Breast cancer in younger patients worse with iron deficiency

Breast cancer has the worst track record in younger patients. According to research just published in BMC Cancer (BioMed Central), iron deficiency may be a treatable risk factor. The authors state:

"Young breast cancer (BC) patients less than 45 years old are at higher risk of dying from the disease when compared to their older counterparts. However, specific risk factors leading to this poorer outcome have not been identified...One candidate is iron deficiency, as this is common in young women and a clinical feature of young age. In the present study, we used immuno-competent and immuno-deficient mouse xenograft models as well as hemoglobin as a marker of iron status in young BC patients to demonstrate whether host iron deficiency plays a pro-metastatic role."

They further note that the breast cancer picture has not improved for younger patients as it has for older, and it seems not to be due to estrogen levels or genetics:

"Although a decline in total BC cases was recently reported, a plot of age-specific BC rates shows a decrease only in older women (≥45 years old), suggesting that recent advances in BC research have just benefited older patients...The differences in clinical outcomes between young and older patients cannot be fully explained by estrogen status and/or family history. Studies in BC risk factors and tumor characteristics indicate that young BC patients have an additional disease entity that is unique to them."

Iron loss due to menstruation is particularly significant:

"A typical characteristic of young premenopausal women is the menstrual cycle. Because of menstruation, iron deficiency is highly prevalent in young women, particularly in poorer, less educated, and minority populations. Interestingly, these populations also suffer more aggressive forms of BC than others. This suggests that iron deficiency may be a risk factor in BC agressiveness of young patients, but its role has not been investigated to date."

The authors raise an extremely important, and universal, point about the 'terrain' of the patient:

"The well-established “seed and soil” theory indicates that host responses are equally important as intrinsic properties of cancer cells in determining cancer outcomes. For example, increasing evidence has demonstrated that iron has a role in the tumor microenvironment and pathways of iron acquisition, efflux, and regulation are all perturbed in cancer. This suggests that reprograming of iron metabolism, either through iron responsive element/iron regulatory proteins or hepcidin/ferroportin axis or some unidentified mechanisms, is a central aspect of tumor cell survival. In distinction to increased iron in cancer cells and its microenvironment, we previously hypothesized that host iron deficiency and macroenvironment as a young women-specific risk factor results in increased susceptibility of young patients to BC metastasis and recurrence. Here we expand on this study and show that host iron deficiency promotes mammary cancer growth and metastasis in mice and is a significant predictor of lymph node invasion in humans."

They showed in their mouse tumor (human) xenograft models thatthat primary tumor volumes from the human cancer cells were significantly higher in iron deficient mice, as were surface lung metastases.

"These results indicate that iron deficiency promotes growth and metastasis of BC of both mouse and human origins."

Moreover, supplementing iron reduced tumor growth:

"Most importantly, iron therapy significantly inhibited iron deficiency- related tumor growth (638.8 ± 90.3 vs. 925.6 ± 147.4 p<0.05, n=9). While iron deficiency enhanced lung metastasis, iron therapy decreases lung metastasis. In this experiment...they were injected into the mammary fat pads, resulting in smaller tumor volumes and less numbers of lung metastasis...Not only did iron therapy reverse lung metastasis, but also reversed iron deficiency-mediated tumor growth, downregulated Snai1, upregulated E-cadherin, and decreased Notch2 expression. These results strongly indicate that iron deficiency leads to tumor growth and metastasis."

Regarding lymph node invasion in young human breast cancer patients, they examined hemoglobin (Hb) levels for 148 breast cancer patients less than 45 years old in association with lymph node positive or negative status. This data told a similar story:

"We found that Hb level is significantly lower in node positive BC patients than node negative BC patients."

Regarding concerns about iron as a pro-oxidant:

"Iron is long known to be a double-edged sword. Previous studies have shown that iron- accumulation-associated pro-oxidant conditions in cancer cells could fuel the activity of iron- dependent proteins and enable enhanced cancer cell proliferation, contributing to both tumor initiation and tumor growth. In the present study, we provide evidence that host iron deficiency-mediated proangiogenic environment could lead to xenografted tumor growth and metastasis as well. Although our study is limited to BC, which has the most epidemiological data on recurrence in young patients, it confirms previous observation that recurrence of other cancers, such as colorectal cancer, tends to have a higher incidence of recurrence in young patients. By linking young age to iron deficiency and then to BC malignancy, our finding may have identified that host iron deficiency represents a clinical entity that is specific to young women and is associated with lower survival and higher recurrence in young BC patients."

Anemia, even 'borderline' anemia, due to chronic inflammation is something that I frequently see in practice and consider it of paramount importance to get to the bottom of. Anemia of chronic inflammation (ACI) is also called anemia of chronic disease (ACD)...

"Moreover, “functional” iron deficiency known as anemia of chronic disease (ACD) is a clinical condition where stored iron is sufficient but circulating iron is deficient. ACD is a well-established risk factor for increased morbidity and mortality of late stage cancer patients...“Absolute” iron deficiency refers to the depletion of iron stores in the body and is highly prevalent in young women as results of menstruation and insufficient dietary iron uptake. If ACD increases mortality in cancer patients, “absolute” iron deficiency could have the same effects...moderate iron deficiency significantly affected tumor growth and metastasis in both immuno-competent and immuno- deficient mice. Furthermore, human studies suggest that mild iron deficiency without advancing to anemia could be a cause of lymph node invasion, because Hb levels in the node positive BC patients were only slightly below normal (119.6 g/L compared to cutoff value of 120 g/L) and iron deficiency proceeds anemia in young women."

However, caution must be observed when contemplating iron supplementation. At this stage in our knowledge we are on the most solid ground by intervening preventively to keep iron in the optimal range. Doing so will likely reduce other risk factors if underlying causes of chronic inflammation are addressed. It is a tantalizing question whether iron supplementation during chemotherapy for beast cancer will increase survival:

"Iron supplementation is a standard therapy to correct iron deficiency. However, the suitability of iron therapy for young BC patients needs further investigation. Our study is designed to prove that iron deficiency leads to BC aggressiveness and, thus, we used a protocol to correct iron deficiency before inoculation of cancer cells. It remains unknown how cancer cells would respond to iron treatment when iron is administrated after cancer cell inoculation. To indicate the utility of iron supplementation during chemotherapy, it has been shown that amenorrhea (no menstruation) for at least six months significantly increases overall survival in young BC patients, regardless of chemotherapy and estrogen receptor status. The average blood loss during menstruation is 35 mL per month [and every 100 mL blood contains about 50 mg of iron. We estimate that iron loss for a period of 6 months is in the amount of 105 mg (35 mL/month x 6 months x 50 mg/100mL). We wonder whether 105 mg iron supplementation during chemotherapy could increase the overall survival in young BC patients with menses. As of now, in clinical practice in oncology, evaluation of iron deficiency is usually not required during BC diagnosis and, thus, not treated during BC therapy. Although clinical trial with iron supplementation in young BC patients requires a further high level of preclinical evidence, this research adds one more reason for practitioners to check whether iron levels in young BC patients are up to their FDA-recommended levels."

The authors conclude:

"In the present study, we showed that iron deficiency, highly prevalent in young women because of the menstruation, could contribute to poor prognosis in young BC patients. By linking young age to iron deficiency and then to BC malignancy, our study may have identified iron deficiency as a clinically treatable risk factor for young BC patients."