Breast cancer surgery appears to trigger accelerated growth of any remaining tumor cells, both in the breast and in more distant locations in the body. Morphine can also increase proliferation and migration of breast cancer cells, as well as promoting angiogenesis. In addition, morphine suppresses the immune system. Animal and human studies comparing surgery with and without morphine or other opiates have demonstrated that use of opiates increases the likelihood of breast cancer recurrence. On the other hand, use of the nonsteroidal anti-inflammatory drug (NSAID) Toradol (ketorolac) during surgery instead of morphine dramatically reduces breast cancer recurrence, according to one study.

Surgery stimulates metastasis

Surgery is the primary and most effective treatment of breast cancer. However, the stress response induced by surgery impairs immune system functioning, promotes postoperative infections, and increases inflammation. In fact, surgery appears to promote metastasis through its effects on both the remaining breast tissue and distant tumor cells that had already been disseminated to other parts of the body prior to surgery.

Changes at the site of the surgical wound have been reported to accelerate the growth of cancer cells and are suspected of increasing their metastatic potential. In other words, surgery that leaves some of the tumor cells behind might promote the proliferation and motility of these cells, thereby allowing their escape into circulation. While there may already be dormant cancer cells in distant sites (which might have been seeded years earlier) that could potentially develop into tumors, cancer cells made suddenly mobile as a result of surgery would result in new waves of micrometastases with at least equal probability of developing into new tumors.

Surgery has been shown to induce modifications in the expression of genes implicated in metastasis, leading to changes that accelerate metastatic tumor growth in remaining tumor cells. In one study, mice prone to lung metastases were implanted with mammary tumors that were allowed to grow for 21 days. The mice were then divided into two groups, one of which had their mammary tumors completely surgically removed. At the end of the study, the lung metastases of the two groups of mice were compared. Surgical tumor removal was associated with increased number and size of metastases. Further analysis demonstrated that primary tumor removal led to increased expression of genes involved in tumor cell adhesion, invasion, and angiogenesis. Another mouse study reported that surgical removal of mammary tumors generated patterns of metastatic dissemination significantly different from those observed in tumors not treated by surgery.

Evidence for morphine's influence on cancer relapse

Morphine appears to amplify the deleterious effects of surgery. Morphine has been found to increase proliferation, inhibit the immune response, and promote angiogenesis of breast cancer cells in the laboratory. Comparisons of breast cancer surgery performed with or without morphine or other opiates have reported lower rates of breast cancer recurrence for surgery without opiates:

• A study of 327 Belgian breast cancer patients that compared various analgesics and anesthetics used in mastectomies performed by a single surgeon reported that use of Toradol (ketorolac) during surgery resulted in far superior disease-free survival during the first five years after surgery than other analgesics used in the study. Toradol, an NSAID, is a non-selective (COX-1 and COX-2) COX inhibitor. The early relapse peak normally seen in breast cancer patients was all but absent: 92% of the Toradol group were relapse-free at the two year mark, compared to 78% of the non-Toradol group (who were given opiates). Toradol was the only anti-inflammatory drug among the pain killers studied, suggesting that suppression of the temporary systemic inflammation resulting from surgery could explain its effect.
• Another study was designed to investigate the properties of serum from breast cancer surgery patients who received different anesthetic techniques. The study was conducted by dividing 22 patients into two groups — one group received propofol for sedation plus a paravertebral block (spinal block) for pain; the second group received sevoflurane general anesthesia plus opiate pain medication. Blood was drawn from the patients after surgery and MDA-MB-231 triple negative breast cancer cells were treated with serum from both patient groups. The effects of the serum on cancer cell proliferation and migration were measured. Proliferation of breast cancer cells treated with serum from the spinal block group was significantly lower than that of cells treated with serum from the opiate group.
• An Irish study of mastectomy patients compared the outcomes of 50 women who had paravertebral anesthesia and analgesia compared to 79 who had general anesthesia plus postoperative morphine. After two years, 94% of the paravertebral patient group were free of breast cancer relapse compared to 82% of the general anesthesia plus morphine patients. After three years, the comparable figures were 94% and 77%.

Use of regional instead of general anesthesia is known to reduce the surgical stress response. However, the first study above did not use this approach — it was the use of Toradol instead of an opiate that appeared to account for the lower recurrence rate.

Bottom line

While larger studies must be completed and confirm the results concerning Toradol, there is enough evidence concerning morphine to warrant taking steps to avoid its use. Many lumpectomies could probably be performed under regional anesthetic without morphine. Breast cancer patients can request that Toradol or another NSAID be used during and after surgery and themselves avoid using morphine after surgery, as well as other opiates such as Vicodin, Oxycodone, and Percocet.

Common NSAIDs include aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), and Celebrex. Although study results concerning NSAIDs are inconsistent, previous studies have reported that aspirin and Celebrex both are associated with reduced breast cancer risk and recurrence, whereas Aleve might have less effect, and ibuprofen could actually increase risk. Over-the-counter NSAIDs should not be used before surgery because they increase risk of bleeding during surgery. Also, note that Celebrex has been shown to interfere with the effectiveness of Adriamycin (doxorubicin) and certain other chemotherapy drugs and should not be used during chemotherapy. Breast cancer patients should discuss this topic with their surgeons.

High intake of dietary fiber appears to be associated with reduced risk of breast cancer. This is not surprising since fiber is found primarily in fruits, vegetables, legumes, nuts, and seeds, most of which have chemopreventive components. However, fiber appears to have its own anti-cancer effects. Increasing fiber intake could be particularly beneficial for those who (1) have high levels of inflammation; (2) have type 2 diabetes; (3) have high cholesterol; (4) need to lose weight; or (5) are undergoing hormone replacement therapy (HRT).

Types of fiber

Dietary fiber comes from edible portions of plant-based foods that are resistant to digestion. Soluble fibers (pectins, gums, mucilages) dissolve in water and form a gel, which slows digestion. Insoluble fibers (cellulose, lignins) do not dissolve in water; they add bulk to the diet and speed up the passage of food and waste.

The following foods are good sources of soluble fiber while also having been found to be associated with reduced risk of breast cancer:

Apples

Broccoli

Brussels sprouts

Buckwheat

Dry beans

Kale

Oats

Seaweed

Turnips

The following foods are good sources of insoluble fiber while also having been found to be associated with reduced risk of breast cancer:

Apples Bell peppers Blackberries Blueberries Broccoli Brussels sprouts Carrots Celery Cranberries Dry beans Flaxseed

Greens Kale Oats Raspberries Rice, brown Spinach Tomatoes Turnips Walnuts Wheat bran Zucchini

Fiber is added to some processed foods in order to qualify the foods as "high fiber" or to improve texture. This "isolated fiber" is extracted or synthesized from plant sources. Examples include inulin (from chicory root or sugar beets), soluble corn fiber (corn), cellulose (wood pulp), maltodextrin (corn, rice, or potato starch) and polydextrose (corn starch). Such fiber-fortified foods typically lack the flavonoids and other biologically active components of fruits, vegetables, grains and nuts, however there is no evidence that isolated fiber is harmful.

Fiber and risk of breast cancer

While not all studies have reported an association, numerous studies have found a reduction in risk of breast cancer among women with high dietary fiber intake:

• A 2012 meta-analysis of 16 prospective studies reported a 7% reduced risk of breast cancer for women with the highest compared to the lowest intake of dietary fiber. When risk reduction was calculated according to the type of fiber consumed, the reduction in breast cancer risk was 9% for soluble fiber and 5% for insoluble fiber.
• A 2011 Chinese study reported that high fruit and vegetable fiber consumption was associated with approximately half the risk of breast cancer as low intake. The results for soy fiber were not significant and no association was found for cereal fiber intake. When the data was analyzed according to hormone receptor status, an inverse association between fiber intake and breast cancer risk was found for progesterone receptor positive tumors (ER+/PR+ and ER-/PR+), but not PR- tumors (ER+/PR-, ER-/PR-).
• A major U.S. prospective population study that included 185,598 postmenopausal women found that overall consumption of dietary fiber was inversely associated with risk of breast cancer, with a 13% lower risk of breast cancer for the highest compared to the lowest quintiles (fifths) of intake. The inverse association was much stronger for hormone receptor negative (ER-/PR-) tumors (44% risk reduction) than for ER+/PR+ tumors (5%). High fiber consumption reduced the risk of lobular more than ductal tumors. When stratified by type of food, fiber intake from grains, fruit, vegetables, and beans was not found to be related to risk of breast cancer.
• A large Swedish prospective study that examined the associations between breast cancer and fiber and various plant food groups reported that high-fiber bread was associated with a 25% lower breast cancer incidence (comparing the highest with the lowest quintile of intake).
• Another Swedish study reported risk reductions for overall (34%) and for ER+/PR+ (38%) breast cancer for the highest versus lowest quintile of fruit fiber, and non-significant inverse associations for other subtypes of cancer and types of fiber. Among ever-users of hormone replacement therapy, total fiber intake and especially cereal fiber were found to be associated with a 50% reduction in risk for breast cancer overall and for ER+/PR+ tumors when comparing the highest to the lowest quartile.
• A major U.S. prospective study of women in the Nurses’ Health Study reported no overall associations between breast cancer risk and dietary carbohydrates or total dietary fiber intake.

Fiber and risk of breast cancer recurrence

There is very little data concerning fiber intake and risk of recurrence in breast cancer survivors. A 2011 U.S. study designed to investigate the associations between dietary fiber, carbohydrates, glycemic index and glycemic load and breast cancer prognosis reported an inverse association between fiber intake and overall likelihood of death (from any cause). However, no additional benefit was observed for fiber intakes above 9 g/day, indicating a threshold effect. Fiber intake also was found to be inversely associated with breast-cancer specific death and risk of non-fatal recurrence or second breast cancer, but the results were not statistically significant.

How fiber influences breast cancer

Most fiber-rich foods contain a variety of compounds that could influence breast cancer growth and development. Therefore, it is difficult to determine whether fiber, per se, has anticancer activities. However, researchers have attempted to solve this puzzle and provided the following explanations of fiber's role:

• Fiber increases frequency of bowel movements (bowel motility), which in turn reduces breast cancer risk by increasing estrogen excretion. Circulating estrogen levels are an established risk factor for breast cancer.
• High fiber intake reduces serum cholesterol levels. There is some evidence that high cholesterol promotes breast cancer.
• Diets high in fiber reduce circulating C-reactive protein, a marker of inflammation. Inflammation is thought to increase breast cancer risk and worsen its subsequent prognosis.
• Fiber intake reduces weight gain for similar levels of calorie intake. Overweight postmenopausal women are at increased risk of breast cancer and recurrence compared to normal weight women.
• A high intake of dietary fiber, particularly soluble fiber, improves blood sugar control and reduces excess circulating insulin (hyperinsulinemia) in patients with type 2 diabetes. Hyperinsulinemia is associated with increased risk of breast cancer and recurrence.

Please see our article on how to optimize your breast cancer diet for information on how to incorporate the fiber-rich foods above into an eating plan that is suitable for your breast cancer type.

Statin drugs, which are used to treat high cholesterol, have been reported to reduce breast cancer risk in some studies but not in others. Similarly, breast cancer recurrence might be influenced by statin use, but the evidence is mixed. As a result, the topic of statin use and its association with breast cancer is controversial. Now a new study has begun to describe how statins interact with breast cancer and which tumors might be treated effectively with statins.

Statin use and risk of breast cancer

Dietary cholesterol has been found to accelerate and promote mammary tumor formation in mice. Circulating cholesterol levels were observed to be reduced during tumor development (but not prior to tumor initiation) in one study, providing evidence for increased use of cholesterol by tumors. In other words, an increase in cholesterol might accelerate the development of breast tumors and increase their aggressiveness.

However, studies have reported contradictory results concerning the association between statin use and risk of breast cancer. Statins are classified either as lipophilic (e.g., Lipitor, Zocor, Mevacor, Lescol) or hydrophilic (Crestor, Pravachol), depending on the compound. A 2008 study reported that lipophilic statin use reduced the risk of triple negative breast cancer, however the results were not confirmed by subsequent studies. A large 2010 study that included 22,486 breast cancer cases concluded that there does not appear to be an association between lipophilic statin use and breast cancer risk in general or the risk of specific receptor subtypes. Any effect, if it exists at all, is likely much smaller than previous studies suggested, according to the authors.

Nevertheless, previous studies found associations between statin use and breast cancer for some women. One study reported that compared to non-users, obese women who used hydrophobic statins had a greatly increased risk of progesterone receptor negative (PR-) breast cancer, but not of progesterone receptor positive (PR+) tumors. Breast cancer risk was also found to be increased among overweight women who used hydrophobic statins for up to four years.

Statin use and risk of recurrence

While not all studies have reported an association, statin use might influence breast cancer recurrence. One study that included women with stage I to IV breast cancer found that while statin use did not affect the three-year overall survival of early stage breast cancer, it appeared to improve the outcome at more advanced stages (stage III and stage IV). Lipitor was the most used treatment among the study participants.

A study that included all 18,769 Danish women diagnosed with stage I-III invasive breast cancer between 1996 and 2003 reported that Zocor users experienced approximately 10 fewer breast cancer recurrences per 100 women after 10 years of follow up compared to women who did not use a statin. On the other hand, exclusive hydrophilic statin users were found to have approximately the same risk of breast cancer recurrence as women not prescribed a statin. The authors concluded that Zocor, a highly lipophilic statin, was associated with reduced risk of breast cancer recurrence among Danish women diagnosed with stage I-III breast cancer.

A small study that sought to examine whether statin therapy influences survival in patients with type 2 diabetes reported that diabetic breast cancer patients receiving statins to treat high cholesterol had better disease-free survival than patients not receiving any cholesterol management medication at diagnosis.

Latest research uncovers mechanism of action of statins

The new study referenced at the beginning of this news article helps explain the anticancer effects of statins and why they appear to be effective only in some women. The study was designed to investigate whether the removal of mutant p53 is sufficient to return breast cancer cells to a normal shape and structure, as well as the possible influence of statin drugs on this process.

p53 is a tumor suppressor protein that is encoded by tumor suppressor p53 gene. Activation of p53 results either in the death of the cell by apoptosis (programmed cell death) or survival of the cell by cell cycle arrest and DNA repair. Some foods that are chemopreventive also increase the expression of p53, thereby inducing cancer cell death. When functioning properly, p53 limits the growth of cells with incorrect numbers of chromosomes and prevents their progression toward cancer.

However, tumor suppressor p53 is the most frequently mutated gene in human tumors. These mutations don't just disrupt the normal functioning of p53, they often also endow p53 with new functions that promote, instead of inhibit, cancer formation. Mutant p53 frequently accumulates in cancer cells and promotes tumor cell invasion, as part of its acquisition of function. However, unlike many other cancers, p53 gene mutations are infrequent in breast cancer, occurring in approximately 20% to 25% of breast tumors. In fact, p53 mutations are rare in early-stage estrogen receptor positive (ER+) breast cancer.

Breast cancer cells display highly disorganized morphology (shape and structure). To conduct the study, the authors used a three-dimensional culture technique to create a realistic tumor model. In the culture, noncancerous breast cells were induced to form spheroids similar to the cellular structures found in the human breast. Cells carrying mutant p53 grew in the misshapen, disorganized manner typical of breast cancer. Reducing levels of mutant p53 was found to be sufficient to return these breast cancer cells to a more normal morphology.

Further analysis demonstrated that the mevalonate pathway, a cholesterol-building pathway, was significantly upregulated by mutant p53. This pathway was shown to be both necessary and sufficient for the effects of mutant p53 on breast tissue architecture. Statin drugs lower cholesterol by inhibiting a step in the same pathway. When cells with mutant p53 were treated with statins, their disorganized, invasive growth was halted and some died. The authors conclude that the study findings imply that the mevalonate pathway may be a promising therapeutic target for tumors bearing mutations in p53. In a separate interview, study author Carol Prives of Columbia University said, "The data raises the possibility that we might identify subsets of patients whose tumors may respond to statins."

The bottom line

The fact that tumor suppressor p53 is not mutated in many breast cancers might explain why statin use influences breast cancer risk and survival inconsistently. Also, the observation that p53 mutations are rare in early-stage ER+ breast cancer could explain the finding that Lipitor appears to improve the outcome of stage III and stage IV breast cancer, but not stage I or stage II. Clearly, it is not currently possible to determine which breast cancer survivors could benefit from statin use. However, for those who need to take statins, lipophilic statins such as Zocor and Lipitor appear to be the best choice.