Cell cycle

Cell-Cycle Dysregulation in Cancer

The proliferative advantage of tumor cells is a result of their ability to bypass quiescence. Cancer cells often show alterations in signal transduction pathways that lead to proliferation in response to external signals. Mutations or alterations in the expression of cell-cycle proteins, growth factors, growth factor receptors, intracellular signal transduction proteins, and nuclear transcription factors all can lead to disturbance of the basic regulatory mechanisms that control the cell cycle, allowing unregulated cell growth and proliferation.

The cell cycle is divided into four phases.

During the synthetic or S phase, the cell generates a single copy of its genetic material, whereas in the mitotic or M phase, the cellular components are partitioned between two daughter cells.

The G₁ and G₂ phases represent gap phases during which the cells prepare themselves for completion of the S and M phases, respectively.

When cells cease proliferation, they exit the cell cycle and enter the quiescent state referred to as G₀.

In human tumor cell-cycle regulators like INK4A, INK4B, and KIP1 are frequently mutated or altered in expression. These alterations underscore the importance of cell-cycle regulation in the prevention of human cancers.

Describe the scientific basis to "Hormone therapy in cancers". Describe the limitations of hormone therapy and its side effects.

• Endocrine therapy with its minimal toxicity is considered a primary option over cytotoxic chemotherapy in patients with hormone receptor-positive disease.
• It has the advantages of good efficiency, low toxicity, and low impact on quality of life.
• Their efficacy depends on the expression of both steroid hormone receptors (ER and PR positive: remission rate (RR) 50–75%; only ER or PR positive: RR 20–50%; ER and PR negative: RR < 10%). Treatment should be continued until disease progression or occurrence of relevant side effects.
• On average, first-line treatment is associated with 8 to 12 months of tumor control, and second-line treatment with 4 to 6 months. Individual patients may experience substantially longer time to progression. Sequential single-agent second- and third-line endocrine treatments are often effective, although typically for shorter durations than initial therapy..

• Endocrine therapy can cause even regression of soft tissue and bone and visceral metastases.
• Eventually many patients with hormone-receptor positive metastatic breast cancer will progress despite first-line endocrine therapy.

Induction Chemotherapy is to be considered in patients presenting with extensive visceral metastases or profound symptoms from breast cancer (visceral crisis) which should then be followed with endocrine therapy.

ENDOCRINE THERAPIES AVAILABLE FOR METASTATIC BREAST CANCER

Commonly Used Endocrine Regimens in the Metastatic Setting

                        Ovarian suppression/ablation (premenopausal women)

                        Selective estrogen receptor modulators - tamoxifen, toremifene

                        Aromatase inhibitors (postmenopausal women)

                        Non-Steroidal- anastrozole, letrozole,

                        steroidal - exemestane

                        Antiestrogens - fulvestrant; postmenopausal women

                        Progestins - megestrol and medroxyprogesterone

                        Other steroid hormones (high-dose estrogens, androgens; only of historical interest)

INITIAL ENDOCRINE THERAPY OPTIONS: (for breast ca)

No prior endocrine therapy or over one year since endocrine therapy

Premenopausal ➙ Antiestrogen or Ovarian Function Suppression (OFS) with endocrine therapy like postmenopausal women

Postmenopausal ➙ Aromatase inhibitor or antiestrogen

Prior endocrine therapy

Second-line endocrine therapy (see below

SUBSEQUENT ENDOCRINE THERAPY OPTIONS

Premenopausal patients

Add OFS and treat like postmenopausal women

Postmenopausal patients

Nonsteroidal (anastrozole, letrozole) or steroidal (exemestane)

aromatase inhibitor ,fulvestrant, tamoxifen,megasterol, fluoxymesterone,ethinyl estradiol.

*Consider chemotherapy if no clinical benefit (response or stable disease) after three endocrine regimens or symptomatic visceral disease

Selective Estrogen-Receptor Modulators

Tamoxifen is the historic standard as treatment for ER-positive metastatic breast cancer, associated with a 50% response rate and median duration of response of 12 to 18 months among treatment-naive patients .Tamoxifen, 20 mg daily is the most

commonly used SERM in many countries. Toremifene has also been approved but has a similar profile and is cross-resistant with tamoxifen.

Aromatase Inhibitors:

In postmenopausal women with no or distant previous exposure to antiestrogen agents, the aromatase inhibitors show similar or modestly superior efficacy compared with tamoxifen. These drugs are ineffective in premenopausal women and should be avoided as single agents in this setting. Aromatase inhibitors are more active and less toxic than megestrol acetate as second-line therapy; they also are more active and less toxic than the first-generation drug aminoglutethimide.

Letrozole is a more potent suppressor of total-body aromatization and plasma estrogen levels than anastrozole in patients with breast cancer12. However in metastatic breast cancer there is no convincing clinical advantage of one aromatase inhibitor over another.

Exemestane is a steroidal compound with the activity of aromatase inhibition.

Antiestrogens:

The nonsteroidal pure antiestrogen fulvestrant downregulates ER without the agonistic activity of tamoxifen. It appears to have inhibitory effects in breast and uterus with neutral effect in bones and lipids, and clinical effects appear similar to aromatase inhibitors.15 It is currently only approved in postmenopausal women as a monthly, deep IM injection

In premenopausal women with metastatic breast cancer, combined endocrine therapy with ovarian suppression and tamoxifen can improve survival compared to treatment with either tamoxifen or ovarian suppression alone. Premenopausal women with metastatic tumor despite tamoxifen use are candidates for ovarian suppression/ablation and aromatase inhibitor therapy.

In Postmenopausal women either tamoxifen, aromatase inhibitors, fulvestrant or progestational agents are used as palliation for metastatic breast cancer. Aromatase inhibitors are preferred as initial agents for women who received prior tamoxifen treatment in the adjuvant setting. 

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