Elsevier

The Lancet

Volume 397, Issue 10286, 8–14 May 2021, Pages 1750-1769
The Lancet

Seminar
Breast cancer

https://doi.org/10.1016/S0140-6736(20)32381-3Get rights and content

Summary

Breast cancer is still the most common cancer worldwide. But the way breast cancer is viewed has changed drastically since its molecular hallmarks were extensively characterised, now including immunohistochemical markers (eg, ER, PR, HER2 [ERBB2], and proliferation marker protein Ki-67 [MKI67]), genomic markers (eg, BRCA1, BRCA2, and PIK3CA), and immunomarkers (eg, tumour-infiltrating lymphocytes and PD-L1). New biomarker combinations are the basis for increasingly complex diagnostic algorithms. Neoadjuvant combination therapy, often including targeted agents, is a standard of care (especially in HER2-positive and triple-negative breast cancer), and the basis for de-escalation of surgery in the breast and axilla and for risk-adapted post-neoadjuvant strategies. Radiotherapy remains an important cornerstone of breast cancer therapy, but de-escalation schemes have become the standard of care. ER-positive tumours are treated with 5–10 years of endocrine therapy and chemotherapy, based on an individual risk assessment. For metastatic breast cancer, standard therapy options include targeted approaches such as CDK4 and CDK6 inhibitors, PI3K inhibitors, PARP inhibitors, and anti-PD-L1 immunotherapy, depending on tumour type and molecular profile. This range of treatment options reflects the complexity of breast cancer therapy today.

Section snippets

Epidemiology and risk factors

Worldwide, breast cancer accounts for about 30% of female cancers, and has a mortality-to-incidence ratio of 15%.1 Worldwide incidence varies between 27 in 100 000 (Africa and east Asia) and 97 in 100 000 (North America), reflecting the association between breast cancer incidence and the degree of economic development and associated social and lifestyle factors.2 In contrast, death rates continue to decline, but not everywhere. Declines in breast cancer mortality could be further accelerated by

Screening

Eight randomised clinical trials have shown that screening mammography reduces breast cancer mortality by at least 20%.16 Conventional screening mammography detects 2–8 cancers per 1000 mammograms, which is increased by 1·6 cancers per 1000 mammograms with the use of digital breast tomosynthesis.17 Ultrasonography screening, particularly in women with dense breasts, detects an additional 4·4 cancers per 1000 screening examinations, but the positive predictive value of ultrasonography is only

Biology and molecular pathology

Breast cancer is very heterogeneous, and clinically divided into three main subtypes by hormone receptor (ER and PR) and HER2 (ERBB2) status: luminal ER-positive and PR-positive, which is further subdivided into luminal A and B; HER2-positive; and triple-negative breast cancer (TNBC).28 Standardised diagnostic evaluation of hormone receptors (ER and PR) and HER2 based on international guidelines is essential for the determination of these subtypes.29, 30 Histochemical staining for the

Diagnosis and therapy: current controversies and scientific discussions

There are still controversies around every aspect of breast cancer diagnosis and care. For example, it has been shown that tumours with low-hormone receptor expression are biologically similar to TNBC. The American Society of Clinical Oncology and the College of American Pathologists have recently defined low-ER tumours as tumours with ER expression between 1% and 10%, without changing treatment recommendations,43 so that treating low-hormone receptor breast cancer as TNBC would be the logical

Early breast cancer: neoadjuvant treatment concept

Neoadjuvant therapy (mainly chemotherapy with targeted agents) has been widely accepted as a standard of care, especially in HER2-positive breast cancer and TNBC, even when the disease is operable. The general concept is to use the same systemic therapy as would be given postoperatively before surgery, followed by surgery and irradiation and further post-neoadjuvant systemic therapy, if required. Primary endocrine therapy is used in ER-positive breast cancer when primary surgery is

Early breast cancer: locoregional therapy

Options for the treatment of early-stage breast cancer include breast-conserving surgery and mastectomy with or without immediate reconstruction. Absolute contraindications to breast-conserving surgery are uncommon, but include inability to obtain negative margins and contraindications to radiotherapy. Multicentric cancer, previously thought to necessitate mastectomy, can be safely managed with breast-conserving surgery if two or more lumpectomies can be done with satisfactory cosmetic outcomes.

Endocrine therapy

Endocrine therapy for 5–10 years is the standard treatment for women with ER-positive early breast cancer. For postmenopausal women, options include tamoxifen or a steroidal (exemestane) or non-steroidal (letrozole or anastrozole) aromatase inhibitor. Front-line therapy with an aromatase inhibitor results in a significant absolute risk reduction of recurrence at 10 years of 3·6% and in an increase in overall survival of 2·1% compared with tamoxifen. The sequential approach of aromatase

Endocrine-responsive metastatic breast cancer

Endocrine therapy is standard of care, unless immediate response needs to be reached in patients with symptomatic breast cancer (which is an indication for chemotherapy).183 A CDK4/6 inhibitor combined with endocrine therapy should be considered a standard of care for patients with ER-positive, HER2-negative metastatic breast cancer. In comparison with endocrine therapy, this combination results in a higher response rate, progression-free survival benefit, and substantially increases overall

Conclusion and future perspectives

Future research in breast cancer will focus not only on new drugs, but even more on the individualisation of therapy for every single tumour in every single patient. Several agents (ie, PARP inhibitors, checkpoint inhibitors, and PI3K inhibitors) approved in recent years work only in patients or tumours with a certain biomarker or mutation. The European Society for Medical Oncology has set a scale for actionability of molecular targets.216 New drugs, such as AKT inhibitors (eg, ipatasertib,

Search strategy and selection criteria

Data for this Seminar were identified by searches of MEDLINE, PubMed, German Association of the Scientific Medical Societies Guideline Register/Clinical Practice Guidelines, and references from relevant articles between Jan 1, 2016, and Dec 31, 2020, using the search term “breast cancer” in combination with specific terms covering the different steps of diagnosis and treatment as appropriate. We mostly selected literature published in the past 5 years, but did not exclude older publications

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