, deletion

TNM Staging System

The TNM system (AJCC/UICC) classifies cancers by three components: Tumor (T), Nodes (N), and Metastasis (M).

Component	Description
T (Tumor)	Size and extent of primary tumor (TX, T0, Tis, T1-T4)
N (Nodes)	Regional lymph node involvement (NX, N0, N1-N3)
M (Metastasis)	Distant metastasis (M0, M1)

TNM Descriptors

Category	Description
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ (non-invasive)
T1-T4	Increasing size and/or local extent of primary tumor
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1-N3	Increasing regional lymph node involvement
M0	No distant metastasis
M1	Distant metastasis present

Stage Grouping

Stage	General TNM	Description
Stage 0	Tis, N0, M0	Carcinoma in situ
Stage I	T1, N0, M0	Early, localized disease
Stage II	T2-3, N0, M0 or T1, N1, M0	Locally advanced, no nodal or limited nodal spread
Stage III	T3-4, N1-2, M0 or Tany, N2-3, M0	Advanced local/regional disease
Stage IV	Tany, Nany, M1	Distant metastatic disease

Grade (Histologic Differentiation)

Grade	Description
GX	Grade cannot be assessed
G1	Well differentiated (resembles normal tissue)
G2	Moderately differentiated
G3	Poorly differentiated
G4	Undifferentiated (anaplastic)

Common Cancers

Lung Cancer

Parameter	Detail
Incidence	2.2 million cases/year (leading cause of cancer death)
Risk factors	Smoking (85-90%), radon, asbestos, air pollution, second-hand smoke, genetic predisposition
Histologic subtypes	NSCLC (85%): adenocarcinoma, squamous cell, large cell; SCLC (15%)

NSCLC vs SCLC

Feature	NSCLC (Non-Small Cell Lung Cancer)	SCLC (Small Cell Lung Cancer)
Histology	Adenocarcinoma (most common), squamous, large cell	Small, round cells with scant cytoplasm, neuroendocrine features
Smoking association	Strong (weaker for adenocarcinoma)	Very strong (>95% of patients are smokers)
Growth rate	Slower	Rapid
Metastasis	Later in course	Early and widespread
Paraneoplastic syndromes	Less common	Common (SIADH, Cushing, Lambert-Eaton)
Driver mutations	EGFR, ALK, KRAS, BRAF, ROS1	Rarely targetable (except DLL3)
Primary treatment	Surgery (early), chemo/immuno/targeted (advanced)	Chemo + immunotherapy + radiation
Prognosis	Better stage-for-stage	Poor (median survival 10-12 months extensive stage)

Lung Cancer Staging (Simplified NSCLC)

Stage	Treatment Approach
Stage I	Surgical resection (lobectomy), consider SBRT if inoperable
Stage II	Surgery + adjuvant chemotherapy
Stage IIIA	Multimodality: chemo + radiation, +/- surgery
Stage IIIB	Definitive chemo + radiation
Stage IV	Systemic therapy: targeted (if driver mutation), immunotherapy +/- chemotherapy, palliative radiation

Breast Cancer

Parameter	Detail
Incidence	2.3 million cases/year (most common cancer in women)
Lifetime risk (women)	~13% (1 in 8)
Risk factors	Female sex, age, BRCA1/2, family history, early menarche, late menopause, nulliparity, HRT, obesity, alcohol

Breast Cancer Molecular Subtypes

Subtype	Receptor Status	Frequency	Treatment	Prognosis
Luminal A	ER+, HER2-, Ki67 low	40%	Endocrine therapy (tamoxifen, AI)	Best
Luminal B	ER+, HER2-/+ , Ki67 high	20%	Endocrine therapy +/- chemo +/- anti-HER2	Intermediate
HER2-enriched	ER-, HER2+	15%	Anti-HER2 therapy (trastuzumab, pertuzumab, T-DM1) + chemo	Good (with targeted therapy)
Triple-negative (basal)	ER-, PR-, HER2-	15%	Chemotherapy, immunotherapy (PD-1/PD-L1), PARP inhibitors (if BRCA)	Worst

Breast Cancer Treatment

Stage	Treatment
DCIS (Stage 0)	Lumpectomy + radiation or mastectomy; +/- endocrine therapy if ER+
Stage I-II	Surgery (breast-conserving or mastectomy), sentinel node biopsy, radiation (if BCT or nodes+), adjuvant systemic therapy
Stage III	Neoadjuvant chemo, then surgery, then radiation, then endocrine (if ER+) and/or anti-HER2 (if HER2+)
Stage IV	Palliative systemic therapy (endocrine, targeted, chemo, immunotherapy); radiation for local control

Colorectal Cancer

Parameter	Detail
Incidence	1.9 million cases/year (third most common)
Risk factors	Age >50, family history, IBD, Lynch syndrome, FAP, diet (red/processed meat), obesity, smoking, alcohol
Precursor lesion	Adenomatous polyp (tubular, villous, tubulovillous)
Carcinogenesis pathway	Adenoma-carcinoma sequence (APC, KRAS, TP53 mutations) or serrated pathway (BRAF, CpG island methylation)

Colorectal Cancer Staging and Treatment

Stage	TNM	5-Year Survival	Treatment
I	T1-2, N0, M0	>90%	Surgical resection alone
II	T3-4, N0, M0	75-85%	Surgery; consider adjuvant chemo if high-risk features
III	Tany, N1-2, M0	40-70%	Surgery + adjuvant chemotherapy (FOLFOX or CAPOX)
IV	Tany, Nany, M1	10-15%	Systemic therapy (FOLFOX/FOLFIRI + bevacizumab, anti-EGFR if RAS wt), +/- metastasectomy

Prostate Cancer

Parameter	Detail
Incidence	1.4 million cases/year (most common cancer in men)
Lifetime risk (men)	~11% (1 in 9)
Risk factors	Age, African ancestry, family history, BRCA2 mutation, Lynch syndrome
Screening	PSA blood test +/- DRE (shared decision-making starting at age 45-50)

Prostate Cancer Risk Stratification

Risk Group	PSA	Gleason Grade	Clinical Stage	Management
Very low	<10 ng/mL	Grade 1 (3+3=6)	T1c	Active surveillance
Low	<10 ng/mL	Grade 1	T1-T2a	Active surveillance or treatment
Favorable intermediate	10-20 ng/mL	Grade 2 (3+4=7)	T2b-T2c	Radical prostatectomy or radiation
Unfavorable intermediate	10-20 ng/mL	Grade 3 (4+3=7)	T2b-T2c	Radical prostatectomy or radiation +/- ADT
High	>20 ng/mL	Grade 4-5 (8-10)	T3-T4	Radiation + ADT or radical prostatectomy
Metastatic	Any	Any	N+/M1	ADT + chemotherapy (docetaxel) or AR-targeted therapy (abiraterone, enzalutamide)

Skin Cancer

Type	Origin	Frequency	Metastatic Potential	Key Features
Basal cell carcinoma (BCC)	Basal layer of epidermis	Most common (80% of skin cancers)	Very low	Pearly nodule with telangiectasias, rolled borders, ulceration (rodent ulcer)
Squamous cell carcinoma (SCC)	Keratinizing cells of epidermis	Second most common (16%)	Low-moderate	Scaly, hyperkeratotic plaque or ulcer; can metastasize to nodes
Melanoma	Melanocytes	4% of skin cancers	High	ABCDE criteria (Asymmetry, Border irregularity, Color variegation, Diameter >6mm, Evolution)

Melanoma Staging and Treatment

Stage	Breslow Thickness	Treatment	5-Year Survival
0 (in situ)	Confined to epidermis	Wide local excision (0.5-1 cm margins)	>99%
IA	<0.8 mm, no ulceration	Wide local excision (1 cm margins)	>95%
IB	<0.8 mm with ulceration or 0.8-1.0 mm	Wide excision + SLNB	90-95%
II	>1 mm without nodal involvement	Wide excision + SLNB; consider adjuvant immunotherapy	45-85%
III	Nodal involvement	Wide excision + lymph node dissection + adjuvant immunotherapy (nivolumab, pembrolizumab)	25-60%
IV	Distant metastasis	Immunotherapy (PD-1 +/- CTLA-4), targeted therapy (BRAF/MEK if BRAF mutant), clinical trials	15-20% (improving)

Treatment Modalities

Surgery

Type	Description	Examples
Curative resection	Complete removal of tumor with negative margins (R0)	Colectomy, mastectomy, prostatectomy
Debulking	Removal of bulk tumor when complete resection not possible	Ovarian cancer cytoreduction
Palliative surgery	Symptom relief without cure	Bypass surgery for obstructing tumors
Sentinel lymph node biopsy	Identification and biopsy of first draining lymph node	Breast cancer, melanoma
Metastasectomy	Surgical removal of isolated metastases	Liver metastases (colorectal), lung metastases

Chemotherapy

Drug Class	Mechanism	Examples	Common Toxicities
Alkylating agents	DNA crosslinking, alkylation	Cyclophosphamide, cisplatin, carboplatin, oxaliplatin	Myelosuppression, nephrotoxicity (cisplatin), neuropathy (oxaliplatin), hemorrhagic cystitis (cyclophosphamide)
Antimetabolites	Inhibition of DNA/RNA synthesis	5-FU, capecitabine, methotrexate, gemcitabine, pemetrexed	Mucositis, diarrhea (5-FU), myelosuppression
Anthracyclines	Topoisomerase II inhibition, DNA intercalation	Doxorubicin, epirubicin, daunorubicin	Cardiotoxicity (cumulative), myelosuppression, alopecia
Taxanes	Microtubule stabilization	Paclitaxel, docetaxel, cabazitaxel	Neuropathy, hypersensitivity, myelosuppression
Vinca alkaloids	Microtubule inhibition	Vincristine, vinblastine	Neuropathy (vincristine), constipation
Topoisomerase inhibitors	Topoisomerase I/II inhibition	Irinotecan, topotecan, etoposide	Diarrhea (irinotecan), myelosuppression
Platinum analogs	DNA crosslinking	Cisplatin, carboplatin, oxaliplatin	Nephrotoxicity, ototoxicity (cisplatin); thrombocytopenia (carboplatin); neuropathy (oxaliplatin)

Radiation Therapy

Type	Description	Examples
External beam radiation (EBRT)	Radiation delivered from external source	3D-CRT, IMRT, VMAT, SBRT, SRS
Brachytherapy	Radioactive source placed inside/near tumor	Prostate, cervical, breast
Stereotactic radiosurgery (SRS)	High-dose, precisely focused radiation	Brain metastases, arteriovenous malformations
Stereotactic body radiation (SBRT)	High-dose radiation to extracranial sites	Early-stage NSCLC, liver metastases
Intraoperative radiation (IORT)	Single dose during surgery	Breast, GI, retroperitoneal sarcomas

Immunotherapy

Modality	Mechanism	Examples	Indications
Immune checkpoint inhibitors (anti-PD-1/PD-L1)	Block PD-1/PD-L1 interaction, reactivate T cells	Nivolumab, pembrolizumab, atezolizumab, durvalumab, cemiplimab	Melanoma, NSCLC, RCC, bladder, HNSCC, Hodgkin lymphoma, MSI-H cancers
Immune checkpoint inhibitors (anti-CTLA-4)	Block CTLA-4, enhance T-cell activation	Ipilimumab	Melanoma, RCC, MSI-H CRC
CAR-T cell therapy	Engineered T cells targeting tumor antigens	Tisagenlecleucel (CD19), axicabtagene ciloleucel (CD19), idecabtagene vicleucel (BCMA)	B-cell ALL, DLBCL, multiple myeloma
Cytokines	Enhance immune response	IL-2, IFN-alpha	RCC, melanoma (limited use)
Oncolytic viruses	Viruses that selectively infect and lyse tumor cells	Talimogene laherparepvec (T-VEC)	Melanoma

Targeted Therapy

Target	Drug Class	Mechanism	Examples	Cancer Types
EGFR	Tyrosine kinase inhibitors (TKIs)	Block EGFR signaling	Erlotinib, gefitinib, osimertinib, afatinib	NSCLC (EGFR-mutant)
EGFR	Monoclonal antibodies	Block extracellular domain	Cetuximab, panitumumab	CRC (RAS wt), HNSCC
HER2	Monoclonal antibodies	Block HER2 signaling	Trastuzumab, pertuzumab, T-DM1, trastuzumab deruxtecan	Breast, gastric (HER2+)
BRAF V600	BRAF inhibitors	Block mutant BRAF	Vemurafenib, dabrafenib, encorafenib	Melanoma, thyroid, NSCLC
MEK	MEK inhibitors	Block downstream MAPK	Trametinib, cobimetinib, binimetinib	Melanoma (with BRAFi), NSCLC
ALK	ALK inhibitors	Block ALK fusion protein	Crizotinib, alectinib, brigatinib, lorlatinib	NSCLC (ALK+)
BCR-ABL	TKIs	Block BCR-ABL fusion	Imatinib, dasatinib, nilotinib, ponatinib	CML, Ph+ ALL
VEGF/VEGFR	Anti-angiogenic	Block tumor angiogenesis	Bevacizumab, ramucirumab, sunitinib, pazopanib, axitinib	CRC, RCC, HCC, GBM
CDK4/6	CDK4/6 inhibitors	Block cell cycle progression	Palbociclib, ribociclib, abemaciclib	Breast cancer (HR+/HER2-)
PARP	PARP inhibitors	Block DNA repair (synthetic lethality in BRCA-mutant)	Olaparib, niraparib, rucaparib, talazoparib	Ovarian, breast, pancreatic, prostate (BRCA-mutant)

Cancer Screening Guidelines

Cancer Type	Screening Test	Population	Frequency
Breast	Mammography	Women 40-74 years (USPSTF: 50-74 biennial; ACS: 45-54 annual)	Every 1-2 years
Cervical	Pap smear +/- HPV testing	Women 21-65 years	Every 3-5 years
Colorectal	Colonoscopy (gold standard), FIT, CT colonography, sigmoidoscopy	Adults 45-75 years (USPSTF)	Colonoscopy every 10 years; FIT annually
Lung	Low-dose CT (LDCT)	Adults 50-80 years with 20 pack-year smoking history, current smoker or quit within 15 years	Annually
Prostate	PSA +/- DRE	Men 45-70 years (shared decision-making)	Every 1-4 years (risk-based)
Skin (melanoma)	Clinical skin exam	High-risk individuals (family history, dysplastic nevi, prior skin cancer)	Annually or as recommended

Cancer Prevention

Strategy	Impact
Smoking cessation	Single most effective intervention (30% of cancer deaths)
Sun protection (sunscreen, clothing, shade)	Reduces skin cancer risk by 50-80%
HPV vaccination	Prevents 90% of HPV-related cancers
Hepatitis B vaccination	Prevents HBV-related HCC
Moderate alcohol consumption	Linked to breast, colorectal, liver, esophageal cancers
Healthy diet (Mediterranean, high fiber)	Reduces colorectal and other cancer risks
Regular physical activity	Reduces risk of breast, colon, endometrial cancers
Weight management (BMI 18.5-25)	Obesity linked to 13 cancer types
Chemoprevention	Tamoxifen/AI for breast cancer risk reduction; aspirin for CRC
Cancer screening	Early detection reduces mortality