Metastatic Breast Cancer Heterogeneous Disease Biology

Breast malignant neoplastic disease is a heterogeneous disease that begins in the breast tissue and is characterized by uncontrolled cell division/proliferation and growth, leading to the formation of a ball or a mass called a “tumor” (1). Breast malignant neoplastic disease is the most common cancer among adult females and is one of the leading causes of death among women worldwide (2).

Breast malignant neoplastic diseases may be classified as in situ when the cancer is localized within the canals and lobules of the breast tissue or infiltrating/invasive when the cancer cells have broken the walls of the canals and lobules and spread to other parts of the breast or other tissues of the body, such as bone, lung, liver, and brain, by the process of metastasis (1).

Breast malignant neoplastic disease accounts for one in four cases of cancer diagnosed among women in the US, and 192,370 new cases of invasive breast malignant neoplastic disease were estimated for 2009-10 (1).

It has been suggested that primary breast tumors originate when cells get mutations in the genes that are responsible for cell cycle progression, mitotic checkpoint regulation, telomere maintenance, and central body function, which leads to a disruption of the normal cell cycle and differentiation (3).

In the case of metastatic breast malignant neoplastic disease (MBC), these cells lose certain important properties of normal cells, including anchorage dependence and contact suppression, which create an ideal environment for metastasis to occur. The process of metastasis occurs when tumor cells from the primary breast tumor become highly aggressive in their proliferation and migrate to form secondary tumors at other sites in the body (4).

Metastasis is a complex process involving several changes, including loss of cell-cell adhesion, loss of cell-extracellular matrix adhesion, invasion of cancerous cells into the adjacent tissue, disruption of basement membrane, invasion into the blood and lymphatic vessels, and establishment of distant metastases and formation of new blood vessels by the process of angiogenesis (4-8). The deregulation of several pathways in cell differentiation, cell cycle progression, programmed cell death, and angiogenesis helps maintain the process of metastasis.

Even though there has been significant progress in early detection and with the development of molecular targeted therapeutic agents, metastatic breast malignant neoplastic disease is still incurable.

Therapeutic options

Over the last two decades, there has been significant advancement in the early diagnosis and treatment of metastatic breast cancer. This is reflected by the decrease in the number of incidences of MBC (9) and an increase in the survival duration of patients diagnosed with MBC (10).

These improvements can be attributed to the availability of newer chemotherapeutic agents, molecular targeted therapy, combination therapy, and novel diagnostic methods. Despite these advances, statistics show that the overall survival of women diagnosed with MBC is still less than 2 years (11-12) and only 20% of the patients diagnosed with distant metastasis will survive beyond a period of 5 years (12-13).

Once the tumor cells have escaped from the primary site in the breast tissue and have started to metastasize, breast cancer (MBC) is a virtually incurable disease; most of the treatment provided is of palliative nature with the aim of increasing progression-free survival (PFS), overall survival (OS), and improving the quality of life (QOL) of the patient (13-14).

The treatment of metastatic breast cancer includes chemotherapy, radiation therapy, hormonal therapy, targeted biological therapy, or a combination of the above, and in certain instances may also involve the surgical removal of the primary tumor or metastatic tissue (12).

Over the last four decades, the taxanes or anthracycline combinations have often been used as the first line of therapy for patients diagnosed with MBC (15-16). Endocrine therapy as first-line intervention for MBC depends on the endocrine receptor status of the patient.

Considering the heterogeneous nature of the disease, the choice of treatment depends on the individual patient features, pre-existing disease conditions, and drug interventions (17). Doctors also depend on important predictive markers such as the expression of the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor – 2 (HER-2) (17).

For pre- and postmenopausal women with estrogen receptor-positive breast cancer, Selective Estrogen Receptor Modulator (SERM), Tamoxifen alone, or in combination with third-generation selective aromatase inhibitors (AI) such as anastrozole, letrozole, and exemestane are among the most effective agents used for adjuvant hormone therapy (18). The menopausal status of the patient helps in deciding the sequence of first-line and adjuvant intervention in endocrine therapy (18).

For pre- and post-menopausal adult females with endocrine receptor positive breast cancer, consecutive hormone therapy administered in correlation with their menopausal status has shown to have equal or improved overall survival compared to polychemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (19-21).

In pre-menopausal adult females with estrogen receptor positive breast cancer, ovarian removal has also been shown to improve the overall survival of the patient (19-20). Only 30% of the ER-positive breast cancer patients treated with first-line hormone therapy respond positively and have a median progression time of 9-11 months (22). The reduced response rate and progression-free survival period may be attributed to the development of resistance to endocrine therapy.

One of the mechanisms of inherent or acquired resistance to Tamoxifen in patients with ER-positive and HER-2-positive breast cancer is due to the continued cross-talk between the ER, EGFR, and HER-2 signaling cascades, where there is an increase in growth factor signaling upon prolonged repression of the mitogenic estrogen receptor genomic signaling by Tamoxifen (23). Genetic polymorphisms in drug-metabolizing cytochrome P450 enzymes and drug-drug interactions are also responsible for the development of resistance to endocrine therapy (24).

Patients who are not eligible for endocrine therapy (ER negative, PR negative, endocrine-resistant), cytotoxic combination chemotherapy is the obvious choice for the first line of intervention (25). However, only 30-65% of the patients respond to first-line anthracycline or taxanes-based chemotherapy, and these patients have a median time to progression period of 7-8 months (16, 26).

Additionally, it has been observed that once hormone receptor-negative MBC patients stop responding to one line of chemotherapy, their response to other chemotherapeutic agents and progression-free survival period decreases (16, 26). The most important factor diminishing the effectiveness of chemotherapy is the development of drug resistance (27).

Multidrug resistance (MDR) may be acquired by one of several mechanisms, which include overexpression of drug outflow proteins (e.g. ABC transporter proteins P-glycoprotein, BCRP, MRP-1, etc.), epigenetic phenomena such as DNA methylation and phosphorylation, activation or inactivation of drugs, and changes in the drug target (27).

The taxanes, anthracyclines, antimetabolites, and vinca-alkaloids that are widely prescribed chemotherapeutic agents for MBC are substrates of P-glycoprotein (28). One way to overcome drug resistance… (the text ends abruptly).

Several of the presently prescribed chemotherapeutic drugs offer combination chemotherapy, which may be one of the options to consider.

Chemotherapy with more than two agents is used when patients do not respond to one line of chemotherapy, but have a much lesser response to other chemotherapeutic agents. For patients with hormone receptor-negative (ER-negative, PR-negative) metastatic breast cancer (MBC), hormonal therapy is not an option for treatment.

Irrespective of the phase of the breast cancer and metastasis, these patients are treated with cytotoxic chemotherapeutic agents such as the anthracyclines and taxanes, apart from other newer cytotoxic agents. Cytotoxic chemotherapeutic agents such as taxanes and anthracyclines have been the first line of treatment.

Significance

Breast malignant neoplastic diseases are classified based on the endocrine receptor position of the tumor.

Currently available curative options

Targeted therapy for breast malignant neoplastic disease

Targeted therapy for breast malignant neoplastic disease aims to treat the tumor by targeting specific molecules that are involved in the growth and spread of cancer.

Current thoughts

Expression of the receptor position of the tumor (ER-negative) means fewer curative options. About 20% of the tumors are HER-2 positive or overexpressing.

Bacteriophage show

Bacteriophage show

References

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