Breast cancer
What is it?
Breast cancer is the most common malignant tumor in women (the cumulative lifetime risk of developing it is 1 in 9 women), while it is rare in men: in Italy, the incidence is around 500 cases per year. It is the main cause of cancer deaths in the female population. However, thanks to the spread of screening programs and therapeutic advances, the mortality rate is steadily decreasing, and the survival rate is 87% at 5 years and 80% at 10 years. Most cases of breast cancer are sporadic and have an unknown or mostly multifactorial etiology. However, there are known risk factors for the development of breast cancer, such as dietetic (consumption of alcohol and animal fats in large quantities), metabolic (obesity, metabolic syndrome), and most importantly, hormonal factors (menopausal hormone replacement therapy and some types of oral contraceptives). Reproductive factors leading to increased estrogen exposure, childlessness, first pregnancy after age 30 and failure to breastfeed, long duration of fertile period with early onset of menarche and late menopause are also associated with an increased risk of breast cancer. Other factors include previous chest radiation therapy, especially at a young age (10 to 30 years), previous dysplasia or neoplasia of the breast, age, family history, and genetic predisposition. Hereditary-family forms of cancer account for 20-30% of cases, of which 5-7% are inherited; mutations in the BRCA1 and BRCA2 genes are the most common. If a mutation is detected, special follow-up programs and, in some cases, bilateral prophylactic mastectomy and oophorectomy may be offered. Breast carcinoma is an extremely heterogeneous disease in terms of morphologic features, clinical course, and response to various treatments. A distinction is made between noninvasive (carcinoma in situ) and invasive forms. As for invasive tumors, 70-80% of cases are infiltrating breast cancer of nonspecific histotype, or ductal carcinoma, and about 10-15% are infiltrating lobular carcinoma. Other histotypes are much less common, including tubular, cribriform, adenoid cystic, mucinous, metaplastic carcinoma. The most important molecular characteristics for breast cancer classification, regardless of histotype, are represented by the expression of three receptors: estrogen receptor [ER], progesterone receptor [PgR] and human epidermal growth factor receptor type 2 [HER2]. The combination of these three biological characteristics makes it possible to define the four molecular subtypes of breast cancer required for therapy selection: ER+ and/or PgR+ and HER2- tumors (65-70%), ER+ and/or PgR+ and HER2+ tumors (8-10%), ER-, PgR- and HER2+ tumors (7-10%), ER-, PgR- and HER2- tumors (so called triple negative tumors) (10-15%).
Which are the symptoms?
The most common sign is a node in the breast, detectable on palpation, usually painless, hard and jagged. Other common signs are swelling or irregularity of the breast contour; redness, retraction or thickening of the skin; orange peel skin; retraction, inversion or ulceration of the nipple; spontaneous release of serous-bloody material from the nipple; eczema of the nipple-areolar complex (Pejeta disease). Immobile or bundled axillary lymph nodes or palpable supraclavicular/subclavicular lymph nodes and/or breast nodes infiltrating the chest wall or skin may be found. In advanced stages of the disease, there may be symptoms suggestive of metastatic disease: bone pain, difficulty breathing, abdominal bloating, jaundice, headache, focal or systemic neurologic signs.
- nodule in the breast/swelling
- redness of the skin of the breast
- nipple retraction/inversion
- serous/bloody release from the nipple
- orange peel skin
- firm and enlarged axillary lymph nodes
- supraclavicular lymphadenopathy
- eczema of the nipple-areolar complex
How is it diagnosed?
Diagnosis of breast cancer in most cases occurs when a nodule in the breast or subsequent locoregional changes is detected, either by self-diagnosis or as part of a screening program. Mammography is used as a screening test; breast ultrasound is usually performed as an adjunct to mammography. Closer monitoring and breast MRI are mandatory for patients with BRCA1 and 2 gene mutations. Breast MRI is a second level examination, recommended before surgery when multifocal/multicenter lesions are suspected and as a problem solving technique in case of unclear pattern of mammografy and ultrasound results. Histologic examination is necessary for the definitive diagnosis of breast cancer, as well as to determine the histotype and molecular characteristics of the carcinoma. It can be performed with needle aspiration (indicated only for cysts or axillary lymph nodes); needle core biopsy (the most commonly used and recommended method) or VABB (vacuum-assited breast biopsy). Staging is indicated only in patients with a high risk or suspected localized metastatic lesion. Staging examination include: chest x-rays and abdominal ultrasound (or chest and abdominal CT), and bone scintigraphy. PET or PET/CT with FDG is considered a second-line examination.
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How is it treated?
Several treatment modalities are possible. The combination of the different options and the order in which they are applied depend on the stage of the disease and the biological characteristics listed above (molecular subtypes).
- Surgery: the most frequent method of surgical treatment of the breast is conservative (quadrantectomy or tumorectomy), less common is mastectomy (removal of the entire breast parenchyma) with or without removal of the nipple-areolar complex. If from a clinical point of view, there are no axillary lymph nodes affected, the signal lymph node method is used; if the lymph nodes appear to be affected, axillary dissection is standard.
- Radiation therapy: after quadrantectomy and in some cases after mastectomy, post-operative adjuvant radiotherapy is indicated. The technologies available allow us to offer patients hypofractionated treatments in 15 fractions that allow to limit the duration of treatment with results in terms of disease control and toxicity comparable to conventional schemes in 25-30 sessions. This modality can also be applied when it is necessary to irradiate the lymph node regions at the same time as the breast / thoracic wall without a significant increase in terms of toxicity. In selected cases, post-operative radiation treatment can be delivered in just 5 sessions, even in PBI (partial breast irradiation) mode. A protocol for single-session irradiation for post-operative adjuvant purposes is being developed. Radiant treatment can be used, in particular cases and after multidisciplinary discussion, also for curative purposes in place of surgery.
- Systemic therapy: at the early stages of tumors (operable), its main goal is to increase the chances of cure by destroying the micrometastatic disease, it can be prescribed before surgery (neoadjuvant) or after surgery (adjuvant or prophylactic therapy). The drugs prescribed (chemotherapy, endocrine therapy or biological agents) depend on the molecular subtype of the tumor, the pathologic stage at the time of surgery, and prognostic factors; genomic testing can provide direction in treatment selection. For metastatic lesions, treatment is usually palliative. Treatment depends on clinical factors and tumor biology and may consist of chemotherapy (e.g., anthracyclines, taxanes, capecitabine, eribulin, vinorelbine, gemcitabine, platinum salt derivatives) used alone or in combination with other treatments. Hormonal therapy with aromatase inhibitors, tamoxifen or fulvestrant remains the mainstay of initial treatment for ER+ tumors and is often used in combination with biologic agents (CDK4-6 inhibitors, PI3K inhibitors in case of PIK3CA mutated tumors). In the subgroup of HER2+ tumors, the main treatment is anti-HER2 maintenance therapy, usually in combination with other drugs. In this case, anti-HER2 antibodies conjugated with chemotherapy drugs (T-DM1, DS8201) are highly effective treatment options. In a subgroup of triple-negative tumors, immunotherapy (atezolizumab), bevacizumab, and PARP inhibitors (olaparib, talazoparib) in patients with germinal BRCA1/2 mutations are the only biological treatments in addition to chemotherapy. In some cases, an extended genomic study (e.g., Foundation Medicine) may be required to verify the presence of molecular alterations that could be used as therapeutic targets.
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