It’s understandable that sexuality may not be the primary focus for many cancer patients, at least not right away. Sexuality is an incredibly personal topic, and each person’s experiences, feelings, and expectations are unique. But at some point, whether because of sexual changes, relationship issues, or difficulties with fertility, patients realize the impact of cancer on their sexuality.

Each patient’s cancer journey is unique, so it’s impossible to know what your experiences will be. You may undergo permanent changes in your body, physical discomforts, emotional struggles, and problems with fertility. But no matter the diagnosis or prognosis, you deserve the best quality of life, and this includes care of your sexual health. By learning about how your sexuality is likely to change and getting suggestions for healing, you become a partner and advocate in your own care.

In a series of articles we would explore this topic and try to answer some of the questions in your mind.This is the first article in this series and we would explore the following questions:

What is sexuality?

When you think of sexuality, your first thought may be the physical act of sexual intercourse. But sexuality goes beyond engaging in sexual activity.

As a human being, your sexuality is a part of your physical, emotional, intellectual, and social self. It affects how you think of yourself and how you relate to others, as well as how they relate to you, and it is a part of you throughout your entire life.

Since every person is different, it is difficult to define “normal” sexuality or sexual activity. Many factors may influence your sexuality, including your gender, sexual orientation, hormone levels, age, and personal perspectives, such as your views on sex and your religious beliefs and values.

You may have certain definitions of how you think a man or woman should look and behave, and these expectations play a part in your sexuality, too.

It’s important to recognize what is normal for you—what makes you feel comfortable and satisfied—and that it may be different from what is normal for someone else. And it’s equally important to remember that cancer and its treatment may cause changes in your sexual function, but they cannot take away the life experience and emotions that make you a sexual person.

What is a normal sexual response?

A “normal” sexual response involves a person experiencing one or more of the following phases:

• Desire
• Arousal
• Orgasm
• Resolution

Cancer and cancer treatment can cause changes in any phase of the sexual response. Understanding these phases may help you explain your experiences to your doctor or nurse. This may help them diagnose changes and prescribe remedies to help you.

Desire

Desire happens when you feel interested in someone sexually. For example, if a man or woman walked by, you may feel an attraction to that person or begin to imagine that person as a partner. Desire may also come from feelings of sexual pleasure and tension in your body, or from a sexual fantasy. The more you think about sex, the more frustrated you may feel if you do not have a chance to have sexual pleasure. All of these feelings can be called “desire.”

Lack of desire is the most common sexual problem for all cancer patients. You may think, “I used to think about sex, but now it doesn’t seem important to me,” or “I want to have a sexual relationship, but I don’t feel desirable or sexy,” or “I just don’t feel like having sex anymore.”

Arousal

Arousal is sexual excitement, which may be caused by touching, stroking, fantasizing, or seeing or hearing sexual sights and sounds. Your heartbeat, pulse, and blood pressure rise. Your breathing may become deeper and heavier. In both men and women, blood flows into the genitals as part of sexual arousal.

• For women, arousal includes both mental excitement and the physical response of vaginal lubrication and expansion. The vagina becomes moist and expands. The outer genitals, including the clitoris, swell and turn a deeper color.
• In men, the penis becomes erect, and arousal includes getting and maintaining an erection sufficient for intercourse.

Most often, loss of desire and trouble getting mentally aroused go together. Instead of feeling good, sexual touch may seem annoying or you may feel “numb.” You may find yourself thinking that your body isn’t responding the way it is “supposed to.” But sometimes you feel turned on in your mind, but your body does not respond physically. You may feel interested in sex, even excited, but also frustrated that you have vaginal dryness if you are a woman, or do not get a firm erection if you are a man. Problems with physical arousal are often caused by damage to the body from cancer treatment.

• After cancer treatment, or just with normal aging, women may respond more slowly to sexual stimulation, produce less or insufficient lubrication, and may feel that breast or genital caressing does not bring pleasure.
• Changes with arousal in men include not being able to get or sustain an erection, having an erection that is not firm or reliable, or not having erections as frequently as desired.

Orgasm

A person who reaches a sexual climax has an orgasm. For men and women, this means a rhythmic contraction of the genitals, which causes intense, pleasurable feelings throughout the body. Overall, you may feel satisfaction, pleasure, and gratification.When women have an orgasm, the vaginal walls contract, and often waves of pleasure are felt in the clitoris and outer vagina. Many women enjoy reaching more than one orgasm, while others prefer to have one intense climax.

• When men have an orgasm, they experience an ejaculation, when the penis releases semen.

When changes with orgasm occur, men and women may find that it takes a longer time to reach orgasm, more stimulation is needed, or that orgasms cannot be achieved at all.

• Women may find that the clitoris or vaginal opening feels less sensitive. Some women have pain with sex or distracting thoughts about cancer or feeling unattractive. It takes some mental focus on pleasure for a woman to reach orgasm.
• After cancer treatment, some men experience “dry orgasms” in which muscles contract and they feel pleasure, but no semen comes out of the penis. Some men also find that their orgasms are weaker and less pleasurable.

Resolution

Resolution is when the body calms down and is no longer excited. Your heartbeat, pulse, and blood pressure return to normal, and blood drains from the genital area. Resolution happens rapidly after an orgasm. If a person doesn’t have an orgasm, resolution happens eventually but just takes longer.

Women can have one orgasm right after another, known as multiple orgasms. Usually men have to wait a certain amount of time after an orgasm before becoming aroused again. This time, called the refractory period, can increase with age or medical conditions.

How can my cancer and cancer treatment affect my sexuality?

Cancer and its treatment may affect your sexuality, but every patient is different. Some patients experience sexual changes in all of the phases of sexual response, while others experience none.

The most common sexual change for cancer patients is an overall loss of desire. Most men and women are still able to have an orgasm even if cancer treatment interferes with erections or vaginal lubrication, or involves removing some parts of the pelvic organs. However, it is common for patients to need more time or stimulation to reach orgasm.

Unfortunately, when sexual changes do occur, they generally do not improve right away; indeed, they may persist until a good remedy is found. Finding the most helpful remedy may take time and patience because sexual changes can be caused by both psychological and physical factors.

Furthermore, the sexual changes caused by cancer treatment may be long term or permanent. Talk with your doctor, nurse, or another healthcare professional before treatment to learn about what to expect from your cancer or cancer treatment concerning your sexuality. By knowing what may happen, you may be better prepared and more knowledgeable about potential sexual changes.

In the next article we would explore this question in more details.

The combination of the immunomodulatory drug lenalidomide and the proteasome inhibitor bortezomib appears to be both safe and potentially able to induce durable responses in patients with relapsed or relapsed/refractory multiple myeloma, U.S. researchers report online in the Journal of Clinical Oncology.

“Lenalidomide and bortezomib is a well tolerated and very active combination that can overcome resistance to either agent separately,” Dr. Paul G. Richardson of the Dana-Farber Cancer Institute, Boston. He called the median overall survival of 37 months for patients in the study “especially noteworthy in a phase 1 population.”

The report notes,

“The regimen showed efficacy even in heavily pretreated patients who were previously exposed to immunomodulatory agents and to bortezomib.”

The study — the first prospective trial to assess this combination of drugs in patients with relapsed and relapsed/refractory multiple myeloma — included 38 patients (median age, 59 years). Patients were grouped into threes, and each successive group received a higher dose of lenalidomide and/or bortezomib.

Lenalidomide was given orally on each of the first 14 days of a 21-day cycle, and bortezomib was given intravenously on days 1, 4, 8 and 11. Patients whose disease progressed following two cycles could also receive dexamethasone.

The study established the maximum tolerated dose as lenalidomide 15 mg/d plus bortezomib 1.0 mg/m2.

Patients received a median of 10.5 treatment cycles of lenalidomide and 10 of bortezomib. Thirteen patients received both drugs for more than a year, and one patient was still being treated when the study closed in November 2008, having received 74 cycles.

Sixty-one percent of patients achieved at least minimum response. Among patients who had been refractory to previous treatment with lenalidomide, bortezomib or thalidomide, 12 achieved at least minimal response and six achieved at least partial response.

Responses were noted as being durable, with median time to progression of 7.7 months.

Four patients discontinued treatment for toxicities considered to be related to lenalidomide. The most common adverse events were neutropenia, thrombocytopenia and fatigue.

Dr. Richardson told that lenalidomide-plus-bortezomib is also showing promise in two current myeloma studies, including one in patients with relapsed or relapsed/refractory disease.

The study was supported in part by Millennium Pharmaceuticals, Johnson & Johnson Pharmaceuticals Research and Development, and Celgene.

October is officially tagged “Breast Cancer Awareness Month”. Of recent, there have been a lot of medical breakthroughs in the detection and treatment of Breast Cancer. Scientists have identified more accurate tools for screening younger women who are more likely to get the most dangerous forms and new strategies have also been developed for the treatment of newly diagnosed pregnant women.  Advanced research has led to the development of better, less toxic drugs to guard against recurrences.

In the Western world, breast cancer deaths have plummeted and survival rates are soaring. Research has made more headway in the fight against breast cancer than any other form of cancer. These milestone achievements are as a result of the constant campaigns, awareness creation and fundraising activities directed toward the cause. Early detection and a study which showed that hormone replacement therapy in postmenopausal women strongly contributed to the development of breast cancer are greatly responsible for the lower incidence rates.

In breast cancer, some cells in the breast for reasons poorly understood start growing abnormally, dividing more rapidly than normal cells and may spread (metastatize) to adjascent tissue, lymph nodes or other parts of the body.The most common type begins in the milk producing ducts while otherforms occur in other breast tissue. It is known that 5 to 10% of breast cancer cases areinherited. There is usually a defect in one of two genes namely BRCA1 and BRCA2 (Breast Cancer Genes 1 and 2).

Most genetic mutations related to breast cancer are not inherited and develop during one’s lifetime such as exposure to polycyclic aromatic hydrocarbons found in tobacco and charred meats and radiation exposure.

Newer drugs such as Herceptin and Tamoxifen that are specifically targeted for the treatment of pathologically different cancer types has greatly reduced deaths as a result of breast cancer. In the past, one drug was used to treat all forms of breast cancer with less than satisfactory results.

Types of Breast Cancer:

The majority of tumours (about 60%) are hormone sensitive and are stimulated by the female sex hormones oestrogen and progesterone. About 25% of cases are the deadlier form associated with an excessive amount of the protein known as HER2.

Some cancers are both hormone sensitive and HER2 positive. There is a form of breast cancer more likely to occur in younger women known as Triple Negative Breast Cancer because it is neither oestrogen sensitive, progesterone sensitive nor HER2 positive. Fortunately, there have been developments in treatments to help all three forms.

Hormone Responsive Cancer is usually treated with Tamoxifen which is given after surgery to suppress hormones that stimulate tumour growth. Tamoxifen has serious side effects such as vaginal bleeding, hot flashes, an increased risk of uterine cancer and the development of blood clots. There are newer oestrogen-blocking aromatase inhibitors namely Femara, Arimidex and Aromasin which have been found to offer the same or even better results.

HER2 Cancer due the HER2 protein triggering the growth of cancer cells is an aggressive form of cancer.

The drug Herceptin is used to stop the action of this protein and is combined with chemotherapy. Tykerb, also a protein suppressor, will be on the market in 2007 and has shown excellent results when combined  with the chemotherapeutic agent, Xeloda.

Triple Negative Cancer is tackled with the use of a colon cancer drug known as Avastin and is combined with chemotherapy with promising results.

In the past, a pregnant woman found to have breast cancer had to make the difficult decision of having to save her own life or the life of the unborn child. New treatment guidelines allow women to have a mastectomy or a breast conserving lumpectomy and commence chemotherapy as early as the second trimester. Some studies have shown that there have been little or no adverse effects on the foetus while others have shown that the development of the foetus may be affected by chemotherapy. Radiation and oestrogen therapy may  harm the foetus and should be delayed until after the birth of the child.

More than 75% of cases of breast cancer occur in women aged over 50 years. Other risk factors include having a first degree relative (mother, daughter, sister) who has had breast cancer, having had breast cancer previously, an abnormal biopsy result, a mutation in the breast cancer genes, postmenopausal obesity, hormone replacement therapy and prolonged exposure to oestrogen such as reaching puberty before the age of 12 years, starting menopause after age 55 years and having children after the age of 30 or not having children at all.

Women are advised to have routine mammograms once they reach age 40. MRI’s are useful for locating difficult to identify tumours.The risk of developing breast cancer may be reduced by checking breasts monthly for lumps, getting regular exercise which boosts immune function and cuts the risk in half, watching your weight as obesity encourages further storage of oestrogen in fatty tissue. Women who are about 30kg overweight are up to 3 times more likely to develop advanced metastatic cancers than women who are not overweight. Exposure to oestrogen should be minimized thus hormone replacement therapy should be dicouraged.

It should be noted that men may also develop breast cancer. As a matter of fact, a male case was the first I was presented with as a medical student. In men, like women, the most common sign of breast cancer is a lump (often painless) or thickening of breast tissue. Other signs include change in the size or contour of the breast, clear or bloody nipple discharge, retraction or indentation of the nipple, flattening or retraction of the skin overlying the breast and redness or pitting of the skin overlying the breast.

“This novel proteasome inhibitor appears to improve response rates and
survival in patients with progressive multiple myeloma.”

Bortezomib (Velcade) is an inhibitor of the proteasome, a ubiquitous multi-enzyme complex that degrades proteins that regulate cell-cycle progression and induces proteolysis of IκB, the inhibitor of nuclear factor-κB. Increased activation of nuclear factor-κB promotes cell survival, stimulates growth, and inhibits apoptosis, as well as induces drug resistance in myeloma cells. Recent studies have demonstrated the efficacy and safety of bortezomib in patients with relapsed, refractory myeloma.

Efficacy studies

In the phase II SUMMIT study (n = 202), treatment with bortezomib 1.3 mg/m2 twice weekly for 2 weeks, followed by 1 week without treatment, for up to 8 cycles (24 weeks) resulted in an overall response rate of 35% (including a complete response in 4% in whom myeloma protein was undetectable and a complete response in 6% in whom myeloma protein was detectable only by immunofixation).1 In the phase II CREST study, treatment with bortezomib 1.0 mg/m2 (n = 28) or 1.3 mg/m2 (n = 26) on days 1, 4, 8, and 11 every 3 weeks for up to 8 cycles (6 months) resulted in an overall response rate of 33% (4% complete response) for the 1.0-mg/m2 dose and 50% (4% complete response) for the 1.3-mg/m2 dose.2 A group of 14 patients from the CREST study and 43 from the SUMMIT study who had a partial or minimal response to bortezomib or stable disease continued receiving the proteasome inhibitor in an extension study. Most of these patients had already received 8 cycles of bortezomib therapy in the original studies. Preliminary data from the extension study indicated that bortezomib can be administered for up to 13 cycles with a safety profile similar to that observed in the first 8 cycles of treatment.

Safety demonstrated in renally impaired patients

Renal impairment is a common complication of myeloma and its treatment, and preclinical studies indicate that bortezomib and its metabolites are eliminated by both the renal and hepatic route. An analysis of outcomes in 10 patients with severe renal impairment (creatinine clearance, 10–30 mL/min) in these two studies suggests that bortezomib may be safely given to such patients, with responses and toxicities being comparable to those in patients without severe renal impairment.3 Of the 10 patients, 2 had a partial response and 1 had a minimal response; treatment was well tolerated, with 7 patients receiving at least 30 of the 32 possible study doses.

Pharmacokinetic analysis of eight patients with an initial creatinine clearance rate of 31–169 mL/min in the SUMMIT study indicated that the maximum concentration and distribution half-life of bortezomib were not affected by renal status and that the area under the concentration-time curve was similar to that obtained in the overall population.

Superior to dexamethasone

The APEX Study Group recently reported findings from their international, multicenter phase III trial comparing bortezomib with dexamethasone in patients with relapsed multiple myeloma.4 Patients were randomized to receive intravenous bortezomib 1.3 mg/m2 (n = 327) on days 1, 4, 8, and 11 every 3 weeks for 8 cycles, followed by the same dose on days 1, 8, 15, and 22 every 5 weeks for 3 cycles, or oral dexamethasone 40mg (n = 330) on days 1–4, 9–12, and 17–20 every 5 weeks for 4 cycles, followed by 40 mg on days 1–4 every 4 weeks for 3 cycles. At the time of the interim analysis, 254 progressive disease events had occurred. Median time to disease progression (using European Group for Blood and Marrow Transplantation criteria) was 5.7 months in the bortezomib-treated group versus 3.6 months in the dexamethasone-treated group (P < 0.0001). Overall survival was significantly longer in patients receiving bortezomib than in those taking dexamethasone (P = 0.038). At the time of the interim analysis, 13 patients treated with bortezomib and 24 patients given dexamethasone had died; median survival had not yet been reached in either treatment arm.

Significantly fewer patients taking bortezomib than those who were treated with dexamethasone developed grade 3 or worse infections (6.7% vs 10.6%, P = 0.096). No other major differences in safety were observed between treatment groups, and no difference was observed between treatment groups with regard to time to skeletal events On the basis of the interim analysis, it was recommended that the dexamethasone treatment arm be terminated in the APEX Study, and patients in the dexamethasone treatment group were permitted to receive bortezomib.

The major side effects of bortezomib are gastrointestinal symptoms, transient thrombocytopenia, fatigue, and peripheral neuropathy. Other, less frequent side effects include fever, rash, headache, and dizziness.

Lung cancer has become more common in China in recent years. The rise in tobacco consumption is the most important factor in this increase. As is the case in many developing countries, indoor air pollution from poorly ventilated stoves is an additional risk factor, particularly for women.

However, it has often been suggested that tuberculosis (TB) might also increase the risk of lung cancer, because it causes lung inflammation and fibrosis that could induce genetic damage. This possibility has been backed up by a number of retrospective case–control studies of lung cancer that have reported a higher prevalence of tuberculosis among lung cancer cases compared with controls. However, until now, there has apparently been no cohort study, which would provide a higher level of evidence, to support the theory.

Erica Engels and colleagues working in the rural county of Xuanwei, in China’s Yunnan Province used data from a retrospective cohort study of 42,422 farmers to examine the association between TB and lung cancer risk. The farmers were followed from 1976, and deaths from lung cancer were ascertained up to 1996. In 1992, the participants completed standardized questionnaires that included lifetime medical history as well as demographic and household characteristics and fuel and stove use.

Tuberculosis was reported by 246 (0.6%) of the participants. During follow-up, 2459 (5.8%) died from lung cancer (mortality 3.1 per 1000 person-years), including 31 of the 246 patients with TB (mortality 25 per 1000 person-years). The hazard ratio (HR) for lung cancer mortality was 6.1 for subjects with TB compared to those without TB.

The association between TB and lung cancer risk was especially pronounced in the first five years after TB diagnosis of, HRs ranging from 6.7 to 13. However, the association remained strong more than 10 years after tuberculosis diagnosis (HR 3.0).

Similar associations between TB and lung cancer were found both for men and for women. The researchers concluded that: “…our study supports the possibility that tuberculosis may act through a process of localized pulmonary inflammation and fibrosis to initiate or promote the development of lung cancer, particularly in conjunction with other carcinogenic exposures.”

If these findings are borne out by further research, then the global mortality for which TB is responsible is even greater than has been recognised. It also provides a further demonstration of the need to improve TB control programmes, particularly in developing countries. The authors furthermore suggest that periodic lung cancer screening of patients with a history of tuberculosis may be an effective strategy for early detection, which might ultimately improve cancer outcomes.

These new tests are now being used in the clinical development of targeted therapies more likely to succeed in treating patients with cancer related to gene mutations. The lab tests, known as mutation assays identifies the genomic changes that occurs in each patient’s cancer and help researchers find the optimum individual treatment plan. This type of personalised medicine supports therapies that are safer, more effective and efficient, and minimise unnecessary or potentially harmful treatments.

“The availability of these new assays is evidence of TMD’s dedication to advancing personalised medicine and targeted therapies,” said TMD founder Dr Sarah Bacus, Senior Vice President, Chief Scientific Officer of Translational Medicine for Quintiles, which acquired TMD in November 2008. “TMD is one of the leading central laboratories to offer these assays for clinical development of oncology therapies.”

TMD’s new mutation assays known as BRAF and PI3KCA, identifies solid tumour mutations. Studies have shown a correlation between changes to BRAF and PI3KCA genes and individual responses to certain cancer treatments.

In many cancers, the BRAF gene may be mutated, which can increase the growth and spread of cancer cells. TMD’s BRAF assay detects the most commonly occurring mutation in this gene. Similarly, PI3KCA gene mutations have been found in various solid tumours, such as breast, colon, lung, ovarian, liver and stomach cancer. TMD’s PI3KCA assay detects the four most common mutations in this gene.

As assays are increasingly used to help in cancer treatment, TMD already offers a test for colorectal cancer related to KRAS gene mutation. Recently, the American Society of Clinical Oncology and the National Comprehensive Cancer Network recommended that all patients with metastatic colorectal cancer be tested for mutations to the KRAS gene.

“TMD was among the first laboratories to offer the KRAS test for the clinical development of treatments,” said Christopher Ung, Vice President Strategic Business and Operations for Quintiles’ TMD lab. “Using mutation assays is likely to become the standard of care in the future. Today, we are among the first to offer BRAF and PI3KCA assays, as these solid tumor mutations are on the leading edge of cancer research and personalised treatment options.”

TMD, a Quintiles Central Laboratory, is dedicated to improving the survival and quality of lives of cancer patients by using biomarker technologies to support the development of targeted therapies. Located in Westmont, Illinois, near Chicago, TMD supports the development of numerous targeted therapies in oncology such as EGFR, HER2, SRC, MEK, PI3K, HDAC and VEGF inhibitors.

Treatment options in non-small-cell lung cancer (NSCLC) have expanded recently due to the demonstration of efficacy of targeted agents alone or in combination with existing cytotoxic chemotherapies. Research with these approaches is ongoing, and the 2006 American Society of Clinical Oncology meeting featured presentations from studies of epidermal growth factor (EGFR) inhibitors and antiangiogenic agents, as well as on the use of other novel compounds.

EGFR Inhibitors

The 2 major classes of EGFR inhibitors in clinical use are, based on their mechanisms of action, tyrosine kinase inhibitors (TKIs) and monoclonal antibodies. The former group is exemplified by gefitinib and erlotinib while the latter includes cetuximab and panitumumab.

Phase 3 trials employing the EGFR TKIs in first-line metastatic disease yielded negative results when these agents were administered concurrently with chemotherapy. Subsequent preclinical evidence suggested that sequencing chemotherapy with EGFR inhibitors may be more efficacious. Therefore, the Southwest Oncology Group performed a randomized phase 2 trial (SWOG 0342)[1] comparing concurrent chemotherapy plus cetuximab vs sequential chemotherapy followed by cetuximab in metastatic NSCLC. The plan was to select the arm with superior overall survival and subsequently compare it with chemotherapy alone in a phase 3 trial. However, the trial, which enrolled 242 patients, revealed virtually identical median progression-free (4 months in both arms) and overall (10 months in concurrent arm, 9 months in sequential arm) survival.

Based on the notion that cancer is a disease with multiple alterations, several agents are being developed that target different pathways at once. Thus, a randomized phase 2 trial evaluated a multikinase inhibitor known as ZD6474, or vanitinib, that targets both the EGFR and vascular endothelial growth factor (VEGF) receptor. This study enrolled patients who had failed platinum-containing first-line chemotherapy and compared docetaxel plus or minus ZD6474 at either 100 mg or 300 mg daily. Progression-free survival, the primary trial end point, was higher in both experimental arms (18.7 weeks in the 100-mg arm and 17 weeks in the 300-mg arm vs 12 weeks in the docetaxel-alone arm), suggesting that the addition of ZD6474 to second-line chemotherapy is efficacious. Currently, a phase 3 trial comparing docetaxel with docetaxel plus ZD6474 100 mg daily as second-line treatment for NSCLC is being conducted.

Another trial in a similar group of patients compared ZD6474 300 mg with gefitinib 250 mg in a randomized, crossover design. Progression-free survival was significantly better in the ZD6474 arm (11 vs 8.1 weeks, P = .025), meeting the trial’s primary end point. Of the 66 patients who crossed over to the alternate arm, there was 1 objective response in a patient who switched from ZD6474 to gefitinib.

In a randomized phase 2 trial, single-agent erlotinib was compared with carboplatin/paclitaxel chemotherapy in poor performance status (PS 2) patients with treatment-naive, advanced NSCLC. The primary end point was progression-free survival. Outcome measures, including response rate (12% vs 2%), progression-free survival (3.5 vs 1.9 months), and overall survival (9.7 vs 6.7 months), favored the chemotherapy arm. Overall, quality of life was equivalent between the 2 groups — compelling the authors to conclude that chemotherapy should remain the standard of care for unselected patients.

Several groups reported on attempts to select patients for EGFR TKI therapy. From prospective trials, it appears that specific mutations in EGFR exons 19 and 21 convey an exquisite sensitivity to these agents, with response rates between 60% and 95%. Of note, tumors with exon 19 mutations appear to be more sensitive compared with those that have mutations on other loci. Moreover, 1-year survival of patients harboring EGFR mutations and receiving TKI therapy appears to be over 80%. These findings were also observed in patients with bronchioloalveolar cell carcinoma, in that those with evidence of somatic EGFR mutations had an 83% observed response rate and a 22-month median overall survival.

In a similar prospective study, investigators examined the effects of gefitinib in NSCLC with respect to EGFR gene copy number, EGFR protein expression by immunohistochemistry, and activation of an EGFR downstream protein, AKT. Subjects were required to be never smokers and/or test positive for increased EGFR gene copy number or AKT activation. The overall response rate in the 42 patients enrolled thus far was 48%, with a 1-year survival of 69%. Increased EGFR gene copy number or exon 19/21 mutations were strongly associated with a positive response.

Conversely, evidence now exists to identify patients who may not derive benefit from treatment with an EGFR TKI. A subset analysis[8] of tissue samples from patients participating in the BR.21 trial comparing erlotinib with placebo in second- or third-line metastatic NSCLC indicated that those harboring a K-ras mutation have a poorer survival (hazard ratio 1.63, P = .03 in multivariate analysis) when treated with the EGFR TKI. These findings must still be viewed as preliminary, keeping in mind the retrospective nature of the analysis and the relatively small number of patient samples available for study. Nevertheless, this report, coupled with the investigators’ prior findings of lack of benefit in EGFR-negative tumors by immunohistochemistry, suggest that patients with K-ras mutations who do not express the EGFR protein are unlikely to benefit from EGFR TKI therapy.

Antiangiogenic Agents

Following the positive results of ECOG 4599, which added bevacizumab, a monoclonal antibody directed against VEGF, to doublet chemotherapy in first-line metastatic disease, a number of antiangiogenic agents have been under investigation in NSCLC. In addition, the combination of bevacizumab and erlotinib was reported to have activity in second-line metastatic NSCLC, prompting a randomized phase 2 trial evaluating bevacizumab in combination with either chemotherapy (docetaxel or pemetrexed) or erlotinib compared with chemotherapy alone in patients whose disease was refractory to first-line chemotherapy. Consistent with the first-line therapy results, the addition of bevacizumab to either erlotinib or chemotherapy was superior with respect to response rate, progression-free survival, and overall survival. The 6-month overall survival was 72.1% for bevacizumab plus chemotherapy and 78.3% for bevacizumab plus erlotinib, compared with 62.4% for chemotherapy alone. The bevacizumab/erlotinib arm was the best tolerated.

The administration of multikinase inhibitors with predominant in vitro activity against VEGF receptors is also being investigated in NSCLC. Clinical trials with 2 similar agents — sunitinib and sorafenib — were reported in patients with disease refractory to chemotherapy. Both studies allowed prior therapy with an EGFR inhibitor. Sunitinib was administered at 50 mg daily on a 4-weeks-on/2-weeks-off schedule to 63 patients enrolled in the United States and Europe. The objective response and disease control rates (responses plus stable disease) were 10% and 53%, respectively. Toxicity with sunitinib was similar to that seen in other settings, with asthenia, myalgia, and nausea being most common. In addition, 3 subjects experienced serious hemorrhages and 5 subjects (8%) experienced grade 3 hypertension.

A phase 2 trial of single-agent sorafenib, 400 mg twice a day, in a similar cohort of patients was also reported. This study enrolled 52 subjects with no objective responses reported but a disease control rate of 59%. Adverse events were typical of the agent in other diseases and included diarrhea, palmar-plantar erythrodysesthesia, and asthenia. Grade 3 hypertension occurred in 4% of subjects, and 1 patient suffered a fatal pulmonary hemorrhage. A regimen of sorafenib plus chemotherapy is currently being investigated in a randomized phase 3 trial in first-line metastatic NSCLC.

The rare but serious incidence of pulmonary hemorrhage associated with bevacizumab was investigated in a retrospective review of patient risk factors from ECOG 4599. Although only 6 cases met the criteria for early-onset hemorrhage related to bevacizumab, there appeared to be an association between these events and the presence of cavitation on pretreatment radiographs. Whether this association is real and whether it applies to all antiangiogenic agents is unknown. Nevertheless, caution should be used when these agents are considered for patients with cavitation.

Other Novel Agents

Several other novel agents have also been tested recently in NSCLC. Two randomized trials employed agents targeting the eicosanoid pathway. This pathway is implicated in several processes, including cell differentiation, and is a key mediator of inflammation. Modulation of this pathway at several points by LY293111, including inhibition of cyclooxygenase (COX)-2 and stimulation of peroxisome proliferators-activated receptor gamma, yielded promising preclinical data; thus, a randomized phase 2 trial  of the agent in combination with cisplatin/gemcitabine was undertaken in chemotherapy-naive patients with advanced NSCLC. This 3-arm trial, which administered LY293111 at 200 mg twice a day or 600 mg twice a day vs placebo, used progression-free survival as its primary end point. After enrolling 201 patients, it appeared that LY293111 was associated with a greater degree of diarrhea, especially at the 600-mg dose, but did not improve efficacy.

The Cancer and Leukemia Group B took a similar approach to inhibition of the eicosanoid pathways by administering a COX-2 inhibitor (celecoxib), a 5-lipoxygenase inhibitor (zileuton), or both in combination with carboplatin and gemcitabine in a randomized phase 2 trial. The primary end point was the rate of failure-free survival at 9 months. The agents appeared well-tolerated in combination with chemotherapy, and, although there was no difference in the primary end point, a trend toward benefit was observed in the arm administering both inhibitors. Moreover, subjects who expressed high levels of COX-2 and received celecoxib appeared to benefit compared with their low expressing counterparts.

A clinical trial administering bortezomib, a proteasome inhibitor currently approved for use in multiple myeloma patients, in combination with gemcitabine and carboplatin was reported by the Southwest Oncology Group. This phase 2 nonrandomized trial enrolled 121 patients and reported a 21% response rate, a median progression-free survival of 5 months, and a median overall survival of 11 months. Although the median survival was encouraging, the other outcome measures suggested that the addition of bortezomib is unlikely to improve efficacy in this setting.

In a phase 3 trial, investigators compared whole brain radiation alone with a combination of motexafin gadolinium and whole brain radiation therapy in 554 NSCLC patients with brain metastases. Time to neurologic progression was the primary end point. Motexafin gadolinium did not interfere with the ability to administer whole brain radiotherapy and was generally well tolerated. Time to neurologic progression trended in favor of the experimental arm (15.4 vs 10 months) but did not reach statistical significance (P = .12). Of note, it appeared that patients who began therapy within 4 weeks of diagnosis derived the greatest benefit from motexafin gadolinium; subset analysis of this group favored the experimental arm.

Conclusion

NSCLC continues to pose a treatment challenge, especially in advanced and metastatic disease. For the first time ever, targeted agents have been shown to have demonstrated efficacy in the treatment of this disease and at least one, erlotinib, is currently approved for use. It is very likely that the next few years will witness a dramatic increase in the number of novel therapies available. Two classes of agents will dominate in the near future — EGFR inhibitors and antiangiogenic agents. However, with increasing understanding of the molecular biology driving NSCLC, a greater number of agents with varied mechanisms of action will become part of individual patient management.

]]> https://genglob.com/genglobmag/2009/10/novel_agents_erlotinib_erlocip_treatment_nslc/feed/ 0 https://genglob.com/genglobmag/2009/10/cancer-second-largest-killer/ https://genglob.com/genglobmag/2009/10/cancer-second-largest-killer/#comments Sat, 10 Oct 2009 07:35:23 +0000 admin https://genglob.com/genglobmag/?p=11 Cancer (medical term: malignant neoplasm) is a class of diseases in which a group of cells display uncontrolled growth (division beyond the normal limits), invasion (intrusion on and destruction of adjacent tissues), and sometimes metastasis (spread to other locations in the body via lymph or blood). These three malignant properties of cancers differentiate them from benign tumors, which are self-limited, and do not invade or metastasize. Most cancers form a tumor but some, like leukemia, do not. The branch of medicine concerned with the study, diagnosis, treatment, and prevention of cancer is oncology. Cancer may affect people at all ages, even fetuses, but the risk for most varieties increases with age. Cancer causes about 13% of all human deaths. According to the American Cancer Society, 7.6 million people died from cancer in the world during 2007. Cancers can affect all animals.

Nearly all cancers are caused by abnormalities in the genetic material of the transformed cells. These abnormalities may be due to the effects of carcinogens, such as tobacco smoke, radiation, chemicals, or infectious agents. Other cancer-promoting genetic abnormalities may be randomly acquired through errors in DNA replication, or are inherited, and thus present in all cells from birth. The heritability of cancers is usually affected by complex interactions between carcinogens and the host’s genome. New aspects of the genetics of cancer pathogenesis, such as DNA methylation, and microRNAs are increasingly recognized as important.

Genetic abnormalities found in cancer typically affect two general classes of genes. Cancer-promoting oncogenes are typically activated in cancer cells, giving those cells new properties, such as hyperactive growth and division, protection against programmed cell death, loss of respect for normal tissue boundaries, and the ability to become established in diverse tissue environments. Tumor suppressor genes are then inactivated in cancer cells, resulting in the loss of normal functions in those cells, such as accurate DNA replication, control over the cell cycle, orientation and adhesion within tissues, and interaction with protective cells of the immune system.

Diagnosis usually requires the histologic examination of a tissue biopsy specimen by a pathologist, although the initial indication of malignancy can be symptoms or radiographic imaging abnormalities. Most cancers can be treated and some cured, depending on the specific type, location, and stage. Once diagnosed, cancer is usually treated with a combination of surgery, chemotherapy and radiotherapy. As research develops, treatments are becoming more specific for different varieties of cancer. There has been significant progress in the development of targeted therapy drugs that act specifically on detectable molecular abnormalities in certain tumors, and which minimize damage to normal cells. The prognosis of cancer patients is most influenced by the type of cancer, as well as the stage, or extent of the disease. In addition, histologic grading and the presence of specific molecular markers can also be useful in establishing prognosis, as well as in determining individual treatments.

Classification

Cancers are classified by the type of cell that resembles the tumor and, therefore, the tissue presumed to be the origin of the tumor. These are the histology and the location, respectively. Examples of general categories include:

• Carcinoma: Malignant tumors derived from epithelial cells. This group represents the most common cancers, including the common forms of breast, prostate, lung and colon cancer.
• Sarcoma: Malignant tumors derived from connective tissue, or mesenchymal cells.
• Lymphoma and leukemia: Malignancies derived from hematopoietic (blood-forming) cells
• Germ cell tumor: Tumors derived from totipotent cells. In adults most often found in the testicle and ovary; in fetuses, babies, and young children most often found on the body midline, particularly at the tip of the tailbone; in horses most often found at the poll (base of the skull).
• Blastic tumor or blastoma: A tumor (usually malignant) which resembles an immature or embryonic tissue. Many of these tumors are most common in children.

Malignant tumors (cancers) are usually named using -carcinoma, -sarcoma or -blastoma as a suffix, with the Latin or Greek word for the organ of origin as the root. For instance, a cancer of the liver is called hepatocarcinoma; a cancer of the fat cells is called liposarcoma. For common cancers, the English organ name is used. For instance, the most common type of breast cancer is called ductal carcinoma of the breast or mammary ductal carcinoma. Here, the adjective ductal refers to the appearance of the cancer under the microscope, resembling normal breast ducts.

Benign tumors (which are not cancers) are named using -oma as a suffix with the organ name as the root. For instance, a benign tumor of the smooth muscle of the uterus is called leiomyoma (the common name of this frequent tumor is fibroid). Unfortunately, some cancers also use the -oma suffix, examples being melanoma and seminoma.

Signs and symptoms

Roughly, cancer symptoms can be divided into three groups:

• Local symptoms: unusual lumps or swelling (tumor), hemorrhage (bleeding), pain and/or ulceration. Compression of surrounding tissues may cause symptoms such as jaundice (yellowing the eyes and skin).
• Symptoms of metastasis (spreading): enlarged lymph nodes, cough and hemoptysis, hepatomegaly (enlarged liver), bone pain, fracture of affected bones and neurological symptoms. Although advanced cancer may cause pain, it is often not the first symptom.
• Systemic symptoms: weight loss, poor appetite, fatigue and cachexia (wasting), excessive sweating (night sweats), anemia and specific paraneoplastic phenomena, i.e. specific conditions that are due to an active cancer, such as thrombosis or hormonal changes.

Every symptom in the above list can be caused by a variety of conditions (a list of which is referred to as the differential diagnosis). Cancer may be a common or uncommon cause of each item.

Causes

Cancer is a diverse class of diseases which differ widely in their causes and biology. Any organism, even plants, can acquire cancer. Nearly all known cancers arise gradually, as errors build up in the cancer cell and its progeny (see mechanisms section for common types of errors). Anything which replicates (our cells) will probabilistically suffer from errors (mutations). Unless error correction and prevention is properly carried out, the errors will survive, and might be passed along to daughter cells. Normally, the body safeguards against cancer via numerous methods, such as: apoptosis, helper molecules (some DNA polymerases), possibly senescence, etc. However these error-correction methods often fail in small ways, especially in environments that make errors more likely to arise and propagate. For example, such environments can include the presence of disruptive substances called carcinogens, or periodic injury (physical, heat, etc.), or environments that cells did not evolve to withstand, such as hypoxia[8] (see subsections). Cancer is thus a progressive disease, and these progressive errors slowly accumulate until a cell begins to act contrary to its function in the animal.

The errors which cause cancer are often self-amplifying, eventually compounding at an exponential rate. For example:

• A mutation in the error-correcting machinery of a cell might cause that cell and its children to accumulate errors more rapidly
• A mutation in signaling (endocrine) machinery of the cell can send error-causing signals to nearby cells
• A mutation might cause cells to become neoplastic, causing them to migrate and disrupt more healthy cells
• A mutation may cause the cell to become immortal (see telomeres), causing them to disrupt healthy cells forever.

Thus cancer often explodes in something akin to a chain reaction caused by a few errors, which compound into more severe errors. Errors which produce more errors are effectively the root cause of cancer, and also the reason that cancer is so hard to treat: even if there were 10,000,000,000 cancerous cells and one killed all but 10 of those cells, those cells (and other error-prone precancerous cells) could still self-replicate or send error-causing signals to other cells, starting the process over again. This rebellion-like scenario is an undesirable survival of the fittest, where the driving forces of evolution itself work against the body’s design and enforcement of order. In fact, once cancer has begun to develop, this same force continues to drive the progression of cancer towards more invasive stages, and is called clonal evolution.

Research about cancer causes often falls into the following categories:

• Agents (e.g. viruses) and events (e.g. mutations) which cause or facilitate genetic changes in cells destined to become cancer.
• The precise nature of the genetic damage, and the genes which are affected by it.
• The consequences of those genetic changes on the biology of the cell, both in generating the defining properties of a cancer cell, and in facilitating additional genetic events which lead to further progression of the cancer.

Mutations: chemical carcinogens

Decades of research has demonstrated the link between tobacco use and cancer in the lung, larynx, head, neck, stomach, bladder, kidney, oesophagus and pancreas. Tobacco smoke contains over fifty known carcinogens, including nitrosamines and polycyclic aromatic hydrocarbons. Tobacco is responsible for about one in three of all cancer deaths in the developed world, and about one in five worldwide. Indeed, lung cancer death rates in the United States have mirrored smoking patterns, with increases in smoking followed by dramatic increases in lung cancer death rates and, more recently, decreases in smoking followed by decreases in lung cancer death rates in men. However, the numbers of smokers worldwide is still rising, leading to what some organizations have described as the tobacco epidemic.

Cancer pathogenesis is traceable back to DNA mutations that impact cell growth and metastasis. Substances that cause DNA mutations are known as mutagens, and mutagens that cause cancers are known as carcinogens. Particular substances have been linked to specific types of cancer. Tobacco smoking is associated with many forms of cancer, and causes 90% of lung cancer. Prolonged exposure to asbestos fibers is associated with mesothelioma.

Many mutagens are also carcinogens, but some carcinogens are not mutagens. Alcohol is an example of a chemical carcinogen that is not a mutagen. Such chemicals may promote cancers through stimulating the rate of cell division. Faster rates of replication leaves less time for repair enzymes to repair damaged DNA during DNA replication, increasing the likelihood of a mutation.

Mutation: ionizing radiation

Sources of ionizing radiation, such as radon gas, can cause cancer. Prolonged exposure to ultraviolet radiation from the sun can lead to melanoma and other skin malignancies. Non-ionizing radio frequency radiation from mobile phones and other similar RF sources has also been proposed as a cause of cancer, but there is currently little established evidence of such a link.

Viral or Bacterial infection

Some cancers can be caused by infection with pathogens. Many cancers originate from a viral infection; this is especially true in animals such as birds, but also in humans, as viruses are responsible for 15% of human cancers worldwide. The main viruses associated with human cancers are human papillomavirus, hepatitis B and hepatitis C virus, Epstein-Barr virus, and human T-lymphotropic virus. Experimental and epidemiological data imply a causative role for viruses and they appear to be the second most important risk factor for cancer development in humans, exceeded only by tobacco usage. The mode of virally-induced tumors can be divided into two, acutely-transforming or slowly-transforming. In acutely transforming viruses, the virus carries an overactive oncogene called viral-oncogene (v-onc), and the infected cell is transformed as soon as v-onc is expressed. In contrast, in slowly-transforming viruses, the virus genome is inserts near a proto-oncogene in the host genome. The viral promoter or other transcription regulation elements then cause overexpression of that proto-oncogene. This induces uncontrolled cell division. Because the site of insertion is not specific to proto-oncogenes and the chance of insertion near any proto-oncogene is low, slowly-transforming viruses will cause tumors much longer after infection than the acutely-transforming viruses.

Hepatitis viruses, including hepatitis B and hepatitis C, can induce a chronic viral infection that leads to liver cancer in 0.47% of hepatitis B patients per year (especially in Asia, less so in North America), and in 1.4% of hepatitis C carriers per year. Liver cirrhosis, whether from chronic viral hepatitis infection or alcoholism, is associated with the development of liver cancer, and the combination of cirrhosis and viral hepatitis presents the highest risk of liver cancer development. Worldwide, liver cancer is one of the most common, and most deadly, cancers due to a huge burden of viral hepatitis transmission and disease.

Advances in cancer research have made a vaccine designed to prevent cancer available. In 2006, the U.S. Food and Drug Administration approved a human papilloma virus vaccine, called Gardasil. The vaccine protects against four HPV types, which together cause 70% of cervical cancers and 90% of genital warts. In March 2007, the US Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) officially recommended that females aged 11–12 receive the vaccine, and indicated that females as young as age 9 and as old as age 26 are also candidates for immunization.

In addition to viruses, researchers have noted a connection between bacteria and certain cancers. The most prominent example is the link between chronic infection of the wall of the stomach with Helicobacter pylori and gastric cancer. Although only a minority of those infected with Helicobacter go on to develop cancer, since this pathogen is quite common it is probably responsible for the majority of these cancers.

Hormonal imbalance

Some hormones can act in a similar manner to non-mutagenic carcinogens in that they may stimulate excessive cell growth. A well-established example is the role of hyperestrogenic states in promoting endometrial cancer.

Immune system dysfunction

HIV is associated with a number of malignancies, including Kaposi’s sarcoma, non-Hodgkin’s lymphoma, and HPV-associated malignancies such as anal cancer and cervical cancer. AIDS-defining illnesses have long included these diagnoses. The increased incidence of malignancies in HIV patients points to the breakdown of immune surveillance as a possible etiology of cancer. Certain other immune deficiency states (e.g. common variable immunodeficiency and IgA deficiency) are also associated with increased risk of malignancy.

Heredity

Most forms of cancer are sporadic, meaning that there is no inherited cause of the cancer. There are, however, a number of recognised syndromes where there is an inherited predisposition to cancer, often due to a defect in a gene that protects against tumor formation. Famous examples are:

• certain inherited mutations in the genes BRCA1 and BRCA2 are associated with an elevated risk of breast cancer and ovarian cancer
• tumors of various endocrine organs in multiple endocrine neoplasia (MEN types 1, 2a, 2b)
• Li-Fraumeni syndrome (various tumors such as osteosarcoma, breast cancer, soft tissue sarcoma, brain tumors) due to mutations of p53
• Turcot syndrome (brain tumors and colonic polyposis)
• Familial adenomatous polyposis an inherited mutation of the APC gene that leads to early onset of colon carcinoma.
• Hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome) can include familial cases of colon cancer, uterine cancer, gastric cancer, and ovarian cancer, without a preponderance of colon polyps.
• Retinoblastoma, when occurring in young children, is due to a hereditary mutation in the retinoblastoma gene.
• Down syndrome patients, who have an extra chromosome 21, are known to develop malignancies such as leukemia and testicular cancer, though the reasons for this difference are not well understood.

Other causes

Excepting the rare transmissions that occur with pregnancies and only a marginal few organ donors, cancer is generally not a transmissible disease. The main reason for this is tissue graft rejection caused by MHC incompatibility. In humans and other vertebrates, the immune system uses MHC antigens to differentiate between “self” and “non-self” cells because these antigens are different from person to person. When non-self antigens are encountered, the immune system reacts against the appropriate cell. Such reactions may protect against tumour cell engraftment by eliminating implanted cells. In the United States, approximately 3,500 pregnant women have a malignancy annually, and transplacental transmission of acute leukaemia, lymphoma, melanoma and carcinoma from mother to fetus has been observed. The development of donor-derived tumors from organ transplants is exceedingly rare. The main cause of organ transplant associated tumors seems to be malignant melanoma, that was undetected at the time of organ harvest[27], though other cases exist. In fact, cancer from one organism will usually grow in another organism of that species, as long as they share the same histocompatibility genes, proven using mice; however this would never happen in a real-world setting except as described above. In non-humans, a few types of cancer have been found to be caused by transmission of the tumor cells themselves. This phenomenon is seen in dogs with Sticker’s sarcoma, also known as canine transmissible venereal tumor, as well as Devil facial tumour disease in Tasmanian devils.

Mechanism

Cancer is fundamentally a disease of regulation of tissue growth. In order for a normal cell to transform into a cancer cell, genes which regulate cell growth and differentiation must be altered. Genetic changes can occur at many levels, from gain or loss of entire chromosomes to a mutation affecting a single DNA nucleotide. There are two broad categories of genes which are affected by these changes. Oncogenes may be normal genes which are expressed at inappropriately high levels, or altered genes which have novel properties. In either case, expression of these genes promotes the malignant phenotype of cancer cells. Tumor suppressor genes are genes which inhibit cell division, survival, or other properties of cancer cells. Tumor suppressor genes are often disabled by cancer-promoting genetic changes. Typically, changes in many genes are required to transform a normal cell into a cancer cell.

There is a diverse classification scheme for the various genomic changes which may contribute to the generation of cancer cells. Most of these changes are mutations, or changes in the nucleotide sequence of genomic DNA. Aneuploidy, the presence of an abnormal number of chromosomes, is one genomic change which is not a mutation, and may involve either gain or loss of one or more chromosomes through errors in mitosis.

Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs when a cell gains many copies (often 20 or more) of a small chromosomal locus, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia, and results in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase.

Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter of a gene and affect its expression, or may occur in the gene’s coding sequence and alter the function or stability of its protein product. Disruption of a single gene may also result from integration of genomic material from a DNA virus or retrovirus, and such an event may also result in the expression of viral oncogenes in the affected cell and its descendants.

Epigenetics

Epigenetics is the study of the regulation of gene expression through chemical, non-mutational changes in DNA structure. The theory of epigenetics in cancer pathogenesis is that non-mutational changes to DNA can lead to alterations in gene expression. Normally, oncogenes are silent, for example, because of DNA methylation. Loss of that methylation can induce the aberrant expression of oncogenes, leading to cancer pathogenesis. Known mechanisms of epigenetic change include DNA methylation, and methylation or acetylation of histone proteins bound to chromosomal DNA at specific locations. Classes of medications, known as HDAC inhibitors and DNA methyltransferase inhibitors, can re-regulate the epigenetic signaling in the cancer cell.

Oncogenes

Oncogenes promote cell growth through a variety of ways. Many can produce hormones, a “chemical messenger” between cells which encourage mitosis, the effect of which depends on the signal transduction of the receiving tissue or cells. In other words, when a hormone receptor on a recipient cell is stimulated, the signal is conducted from the surface of the cell to the cell nucleus to effect some change in gene transcription regulation at the nuclear level. Some oncogenes are part of the signal transduction system itself, or the signal receptors in cells and tissues themselves, thus controlling the sensitivity to such hormones. Oncogenes often produce mitogens, or are involved in transcription of DNA in protein synthesis, which creates the proteins and enzymes responsible for producing the products and biochemicals cells use and interact with.

Mutations in proto-oncogenes, which are the normally quiescent counterparts of oncogenes, can modify their expression and function, increasing the amount or activity of the product protein. When this happens, the proto-oncogenes become oncogenes, and this transition upsets the normal balance of cell cycle regulation in the cell, making uncontrolled growth possible. The chance of cancer cannot be reduced by removing proto-oncogenes from the genome, even if this were possible, as they are critical for growth, repair and homeostasis of the organism. It is only when they become mutated that the signals for growth become excessive.

One of the first oncogenes to be defined in cancer research is the ras oncogene. Mutations in the Ras family of proto-oncogenes (comprising H-Ras, N-Ras and K-Ras) are very common, being found in 20% to 30% of all human tumours. Ras was originally identified in the Harvey sarcoma virus genome, and researchers were surprised that not only was this gene present in the human genome but that, when ligated to a stimulating control element, could induce cancers in cell line cultures.

Tumor suppressor genes

Tumor suppressor genes code for anti-proliferation signals and proteins that suppress mitosis and cell growth. Generally, tumor suppressors are transcription factors that are activated by cellular stress or DNA damage. Often DNA damage will cause the presence of free-floating genetic material as well as other signs, and will trigger enzymes and pathways which lead to the activation of tumor suppressor genes. The functions of such genes is to arrest the progression of the cell cycle in order to carry out DNA repair, preventing mutations from being passed on to daughter cells. The p53 protein, one of the most important studied tumor suppressor genes, is a transcription factor activated by many cellular stressors including hypoxia and ultraviolet radiation damage.

Despite nearly half of all cancers possibly involving alterations in p53, its tumor suppressor function is poorly understood. p53 clearly has two functions: one a nuclear role as a transcription factor, and the other a cytoplasmic role in regulating the cell cycle, cell division, and apoptosis.

The Warburg hypothesis is the preferential use of glycolysis for energy to sustain cancer growth. p53 has been shown to regulate the shift from the respiratory to the glycolytic pathway.

However, a mutation can damage the tumor suppressor gene itself, or the signal pathway which activates it, “switching it off”. The invariable consequence of this is that DNA repair is hindered or inhibited: DNA damage accumulates without repair, inevitably leading to cancer.

Mutations of tumor suppressor genes that occur in germline cells are passed along to offspring, and increase the likelihood for cancer diagnoses in subsequent generations. Members of these families have increased incidence and decreased latency of multiple tumors. The tumor types are typical for each type of tumor suppressor gene mutation, with some mutations causing particular cancers, and other mutations causing others. The mode of inheritance of mutant tumor suppressors is that an affected member inherits a defective copy from one parent, and a normal copy from the other. For instance, individuals who inherit one mutant p53 allele (and are therefore heterozygous for mutated p53) can develop melanomas and pancreatic cancer, known as Li-Fraumeni syndrome. Other inherited tumor suppressor gene syndromes include Rb mutations, linked to retinoblastoma, and APC gene mutations, linked to adenopolyposis colon cancer. Adenopolyposis colon cancer is associated with thousands of polyps in colon while young, leading to colon cancer at a relatively early age. Finally, inherited mutations in BRCA1 and BRCA2 lead to early onset of breast cancer.

Development of cancer was proposed in 1971 to depend on at least two mutational events. In what became known as the Knudson two-hit hypothesis, an inherited, germ-line mutation in a tumor suppressor gene would only cause cancer if another mutation event occurred later in the organism’s life, inactivating the other allele of that tumor suppressor gene.

Usually, oncogenes are dominant, as they contain gain-of-function mutations, while mutated tumor suppressors are recessive, as they contain loss-of-function mutations. Each cell has two copies of the same gene, one from each parent, and under most cases gain of function mutations in just one copy of a particular proto-oncogene is enough to make that gene a true oncogene. On the other hand, loss of function mutations need to happen in both copies of a tumor suppressor gene to render that gene completely non-functional. However, cases exist in which one mutated copy of a tumor suppressor gene can render the other, wild-type copy non-functional. This phenomenon is called the dominant negative effect and is observed in many p53 mutations.

Knudson’s two hit model has recently been challenged by several investigators. Inactivation of one allele of some tumor suppressor genes is sufficient to cause tumors. This phenomenon is called haploinsufficiency and has been demonstrated by a number of experimental approaches. Tumors caused by haploinsufficiency usually have a later age of onset when compared with those by a two hit process.

Cancer cell biology

Often, the multiple genetic changes which result in cancer may take many years to accumulate. During this time, the biological behavior of the pre-malignant cells slowly change from the properties of normal cells to cancer-like properties. Pre-malignant tissue can have a distinctive appearance under the microscope. Among the distinguishing traits are an increased number of dividing cells, variation in nuclear size and shape, variation in cell size and shape, loss of specialized cell features, and loss of normal tissue organization. Dysplasia is an abnormal type of excessive cell proliferation characterized by loss of normal tissue arrangement and cell structure in pre-malignant cells. These early neoplastic changes must be distinguished from hyperplasia, a reversible increase in cell division caused by an external stimulus, such as a hormonal imbalance or chronic irritation.

The most severe cases of dysplasia are referred to as “carcinoma in situ.” In Latin, the term “in situ” means “in place”, so carcinoma in situ refers to an uncontrolled growth of cells that remains in the original location and has not shown invasion into other tissues. Nevertheless, carcinoma in situ may develop into an invasive malignancy and is usually removed surgically, if possible.

Clonal evolution

Just like a population of animals undergoes evolution, an unchecked population of cells also can undergo evolution. This undesirable process is called somatic evolution, and is how cancer arises and becomes more malignant.

Most changes in cellular metabolism that allow cells to grow in a disorderly fashion lead to cell death. However once cancer begins, cancer cells undergo a process of natural selection: the few cells with new genetic changes that enhance their survival or reproduction continue to multiply, and soon come to dominate the growing tumor, as cells with less favorable genetic change are out-competed.This is exactly how pathogens such as MRSA can become antibiotic-resistant (or how HIV can become drug-resistant), and the same reason why crop blights and pests can become pesticide-resistant. This evolution is why cancer recurrences will have cells which have acquired cancer-drug resistance (or in some cases, resistance to radiation from radiotherapy).

Biological properties of cancer

In a 2000 article by Hanahan and Weinberg, the biological properties of malignant tumor cells were summarized as follows:

• Acquisition of self-sufficiency in growth signals, leading to unchecked growth.
• Loss of sensitivity to anti-growth signals, also leading to unchecked growth.
• Loss of capacity for apoptosis, in order to allow growth despite genetic errors and external anti-growth signals.
• Loss of capacity for senescence, leading to limitless replicative potential (immortality)
• Acquisition of sustained angiogenesis, allowing the tumor to grow beyond the limitations of passive nutrient diffusion.
• Acquisition of ability to invade neighbouring tissues, the defining property of invasive carcinoma.
• Acquisition of ability to build metastases at distant sites, the classical property of malignant tumors (carcinomas or others).

The completion of these multiple steps would be a very rare event without :

• Loss of capacity to repair genetic errors, leading to an increased mutation rate (genomic instability), thus accelerating all the other changes.

These biological changes are classical in carcinomas; other malignant tumor may not need all to achieve them all. For example, tissue invasion and displacement to distant sites are normal properties of leukocytes; these steps are not needed in the development of leukemia. The different steps do not necessarily represent individual mutations. For example, inactivation of a single gene, coding for the p53 protein, will cause genomic instability, evasion of apoptosis and increased angiogenesis. Not all the cancer cells are dividing. Rather, a subset of the cells in a tumor, called cancer stem cells, replicate themselves and generate differentiated cells.

Prevention

Cancer prevention is defined as active measures to decrease the incidence of cancer. This can be accomplished by avoiding carcinogens or altering their metabolism, pursuing a lifestyle or diet that modifies cancer-causing factors and/or medical intervention (chemoprevention, treatment of pre-malignant lesions). The epidemiological concept of “prevention” is usually defined as either primary prevention, for people who have not been diagnosed with a particular disease, or secondary prevention, aimed at reducing recurrence or complications of a previously diagnosed illness.

Modifiable (“lifestyle”) risk factors

The vast majority of cancer risk factors are environmental or lifestyle-related in nature, leading to the claim that cancer is a largely preventable disease. Examples of modifiable cancer risk factors include alcohol consumption (associated with increased risk of oral, esophageal, breast, and other cancers), smoking (although 20% of women with lung cancer have never smoked, versus 10% of men[43]), physical inactivity (associated with increased risk of colon, breast, and possibly other cancers), and being overweight / obese (associated with colon, breast, endometrial, and possibly other cancers). Based on epidemiologic evidence, it is now thought that avoiding excessive alcohol consumption may contribute to reductions in risk of certain cancers; however, compared with tobacco exposure, the magnitude of effect is modest or small and the strength of evidence is often weaker. Other lifestyle and environmental factors known to affect cancer risk (either beneficially or detrimentally) include certain sexually transmitted diseases (such as those conveyed by the human papillomavirus), the use of exogenous hormones, exposure to ionizing radiation and ultraviolet radiation, and certain occupational and chemical exposures.

Every year, at least 200,000 people die worldwide from cancer related to their workplace.[44] Millions of workers run the risk of developing cancers such as lung cancer and mesothelioma from inhaling asbestos fibers and tobacco smoke, or leukemia from exposure to benzene at their workplaces. Currently, most cancer deaths caused by occupational risk factors occur in the developed world. It is estimated that approximately 20,000 cancer deaths and 40,000 new cases of cancer each year in the U.S. are attributable to occupation.

Diet

The consensus on diet and cancer is that obesity increases the risk of developing cancer. Particular dietary practices often explain differences in cancer incidence in different countries (e.g. gastric cancer is more common in Japan, while colon cancer is more common in the United States. In this example the preceding consideration of Haplogroups are excluded). Studies have shown that immigrants develop the risk of their new country, often within one generation, suggesting a substantial link between diet and cancer.[46] Whether reducing obesity in a population also reduces cancer incidence is unknown.

Despite frequent reports of particular substances (including foods) having a beneficial or detrimental effect on cancer risk, few of these have an established link to cancer. These reports are often based on studies in cultured cell media or animals. Public health recommendations cannot be made on the basis of these studies until they have been validated in an observational (or occasionally a prospective interventional) trial in humans.

Proposed dietary interventions for primary cancer risk reduction generally gain support from epidemiological association studies. Examples of such studies include reports that reduced meat consumption is associated with decreased risk of colon cancer, and reports that consumption of coffee is associated with a reduced risk of liver cancer.[48] Studies have linked consumption of grilled meat to an increased risk of stomach cancer, colon cancer, breast cancer, and pancreatic cancer, a phenomenon which could be due to the presence of carcinogens such as benzopyrene in foods cooked at high temperatures.

A 2005 secondary prevention study showed that consumption of a plant-based diet and lifestyle changes resulted in a reduction in cancer markers in a group of men with prostate cancer who were using no conventional treatments at the time. These results were amplified by a 2006 study in which over 2,400 women were studied, half randomly assigned to a normal diet, the other half assigned to a diet containing less than 20% calories from fat. The women on the low fat diet were found to have a markedly lower risk of breast cancer recurrence, in the interim report of December, 2006.

Recent studies have also demonstrated potential links between some forms of cancer and high consumption of refined sugars and other simple carbohydrates. Although the degree of correlation and the degree of causality is still debated, some organizations have in fact begun to recommend reducing intake of refined sugars and starches as part of their cancer prevention regimens.

In November 2007, the American Institute for Cancer Research (AICR), in conjunction with the World Cancer Research Fund (WCRF), published Food, Nutrition, Physical Activity and the Prevention of Cancer: a Global Perspective, “the most current and comprehensive analysis of the literature on diet, physical activity and cancer”. The WCRF/AICR Expert Report lists 10 recommendations that people can follow to help reduce their risk of developing cancer, including the following dietary guidelines:

1. reducing intake of foods and drinks that promote weight gain, namely energy-dense foods and sugary drinks,
2. eating mostly foods of plant origin,
3. limiting intake of red meat and avoiding processed meat, limiting consumption of alcoholic beverages, and
4. reducing intake of salt and avoiding mouldy cereals (grains) or pulses (legumes).

Some mushrooms offer an anti-cancer effect, which is thought to be linked to their ability to up-regulate the immune system. Some mushrooms known for this effect include, Reishi,Agaricus blazei, Maitake and Trametes versicolor. Research suggests the compounds in medicinal mushrooms most responsible for up-regulating the immune system and providing an anti-cancer effect, are a diverse collection of polysaccharide compounds, particularly beta-glucans. Beta-glucans are known as “biological response modifiers”, and their ability to activate the immune system is well documented. Specifically, beta-glucans stimulate the innate branch of the immune system. Research has shown beta-glucans have the ability to stimulate macrophage, NK cells, T cells, and immune system cytokines. The mechanisms in which beta-glucans stimulate the immune system is only partially understood. One mechanism in which beta-glucans are able to activate the immune system, is by interacting with the Macrophage-1 antigen (CD18) receptor on immune cells.

Vitamins

The idea that cancer can be prevented through vitamin supplementation stems from early observations correlating human disease with vitamin deficiency, such as pernicious anemia with vitamin B12 deficiency, and scurvy with Vitamin C deficiency. This has largely not been proven to be the case with cancer, and vitamin supplementation is largely not proving effective in preventing cancer. The cancer-fighting components of food are also proving to be more numerous and varied than previously understood, so patients are increasingly being advised to consume fresh, unprocessed fruits and vegetables for maximal health benefits.

Epidemiological studies have shown that low vitamin D status is correlated to increased cancer risk. However, the results of such studies need to be treated with caution, as they cannot show whether a correlation between two factors means that one causes the other (i.e. correlation does not imply causation). The possibility that Vitamin D might protect against cancer has been contrasted with the risk of malignancy from sun exposure. Since exposure to the sun enhances natural human production of vitamin D, some cancer researchers have argued that the potential deleterious malignant effects of sun exposure are far outweighed by the cancer-preventing effects of extra vitamin D synthesis in sun-exposed skin. In 2002, Dr. William B. Grant claimed that 23,800 premature cancer deaths occur in the US annually due to insufficient UVB exposure (apparently via vitamin D deficiency). This is higher than 8,800 deaths occurred from melanoma or squamous cell carcinoma, so the overall effect of sun exposure might be beneficial. Another research group estimates that 50,000–63,000 individuals in the United States and 19,000 – 25,000 in the UK die prematurely from cancer annually due to insufficient vitamin D.

The case of beta-carotene provides an example of the importance of randomized clinical trials. Epidemiologists studying both diet and serum levels observed that high levels of beta-carotene, a precursor to vitamin A, were associated with a protective effect, reducing the risk of cancer. This effect was particularly strong in lung cancer. This hypothesis led to a series of large randomized clinical trials conducted in both Finland and the United States (CARET study) during the 1980s and 1990s. This study provided about 80,000 smokers or former smokers with daily supplements of beta-carotene or placebos. Contrary to expectation, these tests found no benefit of beta-carotene supplementation in reducing lung cancer incidence and mortality. In fact, the risk of lung cancer was slightly, but not significantly, increased by beta-carotene, leading to an early termination of the study.

Results reported in the Journal of the American Medical Association (JAMA) in 2007 indicate that folic acid supplementation is not effective in preventing colon cancer, and folate consumers may be more likely to form colon polyps.

Chemoprevention

The concept that medications could be used to prevent cancer is an attractive one, and many high-quality clinical trials support the use of such chemoprevention in defined circumstances.

Daily use of tamoxifen, a selective estrogen receptor modulator (SERM), typically for 5 years, has been demonstrated to reduce the risk of developing breast cancer in high-risk women by about 50%. A recent study reported that the selective estrogen receptor modulator raloxifene has similar benefits to tamoxifen in preventing breast cancer in high-risk women, with a more favorable side effect profile.

Raloxifene is a SERM like tamoxifen; it has been shown (in the STAR trial) to reduce the risk of breast cancer in high-risk women equally as well as tamoxifen. In this trial, which studied almost 20,000 women, raloxifene had fewer side effects than tamoxifen, though it did permit more DCIS to form.

Finasteride, a 5-alpha-reductase inhibitor, has been shown to lower the risk of prostate cancer, though it seems to mostly prevent low-grade tumors. The effect of COX-2 inhibitors such as rofecoxib and celecoxib upon the risk of colon polyps have been studied in familial adenomatous polyposis patients and in the general population. In both groups, there were significant reductions in colon polyp incidence, but this came at the price of increased cardiovascular toxicity.

Genetic testing

Genetic testing for high-risk individuals is already available for certain cancer-related genetic mutations. Carriers of genetic mutations that increase risk for cancer incidence can undergo enhanced surveillance, chemoprevention, or risk-reducing surgery. Early identification of inherited genetic risk for cancer, along with cancer-preventing interventions such as surgery or enhanced surveillance, can be lifesaving for high-risk individuals.

Vaccination

Prophylactic vaccines have been developed to prevent infection by oncogenic infectious agents such as viruses, and therapeutic vaccines are in development to stimulate an immune response against cancer-specific epitopes.

As reported above, a preventive human papillomavirus vaccine exists that targets certain sexually transmitted strains of human papillomavirus that are associated with the development of cervical cancer and genital warts. The only two HPV vaccines on the market as of October 2007 are Gardasil and Cervarix. There is also a hepatitis B vaccine, which prevents infection with the hepatitis B virus, an infectious agent that can cause liver cancer. A canine melanoma vaccine has also been developed.