Why is the Progesterone/Oestrogen Ratio So Important?

27th Wednesday, 2016  |   Breast Cancer  |  no comments

The levels of different molecules within tumour cells yield information about cancer’s nature – and in breast cancer, one of the most crucial for helping guide treatment is the oestrogen receptor (ER). Women with high levels of this molecule in their cancer cells (called ‘ER-positive’ breast cancer) benefit from hormone therapy – drugs that either lower their oestrogen levels, or prevent cancer cells responding to the hormone. About 7 out of ten women have ER-positive breast cancer.

 

ER-positive Breast Cancer.

But there’s a second molecule – the progesterone receptor (PR) – levels of which inside breast cancer cells also seem to be important.  Doctors have known for a long time that women with high levels of both the oestrogen and progesterone receptors (‘double-positive’) have the best chance of surviving – they respond better to treatment, and their cancer is less likely to spread. But these ‘double-positive’ women are given the same hormone therapy as those who have no progesterone receptor in their breast cancer, so doctors don’t always routinely test for this second molecule any more.

Until now, it’s been unclear why having high levels of both molecules is good news for the patient, or what benefit testing for progesterone brings.

But thanks to Cambridge-based Cancer Research UK researcher Dr Jason Carroll and his team, and their colleagues at the University of Adelaide in Australia, there are finally answers to this mystery. Today, they’ve published surprising results of a study in the journal Nature that finally solves the puzzle of why ‘double-positive’ women do better. And if their findings are confirmed in follow-up studies, it could make a big difference to how women are treated.

 

How do the ER and PR receptors work?

Only certain types of cells that respond to hormones make these receptors – for example breast, ovary and womb cells. Both receptors are directly involved in switching genes on and off – they’re called transcription factors. When oestrogen and progesterone are present, these hormones physically stick to their respective receptor, causing them to move into the nucleus of the cell, where DNA is housed. They can then attach to specific regions of our DNA and turn genes on or off, changing the cell’s behaviour.

When breast cancer develops, the tumour cells become overly sensitive to oestrogen. When oestrogen activates the oestrogen receptor, it turns on a panel of genes that tell the cells to keep dividing, driving tumour growth:

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But what happens when breast cancer cells have a working progesterone receptor too? 

The first piece of the jigsaw fell into place when they looked at the physical relationship between the two receptors. Using ‘double-positive’ breast cancer cells grown in the lab, they made sure the cells had sufficient oestrogen and progesterone to activate both receptors, then they cracked the cells open.

When they used a sophisticated method to ‘fish out’ the progesterone receptor from the resulting mixture, they discovered something unexpected: it was physically stuck to the oestrogen receptor. This was a strong hint that progesterone – via the progesterone receptor – was somehow affecting how the oestrogen receptor works.

Using the same lab-grown breast cancer cells exposed to oestrogen only, the researchers used cutting-edge technology to pinpoint the sites in the cells’ DNA where activated oestrogen receptor attached – hence which genes it was controlling.

But when the scientists then added progesterone to the cells too, it caused a rapid shift in the points where oestrogen receptor attached to DNA.

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At least 470 genes were controlled differently when both hormones were present compared to just oestrogen alone – the progesterone receptor was, in effect, ‘reprogramming’ the oestrogen receptor, changing the genes that it influences.

But, most crucial part was the overall effect this on the cancer cells themselves – progesterone seemed to cause the cells to stop growing as quickly.

By changing the genetic ‘programme’, the progesterone receptor was applying the brakes to the cells’ growth.

The cells used in the above experiments are based on tissue samples taken many decades ago, and kept artificially growing in a lab (called ‘cell lines’). These are a good starting point, but it was important to show this ‘ER reprogramming’ actually happens in human disease.

So the team turned a special technique developed by scientists in Professor Wayne Tilley’s laboratory at the University of Adelaide in Australia. This allowed small samples of tumour tissue to be removed from women with breast cancer and grown in the lab for a short time. Remarkably, the team saw exactly the same effect – adding progesterone at the same time as oestrogen slowed down the rate tumours grew.

 

They also saw exactly the same phenomenon in mice transplanted with human breast cancer cells: oestrogen fuelled tumours’ growth, but progesterone put the brakes back on.

The final, and most crucial, experiment was to see if their findings had any potential implications for treating breast cancer.  Again working with mice transplanted with tumour samples and given oestrogen, the researchers used the standard treatment for hormone-responsive breast cancer – tamoxifen, which slowed down tumour growth.

But when they gave the mice tamoxifen AND progesterone, the tumours grew even more slowly.

Changing the way breast cancer is treated? Dr Carroll’s research is a big step forward in understanding the role of progesterone receptor in breast cancer. Until now, its presence was simply considered an indication of how good a woman’s chances of surviving were.

 

But Dr Carroll’s study findings reveal that the receptor itself is the direct reason why these women have a better outlook.

Understanding the progesterone receptor’s role as a molecular handbrake on oestrogen-fuelled growth could also explain the observation that breast cancers frequently evolve to get rid of their progesterone receptors – this is an advantage to cancer, helping it grow quicker.

This new research offers a unique opportunity to exploit the braking action of the receptor with hormone therapy to improve breast cancer outcomes. According to Dr Carroll, this is precisely what needs to be done, and the next steps are obvious.

“The results are pretty clear and potentially have direct benefits for many women with breast cancer,” he told us.

“We’re already discussing a clinical trial to test whether giving women with ER/PR double-positive breast cancer progesterone, alongside oestrogen-blocking drugs, helps more women survive this disease”. If proven successful, they suggest that it could benefit up to half of women diagnosed with the disease.

Reference

Mohammed H. et al. Progesterone receptor modulates estrogen receptor-? action in breast cancer, Nature (2015), DOI: 10.1038/nature14583

Management of lymphedema related to breast cancer

26th Tuesday, 2016  |   Breast Cancer  |  no comments

ona_news0413_app_365555 Breast cancer–related lymphedema is an ongoing challenge for many survivors. A variety of treatments are available for the management of lymphedema, but the evidence supporting them varies. Complex decongestive therapy is a common treatment for lymphedema; however, the evidence supporting it is weaker than that supporting exercise.   Physicians can play a pivotal role as educators by informing breast cancer patients about the risk of secondary lymphedema, prevention strategies, early signs and symptoms, and treatment options. Evidence shows that early intervention is the key to effective treatment. Physicians can also help their patients by referring them to trained health care providers such as physiotherapists or lymphedema therapists.   Exercise prescription and compliance Lower incidences of lymphedema were found in women who exercised regularly, received lymphedema education before treatment, and performed preventive self-care activities (Park et la., 2008). Bani et al (2007) found that provision of education on lymphedema was associated with use of lymph-drainage massage services. Other factors associated with lower lymphedema incidence and severity included chemotherapy and antiestrogen drugs (Vignes et al., 2007).   Two main treatments were identified in the literature for the management of breast cancer–related lymphedema: complex decongestive therapy (CDT)—also known as combined decongestive therapy and complex decongestive physiotherapy—and exercise. Complex decongestive therapy has 4 components: manual lymphatic drainage (MLD); compression therapy; remedial arm and shoulder exercises; and deep-breathing exercises to promote venous and lymphatic flow (Koul et al., 2007).   Source Canadian Family Physician December 2010 vol. 56 no. 12 1277-1284 http://www.cfp.ca/content/56/12/1277.full   References Bani HA, Fasching PA, Lux MM, Rauh C, Willner M, Eder I, et al. Lymphedema in breast cancer survivors: assessment and information provision in a specialized breast unit. Patient Educ Couns 2007;66(3):311-8. Koul R, Dufan T, Russell C, Guenther W, Nugent Z, Sun X, et al. Efficacy of complete decongestive therapy and manual lymphatic drainage on treatment-related lymphedema in breast cancer. Int J Radiat Oncol Biol Phys 2007;67(3):841-6. Park JH, Lee WH, Chung HS. Incidence and risk factors of breast cancer lymphoedema. J Clin Nurs 2008;17(11):1450-9. Vignes S, Arrault M, Dupuy A. Factors associated with increased breast cancer-related lymphedema volume. Acta Oncol 2007;46(8):1138-42.

Dietary total antioxidant capacity is inversely associated with prostate cancer aggressiveness in a population-based study

2nd Wednesday, 2016  |   Prostate Cancer  |  no comments

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A study by Vance et al., (2016) was to determine the relationship between total antioxidant capacity (TAC) from diet and supplements and prostate cancer aggressiveness among 855 African Americans (AA) and 945 European Americans (EA) in the North Carolina–Louisiana Prostate Cancer Project (PCaP). Cases were classified as either high aggressive, low aggressive, or intermediate aggressive. TAC was calculated from the vitamin C equivalent antioxidant capacity of 42 antioxidants measured via food frequency questionnaire.
EA reported greater dietary TAC from diet and supplements combined (P < 0.0001). In both minimally and fully adjusted logistic regression models, TAC from diet and supplements combined was associated with a reduced odds of high aggressive prostate cancer in all men, AA and EA: odds ratios for highest vs. lowest level (>1500 vs. These associations did not appear to differ between AA and EA. These data suggest that greater intake of antioxidants is associated with less aggressive prostate cancer.

Source
Nutrition and Cancer. DOI: 10.1080/01635581.2016.1134596

Visceral obesity is associated with poor prognosis in pancreatic adenocarcinoma

1st Tuesday, 2016  |   Uncategorized  |  no comments

visceral-fat

An association between obesity and unfavorable outcomes for various types of malignancy has been established. Nevertheless, the impact of visceral obesity (VO) on outcomes in pancreatic cancer is still unknown and controversial. The aim of this study was to uncover an association between VO and pancreatic cancer outcomes. We retrospectively reviewed 499 patients with pancreatic cancer who were diagnosed and treated in Severance Hospital from January 2006 to December 2011. Compared to the low-VO group, the high-VO group was mostly male and was more likely to have current smoking status, current alcohol intake status and diabetes mellitus.
The progression free survival (PFS) and overall survival (OS) were found to be significantly shorter by the Kaplan-Meier method in the high-VO group than in the low-VO group. In addition, the higher percentage of visceral fat was correlated with more lymph node metastasis and shorter OS. In patients with pancreatic cancer, VO at the time of diagnosis is associated with negative outcomes, such as shorter PFS and OS.
Source
Kim B, Chung MJ, Park SW, et al. Nutrition and Cancer. 2016 DOI: 10.1080/01635581.2016.1134600

Blood Draw Predicts Breast Cancer Relapse

4th Friday, 2015  |   Breast Cancer  |  no comments

Untitled-1 Circulating tumor DNA (ctDNA) is a promising biomarker for noninvasive assessment of cancer burden, but existing ctDNA detection methods have insufficient sensitivity or patient coverage for broad clinical applicability. Here Newman et al., (2014) introduce cancer personalized profiling by deep sequencing (CAPP-Seq), an economical and ultrasensitive method for quantifying ctDNA. They implemented CAPP-Seq for non–small-cell lung cancer (NSCLC) with a design covering multiple classes of somatic alterations that identified mutations in >95% of tumors. They detected ctDNA in 100% of patients with stage II–IV NSCLC and in 50% of patients with stage I, with 96% specificity for mutant allele fractions down to ~0.02%. Levels of ctDNA were highly correlated with tumor volume and distinguished between residual disease and treatment-related imaging changes, and measurement of ctDNA levels allowed for earlier response assessment than radiographic approaches. Finally, we evaluated biopsy-free tumor screening and genotyping with CAPP-Seq. They envision that CAPP-Seq could be routinely applied clinically to detect and monitor diverse malignancies, thus facilitating personalized cancer therapy. Blood contains two types of cancer-derived materials that are susceptible to detailed molecular analysis: intact circulating tumor cells (CTC) and cell-free circulating tumor DNA (ctDNA). The former are shed from primary or metastatic tumor deposits, and although they are rare, they are thought to be enriched for metastatic precursors (Hater & Velculescu, 2014). Initially detected in an 1869 autopsy within the blood of a patient with widespread breast cancer (Ashworth, 1869), CTCs are now isolated with increasingly sophisticated technologies (Maheswaran & Haber, 2010; Pantel & Alix-Panabieres, 2010; Yu et al., 2011). However, the advantage of applying multiple DNA, RNA, and protein-based assays to study whole tumor cells in the circulation (so-called liquid biopsies) is currently restricted by the need for complex cellular isolation platforms. Recent advances in technologies to analyze circulating tumor cells and circulating tumor DNA are setting the stage for real-time, noninvasive monitoring of cancer and providing novel insights into cancer evolution, invasion, and metastasis. Source: Newman AM, Bratman SV, To J, et al. Nature Medicine. 20, 548–554 (2014) doi:10.1038/nm.3519 References: Ashworth TR. A case of cancer in which cells similar to those in the tumors were seen in the blood after death. Aust Med J 1869;14:146–9. Hater DA, Velculescu VE. Blood-Based Analyses of Cancer: Circulating Tumor Cells and Circulating Tumor DNA. Cancer Discovery June 2014 4; 650 doi: 10.1158/2159-8290.CD-13-1014 Maheswaran S, Haber DA. Circulating tumor cells: a window into cancer biology and metastasis. Curr Opin Genet Dev 2010;20:96–9. Pantel K, Alix-Panabieres C. Circulating tumour cells in cancer patients: challenges and perspectives. Trends Mol Med 2010;16:398–406. Pantel K, Alix-Panabieres M, Stott S, Toner M, Maheswaran S, Haber DA. Circulating tumor cells: approaches to isolation and characterization. J Cell Biol 2011;192:373–82. F1.large The management of metastatic breast cancer needs improvement. As clinical evaluation is not very accurate in determining the progression of disease, the analysis of circulating tumor DNA (ctDNA) has evolved to a promising noninvasive marker of disease evolution. Indeed, ctDNA was reported to represent a highly sensitive biomarker of metastatic cancer disease directly reflecting tumor burden and dynamics. However, at present little is known about the dynamic range of ctDNA in patients with metastatic breast cancer. In this study, 74 plasma DNA samples from 58 patients with metastasized breast cancer were analyzed with a microfluidic device to determine the plasma DNA size distribution and copy number changes in the plasma were identified by whole-genome sequencing (plasma-Seq). Furthermore, in an index patient we conducted whole-genome, exome, or targeted deep sequencing of the primary tumor, metastases, and circulating tumor cells (CTCs). Deep sequencing was done to accurately determine the allele fraction (AFs) of mutated DNA fragments. Although all patients had metastatic disease, plasma analyses demonstrated highly variable AFs of mutant fragments. analyzed an index patient with more than 100,000 CTCs in detail. Heidary et al., (2014) first conducted whole-genome, exome, or targeted deep sequencing of four different regions from the primary tumor and three metastatic lymph node regions, which enabled us to establish the phylogenetic relationships of these lesions, which were consistent with a genetically homogeneous cancer. Subsequent analyses of 551 CTCs confirmed the genetically homogeneous cancer in three serial blood analyses. However, the AFs of ctDNA were only 2% to 3% in each analysis, neither reflecting the tumor burden nor the dynamics of this progressive disease. These results together with high-resolution plasma DNA fragment sizing suggested that differences in phagocytosis and DNA degradation mechanisms likely explain the variable occurrence of mutated DNA fragments in the blood of patients with cancer. The dynamic range of ctDNA varies substantially in patients with metastatic breast cancer. This has important implications for the use of ctDNA as a predictive and prognostic biomarker. Clinical response evaluation of patients with cancer is often not accurate. Therefore, the use of ctDNA has been proposed as a biomarker for monitoring tumor burden and treatment response. Indeed, several studies have suggested that ctDNA analysis is an effective indicator of tumor load, allowing more accurate monitoring of tumor dynamics (Diehl et al., 2008; Leary et al., 2010; McBride et al., 2010). Circulating tumor DNA was successfully detected in 29 of the 30 women (97%) in whom somatic genomic alterations were identified; CA 15-3 and circulating tumor cells were detected in 21 of 27 women (78%) and 26 of 30 women (87%), respectively. Circulating tumor DNA levels showed a greater dynamic range, and greater correlation with changes in tumor burden, than did CA 15-3 or circulating tumor cells. Among the measures tested, circulating tumor DNA provided the earliest measure of treatment response in 10 of 19 women (53%). In breast cancer, a recent study has provided evidence that ctDNA levels had a greater dynamic range and greater correlation with changes in tumor burden than CA 15-3 or CTCs (Dawson et al., 2013). Source Heidary M, Auer M, Ulz P, et al. The dynamic range of circulating tumor DNA in metastatic breast cancer. Breast Cancer Research 2014, 16:421 http://breast-cancer-research.com/content/16/4/421 References Dawson SJ, Tsui DW, Murtaza M, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med 2013, 368:1199–1209. Diehl F, Schmidt K, Choti MA, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med 2008, 14:985–990. Leary RJ, Kinde I, Diehl F, et al. Development of personalized tumor biomarkers using massively parallel sequencing. Sci Transl Med 2010, 2:20ra14. McBride DJ, Orpana AK, Sotiriou C, et al. Use of cancer-specific genomic rearrangements to quantify disease burden in plasma from patients with solid tumors. Gene Chromosome Canc 2010, 49:1062–1069. Tracking tumor DNA in the blood of early breast cancer patients after surgery can detect relapse 7.9 months earlier than conventional imaging, according to the results of a study published in Science Translational Medicine. Using a non-invasive circulating tumor DNA (ctDNA) analysis, Isaac Garcia-Murillas, PhD, of the Institute of Cancer Research in London, and colleagues tracked breast tumor–specific mutations in 55 patients who had undergone surgery and chemotherapy as a potentially curative treatment. The results of the prospective study suggest that patients at risk for relapse may be identified earlier and given more aggressive treatment to prevent metastasis. Of the 15 patients who relapsed on study, the presence of ctDNA predicted the relapse of 12 patients. Among the patients who did not relapse, 96% had no detectable ctDNA in either the post-surgery sample (24 of 25; P = .0038) or during temporal tracking of tumor mutations (27 of 28; P < .0001). One patient, with triple-negative disease, had detectable ctDNA after surgery but did not relapse on study. All metastatic tumors were detectable by ctDNA except for three patients who had recurrence in the brain. The study also showed that ctDNA analysis could identify the genetic events that define minimal residual disease among breast cancer patients. This genetic analysis of minimal residual disease also predicted the genetics of the relapsed tumor better than sequencing analysis of the primary breast tumor. The study authors concluded that tracking of ctDNA linked to cancer relapse could facilitate the tailoring of adjuvant therapies based on the mutations captured in patients’ blood samples. The utility of ctDNA analysis in late-stage cancer patients has already been demonstrated in previous research studies, although the technique is not yet ready to be used in the clinical setting. The current study, however, is among the first to demonstrate the ability to capture ctDNA from blood samples of earlier stage cancer patients. Tumor DNA circulates in the blood in minute amounts, and whether these molecules can be consistently detected using current technologies has been an open question. Garcia-Murillas and his colleagues first sequenced each patient’s primary tumor, identifying tumor-specific somatic mutations to track in the ctDNA following surgery. ctDNA detected at baseline, prior to any therapy, was not associated with early relapse. ctDNA detected at 2 to 4 weeks after surgery was indicative of early relapse—those who had detectable ctDNA (19%; 7 of 37 patients) had a median disease-free survival (DFS) of 6.5 months; median DFS among patients with no detectable ctDNA was not reached. “In addition to confirming the feasibility of ctDNA detection in non-metastatic breast cancer, Garcia-Murillas et al have extended these findings in a prospective study, demonstrating that longitudinal monitoring of ctDNA is more reliable than single baseline measurements in predicting recurrence in women treated with neoadjuvant chemotherapy for localized breast cancer,” stated Tilak Sundaresan, MD, and Daniel Haber, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston.

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