Overview

Breast Cancer (BC) is a common cause of death in assigned females at birth [AFAB] worldwide, and the most frequent type of cancer that AFABs have been diagnosed with. Breast cancer can be classified into four molecular subtypes in terms of the expression of oestrogen receptor (ER), progesterone receptor (PR), and the overexpression of the human epidermal growth factor receptor 2 (HER2). These subtypes are called luminal A, luminal B, and HER2 breast cancer, respectively, however, it is known as triple-negative breast cancer (TNBC) in the absence of the expression of these receptors (targeted by oestrogen, progesterone and HER2 hormones).

Breast cancer stages are determined by tumour size, the presence of metastases, nodal involvement level and certain biomarkers such as oestrogen receptors, progesterone receptors and the ERBB2 receptors (HER2). The current BC treatments depend on these staging factors.^1,2 Non-metastatic BC includes non-invasive BC (stage 0), early invasive cancer (stages I, IIa and IIb) and locally advanced (stages IIIa, IIIb and IIIc) and metastatic BC being the stage IV.

Treatment involves surgical interventions, endocrine and anti-HER2 therapies used in the presence of receptor expression, along with radiotherapy and chemotherapy which is widely used in different BC stages, but this depends on chemotherapy efficacy that is linked to the level of risk to the patient.^1–3

Breast cancer chemotherapy 

Mechanism of action

Chemotherapy is a treatment that includes cytotoxic drugs of several families acting by destroying cancerous cells. Chemotherapy is classified into alkylating agents, antimetabolites and tubulin inhibitors. The mechanisms of action of these groups are; breaking the DNA strands resulting in interruption of its normal function, inhibiting deoxyribonucleic acid (DNA) replication and binding to microtubules causing cell cycle arrest, preventing cell division and cell death.^1,2

Administration and uses

Chemotherapy can be administered in the neoadjuvant (before surgery) or adjuvant (after surgery) regimens during primary breast cancer (non-metastatic) and for secondary breast cancer (metastatic breast cancer).²

Neoadjuvant chemotherapy (NAC)

Primary chemotherapy was initially used for non-metastatic BC to slow the growth of rapidly multiplying cancerous cells or shrink their size. Studies showed that chemotherapy given before surgery was of the same efficacy as that given after surgery, as a clinical trial demonstrated a reduction in metastatic rate in node-negative BC patients (lymph nodes without cancer) using cyclophosphamide and doxorubicin preoperatively and postoperatively. Certain patients fail to achieve a complete response after a full course of NAC. Indeed, this depends on the BC subtype, NAC is an appropriate setting followed in patients classified as TNBC and HER2+ BC, these two subtypes are more sensitive to NAC strategy. 

Adjuvant chemotherapy

It is used after surgery in primary BC (non-metastatic breast cancer) to reduce the risk of cancer recurrence or spread. Iit is also used in patients with lymph node metastasis. The standard chemotherapy treatment is an anthracycline and a taxane and the two most commonly applied regimens are cyclophosphamide and doxorubicin for four cycles followed by paclitaxel for four cycles. Then the second step is administering the previous therapeutic combination followed by either docetaxel every 3 weeks for four cycles, or weekly paclitaxel for 12 weeks.

The same concept for neoadjuvant CT is applied to adjuvant CT. Patients with HR-negative BC (TNBC and HER2+ BC, or BC negative to sexual hormones progesterone and oestrogen) will receive an effective outcome compared to HR+ BC patients, for example, lower recurrence rates.²

Regarding patients with molecular BC subtypes who express positive molecular structures as HER2+ and HR+ BC patients should have certain therapeutic plans, HR+ BC patients are highly recommended to receive endocrine therapy after completion of the chemotherapy course as these patients express sexual hormones oestrogen and progesterone, thus they will require an endocrine treatment that opposes the effect of these hormones. However, HER2+ BC patients should receive trastuzumab combined with chemotherapy. 

Secondary breast cancer recommendations

Chemotherapy is used as well to treat secondary breast cancer (metastatic BC) which has spread to other parts of the body. It can be given alone or as a combination therapy with other treatments such as hormone therapy, targeted therapy, immunotherapy or radiotherapy; this depends on the subtype of breast cancer.⁴

Before starting breast cancer chemotherapy

Before initiating breast cancer chemotherapy, chemotherapy information sessions could be arranged by the hospital to educate, advise and guide the patient about the BC chemotherapy side effects and how it can be managed.⁴

Moreover, depending on each case, the patient will have blood tests, an electrocardiogram (ECG), an echocardiogram, an ultrasound scan of the heart and heart rhythm checks. In addition to height and weight measurement, this will specify the correct chemotherapy dose. 

The patient will be asked to sign a consent form before chemotherapy initiation. Also, the advantages and risks of the treatment will be discussed with the patient. The patient will have a blood test before each chemotherapy cycle and may be in between to check blood cell count which may become low due to chemotherapy side effects. Anti-sickness medication and dexamethasone will be given, this depends on the type of chemotherapy. 

Chemotherapy side effects

 Early side effects (0-6 months) of treatment

• Cytopenia (reduced count of normal blood cells)
• Fatigue
• Alopecia
• Neurocognitive dysfunction
• Chemo-induced peripheral neuropathy
• Muscle pain²

Chronic or late side effects (after 6 months of treatment)

• Sterility
• Cardiomyopathy
• Early menopause
• Second cancers
• Psychosocial concerns 

Single agent chemotherapy vs combination therapy

According to approval studies, outcomes of combination chemotherapy showed to be advantageous over single-agent chemotherapy, this was based on the parameters of PFS (Progression-free survival) and/or OS (overall survival) outcomes. Single-agent chemotherapy resulted in a median PFS  between 3.1-6.9 months, and a median OS  between 8.6-21.0 months. However, doublet chemotherapy resulted in a median PFS  between 5.1-8.6 and a median OS  between 14.5-20.4 months.⁵

Other randomised controlled trial studies (RCT) showed elevated rates based on overall response rate (ORR) parameters for combination chemotherapy compared to single-agent chemotherapy. Also, another two meta-analysis studies indicated a significantly increased rate of ORR for combination chemotherapy. 

Furthermore, 4 out of 5 systematic reviews demonstrated high rates of PFS for combination chemotherapy compared to single-agent chemotherapy. The majority of the individual clinical trials and reviews showed higher toxicity levels for combination chemotherapy, particularly in terms of haematological and gastrointestinal toxic effects.

Although of the higher survival rates of combination chemotherapy, the use of single-agent chemotherapy is recommended by the 4th ESO-ESMO international consensus guideline for advanced breast cancer (ABC4). The combination chemotherapy is advised to be reserved for the rapidly growing BC subtypes. According to observational studies, single-agent chemotherapy strategies were used more than combination ones during clinical practice. 

Chemotherapy resistance 

Chemotherapy resistance occurs when cancer cells oppose the efficacy of chemotherapy. By other means, there will be no more response to the chemotherapy treatment, thus cancer will keep growing due to the acquired ability against the chemotherapy effect. This resistance includes cyclophosphamide, anthracyclines, and taxanes.²

Resistance to anthracyclines and taxanes is linked to the overexpressing of a type of protein known as p-glycoprotein, which is an ATP-binding transporter (Adenosine triphosphate binding transporters) responsible for the conversion of energy gained from ATP into a type of energy for the movement of substrates. 

Resistance to anthracyclines but not taxanes can also be due to the overexpression of a type of protein called breast cancer resistance protein (BCRP), an ABC family member. 

Microtubule alterations are a leading cause of taxane resistance. The overexpression of β-tubulin III triggers paclitaxel resistance. Moreover, mutations in microtubule-associated proteins (MAPs) affect microtubule mechanisms and induce taxane resistance. 

Furthermore, several enzymes play a role in inducing chemotherapy resistance. For example, aldophosphamide (a type of cyclophosphamide) can be detoxified via the augmentation of the aldehyde dehydrogenase enzyme. Also, this detoxification can occur in the same manner but through the mutation in glutathione S-transferases enzymes, these enzymes are involved in drug-metabolising conjugation reactions. 

Chemotherapy and all breast cancer molecular subtypes

All medical interventions and treatment strategies should be considered in BC molecular subtypes. Surgery, radiotherapy and chemotherapy are complementary to each other, particularly in types other than triple-negative breast cancer. However, these strategies might not be enough to treat all BC molecular subtypes, as chemotherapy or radiotherapy could fail to achieve the required efficacy. Thus, in this case, personalised treatment plays an essential role in the treatment of such types of BC.²

Special considerations

Pregnancy and breast cancer in young AFABs

Before beginning chemotherapy, discussing future pregnancy plans with BC young AFABs is an important matter as chemotherapy is a leading cause of premature ovarian failure. In this case, the available options that could be offered are embryo preservation, oocyte preservation and gonadotropin-releasing hormone (GNRH) agonist, which aims to protect ovarian functions. However, the first two options are financially burdensome, unlike gonadotropin-releasing hormone agonists, which are affordable and safe. Therefore, it is highly recommended to discuss future pregnancy with a reproductive endocrinologist before starting the chemotherapy, knowing that pregnancy after breast cancer doesn’t seem to affect mortality and survival rates.⁶

Patients with hormonal (HR) positive ductal carcinoma

Patients who were diagnosed with this subtype of breast cancer may be offered endocrine therapy as aromatase and tamoxifen to reduce the progression of a future BC in the affected breast if preserved.

Breast cancer management in postmenopausal AFABs and elderly

Postmenopausal AFABs who receive chemotherapy treatment for non-metastatic breast cancer should be offered bisphosphonate therapy as it demonstrates to decrease the risk of bone fractures, bone metastasis and improves mortality rates. Before starting bisphosphonate therapy, patients should be on calcium and vitamin D supplements and advised to perform a dental check-up.²

Management of BC in the elderly is accurate and requires multiple medical strategies including medical oncology, radiation oncology and surgical oncology. It is important to keep performing several assessments regarding life expectancy, complications and medical comorbidities. Thus, BC management in elderly patients is highly personalised and should be followed up regularly due to their critical cases. Regarding patients older than 65, standard chemotherapy regimens are superior to capecitabine monotherapy.⁶

FAQ’s

Which patients are the best candidates for neoadjuvant BC chemotherapy?

Neoadjuvant BC chemotherapy is a treatment of choice for those who have locally advanced breast cancer or inflammatory breast cancer.⁷

How to measure the degree of response to breast cancer neoadjuvant chemotherapy?

Breast imaging is used to measure the efficacy of the used BC chemotherapy such as mammography, ultrasound, magnetic resonance imaging (MRI), computed tomography (CT) and positron emission tomography (PET) scans particularly in metastatic breast cancer. These techniques should be done regularly to follow up on patient prognosis. 

What systemic neoadjuvant chemotherapy is recommended for BC patients with TNBC?

Patients with triple-negative breast cancer should be given anthracycline and taxanes in the neoadjuvant regimens. 

What is the most aggressive type of breast cancer?

Triple-negative breast cancer is the most aggressive type as it lacks expression of oestrogen and progesterone receptors and overexpression of human epidermal growth factor 2 (HER2). Thus, in this case, the only suitable option would be BC chemotherapy.⁸

What are the available treatment options if there is recurrent breast cancer?

In recurrent breast cancer, a multidisciplinary approach should follow. Treatment regimens include additional endocrine therapy, chemotherapy and other targeted therapies. In addition to palliative and supportive care.¹

Summary 

Breast cancer is the leading cause of death worldwide. There are different subtypes of breast cancer, this depends on the presence or lack of sexual hormonal receptors and HER2 factor. Breast cancer chemotherapy is used to destroy cancer cells either by reducing tumour size before surgery (neoadjuvant), or after surgery (adjuvant) to treat breast cancer types that express oestrogen, progesterone and hormonal growth factor 2 receptors. Chemotherapy is a core treatment for triple-negative breast cancer (TNBC) as immunotherapy is useless in this type. Taxane-based and non-anthracycline groups of chemotherapy are used for lower risk cancers, however, anthracyclines are administered for triple-negative breast cancer with lymph nodes involved. Some data supports the use of capecitabine for TNBC patients with lymph node involvement who showed residuals after surgery. 

For molecular types of breast cancer which express progesterone, oestrogen, and HER2 factors, hormonal and endocrine therapies should be used as well. Before chemotherapy begins, several blood tests should be carried out, in addition to heart imaging if needed. Also, chemotherapy side effects should be discussed with the patient and how to manage them. Chemotherapy resistance occurs when there is no more response to the chemotherapy treatment, thus cancer will keep growing. This resistance includes cyclophosphamide, anthracyclines, and taxanes. Breast cancer chemotherapy side effects include hair loss, fatigue, low blood count, loss of appetite, weight changes, nausea and vomiting, and neuropathy.