Breast cancer

Breast cancer is the most common cancer in women and the leading cause of cancer-related mortality among females. It will affect 1 in 7 women in Western countries and is rare in men. Its incidence is increasing (due to rising risk factors).

Risk Factors

• Age, obesity, animal fats, alcohol (more than 2 glasses/day), sedentary lifestyle
• Nulliparity or low parity, first pregnancy after age 30, early menarche, late menopause
• Personal history of breast cancer or certain benign breast conditions (macro-cysts, presence of cellular atypia)
• Family history of breast or ovarian cancer in premenopausal first-degree relatives
• Hormonal treatment (slight increase with COCs, but it disappears 10 years after stopping; debated risk for hormone replacement therapy)
• Absence of breastfeeding

Hereditary Breast Cancers: BRCA1 and BRCA2 Mutations

One of these abnormalities is found in about 10% of young women with breast cancer. Their presence seems to indicate a worse prognosis than sporadic cancers.

In the United States, many doctors recommend oophorectomy and bilateral total mastectomy as early as puberty for mutation carriers... A radical solution but reduces the risk of breast cancer by 90%, and even more so for ovarian cancer. Given the traumatic nature of such interventions, a more conservative approach is taken in most countries, involving discussions with the patient about prophylactic surgery versus early, careful breast monitoring and bilateral oophorectomy once reproductive desires are fulfilled (as there are no truly effective early detection methods).

These are tumor suppressor genes. The mutations are dominant with incomplete penetrance.

• BRCA 1 mutations (autosomal dominant with incomplete penetrance): the risk of developing breast cancer for a woman is 60 to 90% and ovarian cancer 20 to 50%. Little or no risk for men.
• BRCA2 mutations (autosomal dominant with incomplete penetrance): the risk of developing breast cancer for a woman is 60 to 90% and ovarian cancer 10 to 20%. The risk of breast cancer for a man is 6% (relative risk x 100). The role of this mutation is also discussed in prostate and laryngeal cancers...

Clinical Examination

Examination of both breasts, as cancer is bilateral from the outset in 10% of cases.

• Inspection:
  • Deformation, skin retraction, "peau d’orange" (obstruction of lymphatics)
  • Nipple invasion
  • Paget's disease of the breast: red and painful nipple with extensive ulceration
• Palpation:
  • Hard, poorly defined, painless tumor, adherent to the skin or deep planes, rapidly increasing in size. Lymphadenopathy.
• Pressure:
  • Nipple discharge (bloody, watery,…)

Additional Examinations

Mammography

• Front + profile
• Comparison with previous images
• Galactography

The performance of the examination increases with age (cancer is primarily revealed by an opacity, whereas younger breasts are mainly glandular [radiopaque] while older breasts undergo fatty involution [radiotransparent]).

Ultrasound

• of breast and axillary regions
• dynamically examining by mobilizing the tumor
• preferred examination for younger women (more radiopaque breasts)
• malignant signs: heterogeneity, poor delimitation, infiltrative tumor, micro-calcifications, asymmetries, and architectural distortions

Biopsies

• In case of discharge: cytology
• Tumor puncture under ultrasound
  • Fine needle: cytology
  • Tru-cut, spirotome, or mammotome: histology, good performance for diagnosis

Anatomopathological Classification

"Breast cancers" (improper terminology):

• In situ (dysplasia)
  • CLIS = "lobular carcinoma in situ". Considered a "simple" risk factor for the occurrence of invasive cancer = DLIS
  • CCIS = "ductal carcinoma in situ". Considered a true precancerous lesion = DCIS
• Invasive (neoplasias)
  • CLI = invasive lobular cancer (20%)
  • CCI = invasive ductal cancer (80%)

The CLIS

It is not considered a true cancerous or precancerous lesion but as a risk factor for the development of cancer: 25 to 30% of cases will progress to invasive cancer in one of the two breasts.

Treatment:

• Tumor > 3cm: tumorectomy, no adjuvant treatment
• Tumor < 3 cm: simple follow-up

The follow-up is the same as for screening women at risk

The CCIS

On the other hand, the CCIS is considered a true precancerous lesion: 30 to 60% of cases will progress to invasive cancer in the affected breast.

Van Nuys Score (anatomopathological-clinical):

Points to assign	1	2	3
Size	< 15 mm	16-40 mm	> 40 mm
Healthy margins	>10 mm	1-9 mm	< 1mm
Age	> 60 years	40-60 years	< 40 years
Histological Grade	1-2 without necrosis	1-2 with necrosis	3

Treatment:

According to the Van Nuys score:

• 4-6: tumorectomy
• 7-9: tumorectomy + radiotherapy
• 10-12: mastectomy + sentinel lymph node

For all: consider the use of tamoxifen as adjuvant treatment.

Cancers: CLI AND CCI

TNM Staging (clinical)

• T (size and extent of the tumor)
  • T1: < 2 cm
    • T1 mic: < 0.1 cm
    • T1a: 0.1 < x < 0.5 cm
    • T1b: 0.5 < x < 1 cm
    • T1c: 1 < x < 2 cm
  • T2: 2 < x < 5 cm
  • T3: > 5 cm
  • T4 = locally advanced cancer = infiltrating cancer
    • T4a: infiltrates the chest wall
    • T4b: infiltrates the skin
    • T4c: infiltrates both the chest wall and the skin
    • T4d: inflammatory = carcinomatous mastitis
• N (lymphadenopathy)
  • N0: no lymph nodes involved
  • N1: 1-3 axillary nodes
  • N2: 4-9 axillary nodes
  • N3: 10 or more axillary nodes
    • N3a: clinically involved supraclavicular nodes
    • N3b: axillary + supraclavicular
  • M (metastases)
  • M0: no metastases
  • M1: metastases

pTNM Staging (Anatomopathological)

The same criteria as for clinical TNM but based on histological findings, except for N (lymphadenopathies), which is determined by the number and location of lymph node metastases in the samples.

Extension Assessment

• Chest X-ray or CT scan
• Liver ultrasound
• Bone scintigraphy
• Biology with CA 15-3 level measurement

+- other tests based on clinical indications.

Therapeutic Management - Treatments

The treatment is typically "aggressive," with a 5-year survival prognosis (80% to 90% for non-metastatic cancers) being excellent under optimal treatment.

Surgery

Surgery forms the basis of treatment, provides definitive diagnosis, and offers useful prognostic and therapeutic information.

Subclinical Lesions

• Preoperative localization with hook wire
• Localization with methylene blue (for galactophorous lesions)
• Intraoperative radiology if micro-calcifications are present

Tumorectomies

• Curved incisions if above the nipple, straight diagonal incisions if below the nipple
• Orientation of the surgical specimen (right/left, cranial/caudal, internal/external)
• Margins marking
• Intraoperative assessment of the tumor and margins

Mastectomy

Indications:

• After intraoperative assessment of a tumorectomy if margins are not clear
• Multicentric tumors
• Refusal or contraindication for radiotherapy
• Recurrence after tumorectomy
• Aesthetic reasons?
• (High-grade DCIS)

Axillary Dissection

2 options:

• Intraoperative assessment of a sentinel node and complete dissection based on the histopathological result
• Complete dissection upfront

Radiotherapy

• Always post-tumorectomy
• Post-mastectomy
  • Always if:
    • > 3 involved nodes
    • T3 and T4
  • To be discussed if:
    • Tumor > 3 cm + presence of risk factors
    • 1-3 nodes + presence of risk factors
    • Involved margins or margins less than 2 mm

Hormone Therapy

If ER or PR positive receptors.

• Premenopausal: Zoladex for 2-3 years + Tamoxifen for 5 years
• Postmenopausal: Tamoxifen or aromatase inhibitors

Chemotherapy

• Always if ER or PR negative receptors
• Otherwise:
  • If negative nodes: possibly in cases of intermediate risk (> 2 cm, T2-3, < 35 years)
  • If positive nodes (to be discussed if postmenopausal)

Follow-up After Curative Treatment

• Clinical: once every 3 months in the first year, once every 4 months for the following 4 years, once every 6 months thereafter
• Ultrasound + mammography once every 6 months for 3 years, then once a year

New Therapeutic Management - Immunotherapy

Immunotherapies (e.g., Pembrolizumab, Nivolumab, ...) aimed at stimulating the patient’s immune system (lymphocyte activation, checkpoint blockade, ...) are specific forms of chemotherapy currently in development.

They are currently routinely reserved as adjuvant treatment for initially inoperable, multi-metastatic cancers or recurrences, aiming to prolong survival. Evidence-based medicine is currently of low quality, but results based on small series are very encouraging. It is likely that in the future they will be integrated into all treatment protocols.

Regarding breast cancer, they are also routinely included in the management of hormone-negative forms.

Screening

Screening of the General Population (absence of risk factors)

Studies have shown that systematic mammography in women over 50 leads to a 22% reduction in mortality and a 16% reduction in women aged 40-49. However, there are many false positives, the number of which increases with decreasing age. The American Cancer Society recommends annual mammography for all women over 40 years old.

The Mammotest in Belgium since 2001

• For all women aged 50 to 69
• Free of charge
• By invitation since 2005
• Consists of a digital mammography once every 2 years, with double reading

Screening of the At-Risk Population

• To start 5 years before the age of family cases
• For very young women: clinical + ultrasound (+- MRI) 1-2 times a year
• For others: clinical + ultrasound (+- MRI) 1-2 times a year + mammography once a year

Who is likely to benefit?

• Family history of breast or ovarian cancer in first-degree relatives (in premenopausal)
• Personal history of breast cancer, macro-cysts, atypical cells, or CLIS

Bibliography

EMC, Traité de gynécologie, 2018