I am occasionally asked what the significance is for a blood marker test known as PHI, especially as it relates to breast cancer, so this article is devoted to answering that.

PHI stands for phosphohexose isomerase and it is an enzyme that is encoded by the GPI gene. PHI is also known as Glucose-6-phosphate isomerase or GPI. [1]

PHI or GPI is known as a “housekeeping enzyme” because it plays an important role in glycolysis (the breakdown of glucose by enzymes to create cellular energy) and gluconeogenesis (the creation of glucose by enzymes from non-carbohydrate sources). These are absolutely critical jobs for this enzyme to perform. [2]

So why is it used for breast cancer patients?

The PHI test is not new – it has been used for many decades, and it has been known since the 1950s that elevated levels are seen in patients with metastatic carcinoma. [3]

A high PHI level can indicate not only malignancy but the propensity of cancer cells to migrate elsewhere in the body, the process known as metastasis. PHI also plays an important role in cells because it turns them into sugar users. PHI is responsible for channeling cells into low oxygen glycolysis, also known as fermentation. This is relevant because cancer cells favor anaerobic (meaning without oxygen) conditions.

Some doctors find PHI results to be useful, some do not. Knowing your PHI level may aid your doctor in their decision on how best to treat you. There does appear to be research which indicates that high levels of PHI can be associated with a higher risk for invasion and metastasis in some cancers, as it has been found to stimulate cell motility (ability to move around), migration, invasion, and metastasis [3].

Be aware, however, that PHI can be elevated in not only developing and existing cancers, but also in acute liver conditions, heart attack, muscle disease or injury, or viral infections. If your doctor can rule out all of these acute conditions, an elevated PHI can be a sign of malignancy but also of an increased risk of metastasis.

The PHI readings for normal healthy adults are reported to be within a range of <34.0 (less than 34), with a grey zone of 35.0 – 40.0 iu. Sometimes your doctor will check the PHI when malignancy has been established because a change even within the normal range could be significant.

The Research

Being the curious sort, I looked into this issue to see whether the PHI test was a valid one. Older studies had mixed findings.

One 1966 study [3] found that a normal PHI level did not exclude a primary tumor growth or microscopic secondaries.

One small 1978 study [4] with 94 patients who had breast and uterine cancer found :
(a) the PHI was within normal limits in patients who had pre-malignant lesions; (b) in patients who had localized breast cancer (it had not metastasized) had normal levels of PHI;
(c) in patients with breast cancer that had metastasized, 5 patients had normal PHI levels, 5 patients had levels of PHI within limits, and 10 patients had high (pathological) levels of PHI
(d) in patients with uterine cancer without metastases, 6 patients had high levels of PHI, 6 patients had normal levels of PHI, and 6 patients had above normal levels of PHI;
(e) the value of PHI was always high in patients with uterine cancer with metastases.

This appears that PHI was a better indicator for those with uterine cancer than those with breast cancer.

A 1990 study [5] of patients with gastrointestinal, kidney and breast cancer had similar findings. Study authors stated “Even in early stages without metastasis, elevated PHI serum levels were found in about 60% of the patients. In mammary cancer, however, a sensitivity of only 40% was observed. PHI activity can be measured without the need for highly technical skills and equipment, in a short time and at low cost. These data suggest that serum PHI can be a useful indicator in the preventive checkup of gastrointestinal and renal cancer in medical practice.” Again – a better indicator for other types of cancer than for breast cancer.

A 1994 Korean study [6] showed that PHI was more reliable for gastrointestinal cancer than for breast cancer.

A small 1997 study [7] including 51 breast cancer patients investigated the usefulness of the PHI test as an index for metastatic cancer. These researchers did not find the PHI test to be useful for early detection of metastatic breast cancer.

I was unable to locate any randomized controlled trials, nor any research done in the 2000s with regard to the usefulness of the PHI test as metastatic breast cancer indicator.

A recent study, however, looked at blocking the action of enzymes like PHI as a treatment for breast cancer. They call it cellular metabolism reprogramming – switching off the glycolytic energy to a cancerous tumor has been shown to be a good anti-cancer strategy, as discussed in a 2020 Chinese study [8]. We know that glucose (sugar) is the favorite food for cancer, so this makes sense.

Back to the original question of whether or not the PHI test is a good, solid indicator of metastatic cancer, I think it’s safe to say the jury is still out. Some doctors rely upon it, others appear to ignore it entirely.

References:

[1] Wikipedia https://en.wikipedia.org/wiki/Glucose-6-phosphate_isomerase
[2] Phosphoglucose Isomerase/Autocrine Motility Factor Mediates Epithelial-Mesenchymal Transition Regulated by miR-200 in Breast Cancer Cells – https://cancerres.aacrjournals.org/content/71/9/3400
[3] Serum Phosphohexose Isomerase in Disease – https://journals.sagepub.com/doi/pdf/10.1177/036985646600400401
[4] The determination of phosphohexose isomerase in patients with cancer of breast and uterus. A comparison with other tests (author’s transl) – https://pubmed.ncbi.nlm.nih.gov/37546/
[5] The diagnostic validity of the serum tumor marker phosphohexose isomerase (PHI) in patients with gastrointestinal, kidney, and breast cancer – https://pubmed.ncbi.nlm.nih.gov/2207761/
[6] A Study on the Value of Serum Phosphohexose Isomerase ( PHI ) as a Tumor Marker – https://www.e-crt.org/journal/view.php?number=1966
[7] Evaluation of phosphohexose isomerase as a metastasis marker in breast cancer patients – https://europepmc.org/article/med/9378161
[8] Human haptoglobin contributes to breast cancer oncogenesis through glycolytic activity modulation – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539774