Genetic Testing Misses Half of Women at Risk for Breast Cancer

Nearly half of patients with breast cancer who, on multigene panel testing, are found to have a pathogenic or likely pathogenic variant for breast cancer do not meet current National Comprehensive Cancer Network (NCCN) guidelines for genetic testing, new research shows.

In a cohort of 959 women who were either currently undergoing treatment or had previously been treated for breast cancer, 49.9% met established 2017 NCCN germline genetic testing guidelines, and 50% did not, lead author Peter Beitsch, MD, Dallas Surgical Group–TME/Breast Care Network, Texas, and colleagues report.

Of those patients who met NCCN guidelines for germline testing, 9.39% had either a pathogenic or a likely pathogenic variant; 7.9% of those who did not meet the guidelines also had a pathogenic or likely pathogenic variant. The difference between the two groups was not statistically significant, the investigators add.

“Our results indicate that nearly half of patients with breast cancer with a P/LP [pathogenic/likely pathogenic] variant with clinically actionable and/or management guidelines in development are missed by current testing guidelines,” the investigators observe.

“We recommend that all patients with a diagnosis of breast cancer undergo expanded panel testing,” they conclude.

The study was published online December 7 in the Journal of Clinical Oncology.

However, in a related editorial, breast cancer experts argue that widespread testing would detect genetic variants of unknown significance for which there are currently no established clinical courses of action.

Study Details

For their study, Beitsch and colleagues set up a multicenter, prospective registry with the help of 20 community and academic sites, all of which were experienced in cancer genetic testing and counseling.

They focussed on 959 patients who had a history of breast cancer but had not undergone prior single-gene or multigene testing.

“All patients underwent germ line genetic testing with a multicancer panel of 80 genes,” the authors explain.

“Overall, 83 (8.65%) of 959 patients had a P/LP variant,” they write.

The investigators then considered findings from only BRCA1 and BRCA2 genetic testing.

In this subgroup analysis, positive BCRA1/2 rates were fourfold higher among those who met current NCCN germline testing guidelines, at 2.51%, compared to those who did not, at 0.63% (P = .020).

However, the authors point out that patients with a clearly identifiable personal and family history consistent with NCCN testing guidelines were likely to have already undergone genetic testing and therefore would have been excluded from the study.

In contrast, rates of variants of “uncertain significance” were virtually identical between those who met current NCCN guidelines for genetic testing and those who did not.

“Carriers of clinically actionable variants in genes other than BRCA1/2 are likely to fall outside of the current guidelines,” Beitsch and colleagues point out.

“Results of our study suggest that a strategy that simply tests all patients with a personal history of breast cancer would almost double the number of patients identified as having a clinically actionable genetic test result,” they reason.

Variants of Unknown Significance

In a related editorial, Kara Milliron, MS, and Jennifer J. Griggs, MD, MPH, both from the University of Michigan Cancer Center in Ann Arbor, argue that widespread uptake of genetic testing would increase the likelihood of identifying pathogenic variants of genes for which there are no established guidelines for reducing cancer risk.

For example, pathogenic variants in ATM are associated with an increased breast cancer risk, “but there is insufficient evidence to support risk-reducing breast surgery or bilateral salpingo-oophorectomy,” they point out.

Furthermore, more widespread testing is likely to increase detection rates of variants of unknown significance, which were common in the study by Beitsch and colleagues.

“These variants present challenges for both patients and medical providers in the management of ambiguity that arises in a patient with a malignancy and family members,” Milliron and Griggs write. This issue is particularly problematic in certain racial and ethnic groups in which such variants are both more common and more poorly characterized, they add.

Of greater concern are barriers to high-quality counseling following genetic testing.

“The shortage of genetic counselors has been well documented,” the editorialists note, and currently, “many patients receive genetic testing without seeing a genetic counselor,” they state.

Lastly, the cost of widespread testing and counseling cannot be overlooked, especially when considering expanding that testing to all patients with breast cancer.

Medicare does cover BCRA1/2 testing, and some states cover genetic testing.

“Thus, costs to patients may be prohibitive in the most vulnerable populations,” the editorialists write.

NCCN guidelines for genetic testing were published about 20 years ago and were designed to identify patients who were most likely to carry BRCA1/2 variants.

This was done to reduce the number needed to test; at that time, the cost of genetic testing was $2000 to $5000 per test.

Now, it is approximately 10 times less costly to conduct germline testing than it was when the guidelines were originally established.

Still, Milliron and Griggs calculate that the call to have all women with breast cancer undergo genetic testing would amount to about $400 million in total costs to insurance companies. They arrive at this estimate by considering the current cost of $1500 per test multiplied by the number of new breast cancer cases diagnosed each year in the United States.

Revised Classification for Head and Neck CSCC

The latest staging criteria for cutaneous squamous cell carcinoma (CSCC) from the American Joint Committee on Cancer (AJCC) improves the previous version in stratifying risk of disease-related outcomes, suggests a study published in December.

Using the AJCC Cancer Staging Manual, 8th edition (AJCC 8) tumor classification, which is specific to CSCCs of the head and neck, 17.8% of the cohort was classified in the high tumor categories (T3 and T4), and those accounted for 70.4% of poor outcomes in the overall cohort.

 By comparison, using the 7th edition (AJCC 7), just 0.7% of tumors were T3 or T4, and they accounted for only 16.9% of poor outcomes, according to the results published in JAMA Dermatology.

That suggests that the upper categories of AJCC 8 have a strong ability to stratify tumors with significant risk of disease-related poor outcomes, said the study’s senior author, Chrysalyne Schmults, MD, director of the Dermatologic Surgery Center at Brigham and Women’s Hospital in Boston.

“The biggest improvement with AJCC 8 is that there’s been a large expansion of cases that now qualify to be T3, and this has made it such that T3 and T4 now capture a lot more of the poor outcomes.”

T3 in particular is capturing most of the poor outcomes because T4 is still quite restrictive, according to Schmults, although between the two systems, they are capturing 71% of nodal metastases and 85% of deaths due to CSCC.

Using AJCC 7 criteria, the majority of poor outcomes occur in patients with tumors classified as T2, which is actually a large, heterogeneous group in terms of outcomes, she said.

 “There is a subset of people who are doing poorly — in T2 under AJCC 7 — but they are mixed in with all these people who are doing well. It becomes impossible to pull them out of that larger group and decide, for example, who needs staging of their lymph nodes, who needs adjuvant treatment after surgery, or who would be good candidates for clinical trials.”

Staging Evolution

Most CSCCs have a favorable prognosis. Estimates previously published by Schmults and colleagues suggest a risk of 3.0% for local recurrence, 4.0% for nodal metastasis, and 1.5% for death.

Staging is pivotal to helping separate the rare, high-risk cases from the low-risk majority, she explained.

The AJCC 7 criteria, introduced in 2010, represented an improvement over the previous edition, which had grouped all non-melanoma skin cancers together and used just a limited set of staging factors including tumor diameter and bone and intracranial invasion. AJCC 7 included, for the first time, risk factors including tumor thickness greater than 2 mm, perineural invasion, Clark level of IV or higher, and poorly differentiated histology.

However, studies began to show that AJCC 7 was not adequately stratifying disease-related outcomes.

In a retrospective cohort study published in JAMA Dermatology in 2013, Schmults and colleagues reviewed 256 primary high-risk CSCCs and found that outcomes for AJCC tumor stages T2-T4 were “statistically indistinguishable,” since less than 2% of the cohort qualified as stage T3 or T4; thus 83% of nodal metastases and 92% of deaths from CSCC occurred in cases classified as T2.

As part of that study, the team proposed an alternative CSCC staging system to more precisely identify the small number of cases at high risk of metastasis and death. That system incorporates risk factors including poor differentiation, perineural invasion, tumor diameter ≥2 cm, and invasion beyond subcutaneous fat.

Using the alternative system, the tumors classified as T2b (i.e., having two to three of those risk factors present) or T3 (all four risk factors or bone invasion) comprised 19% of tumors and accounted for 72% of nodal metastases and 83% of deaths from CSCC, according to the published report.

In a subsequent study published in 2014 in the Journal of Clinical Oncology, Schmults and colleagues compared AJCC 7, the International Union Against Cancer (UICC) staging system, and a modified version of their own previously published alternative system in a larger cohort of patients (N = 1,818). Results suggested that the alternative system offered better prognostic discrimination versus AJCC 7 and UICC, leading the authors to call for further population-based validation.

 Subsequently, the team sought to validate the CSCC staging system released in AJCC 8, which is specific to CSCC tumors of the head and neck, since it was developed in conjunction with AJCC’s head and neck cancer committee.

“The head and neck surgical community — they grapple with the worst of these cases — and they really felt like, for their purposes, they needed something,” said Schmults, who also participated in development of the AJCC 8 staging system.

The new staging criteria, which were implemented in clinical practice starting in January 2017 and were set to be implemented by tumor registrars as of January 2018, includes changes based on findings related to independent prognostic factors in CSCC that have become available since AJCC 7, Schmults said.

Notably, T2 is now restricted to tumors that are at least 2 cm yet less than 4 cm in largest dimension with no risk factors, while the T3 definition was expanded to encompass tumors at least 4 cm in largest dimension or at least one risk factor. Risk factors for T3 upstaging in AJCC 8 include deep invasion, perineural invasion, and minor bone invasion, while poorly differentiated histologic features was dropped as a risk factor for upstaging.

Schmults said that although she is pleased with the improved performance of AJCC 8 in this most recent cohort study, more changes will be needed. In particular, the cohort study of AJCC 8 demonstrated a considerable overlap between T2 and T3 categories in terms of the 10-year cumulative incidence of local recurrence, nodal metastasis, and disease-specific death.

Together, T2 and T3 comprised about 23% of squamous cell cancers in this study. “If we suddenly started doing lymph node staging or offering treatment beyond surgery to 23% of squamous cell patients, we would be overtreating. We know that probably only around 5% to 10% of those people would ever really need or benefit from that.”

Nevertheless, she said she was hopeful that AJCC 8 will make an impact in the community and possibly allow for population-based registry tracking through the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute to validate and refine CSCC tumor classification.

“I hope that we can come to some kind of standardization across the country in reporting clinical tumor diameter and other prognostic factors on SCC pathology reports, so that whether SEER is able to do it or not, then at least on institutional levels, people would be able to use AJCC 8 staging and track SCC outcomes better,” she said.

Since the current staging system applies to head and neck CSCCs, “I think it will be up to clinicians and researchers how to stage everybody else. I think a lot of people are going to end up using [AJCC 8 head and neck staging] for those non-head and neck CSCCs, rather than continuing to use AJCC 7, which had a lot of trouble.”

ASCO Backs Bone Drugs for Myeloma

Recommended for patients with or without evidence of lytic damage

Patients with symptomatic multiple myeloma should receive bone-modifying therapy irrespective of evidence of lytic destruction or spinal compression fracture, according to an updated guideline from the American Society of Clinical Oncology (ASCO).

Treatment options consist of the intravenous bisphosphonates pamidronate and zoledronic acid (Zometa) or, alternatively, the RANK ligand inhibitor denosumab (Xgeva). Denosumab might be preferred over zoledronic acid for patients with renal impairment, as the RANKL inhibitor has been associated with fewer renal adverse events.

 The primary purpose of the update, and associated expert-panel review, was to determine whether the 2007 recommendations remain valid. ASCO initially published clinical guidance about the use of bone-modifying agents in myeloma in 2002.

“These recommendations are consistent with the previous recommendations, with new information on denosumab,” the guideline authors stated. “Additional modifications were made to some of the recommendations on the basis of recent data to better clarify the indications for treatment, duration of treatment, and associated complications of treatment.”

The panel, chaired by Kenneth Anderson, MD, of Dana-Farber Cancer Institute in Boston, and Robert A. Kyle, MD, of the Mayo Clinic in Rochester, Minnesota, updated the ASCO recommendations after examining 35 relevant studies identified by means of a targeted systematic literature review. The review included randomized controlled trials, systematic reviews, meta-analyses, clinical practice guidelines, and observational studies.

Key recommendations included:

  • Initiate bone-modifying therapy for patients with imaging-based evidence of lytic disease and for patients with osteopenia in the absence of lytic disease
  • Use bone-targeted agents as adjunctive therapy for controlling pain associated with osteolytic disease and for patients receiving other interventions for existing or impending fractures
  • Initiate intravenous bisphosphonates in patients with normal radiographs or osteopenia by bone mineral density measurements
  • Do not use bone-modifying agents in patients who have monoclonal gammopathy of undetermined significance, except when osteopenia exists
  • Reduce the dose of zoledronic acid in patients who have pre-existing mild or moderate renal impairment
  • Consider denosumab as an alternative to zoledronic acid for patients with compromised renal function
  • Use serum creatinine monitoring before each dose of a bisphosphonate, in accordance with FDA labeling
  • Perform intermittent evaluation of all bisphosphonate-treated patients for presence of albuminuria

The updated guideline also includes a table with the estimated cost of bone-modifying agents. Pamidronate and zoledronic acid had per-dose costs of $30.67 and $53.64, respectively, whereas each dose of denosumab cost $1,995.48. The estimated 1-year costs were $398.71 for pamidronate, $214.56 for zoledronic acid administered every 12 weeks, $697.37 for zoledronic acid every 4 weeks, and $25,9341.24 for denosumab every 4 weeks.

A compendium of ASCO recommendations related to bone-modifying therapy in myeloma is available on the organization’s website. The update was also published in the Journal of Clinical Oncology.

Pembrolizumab Promising in Advanced Esophageal Cancer

The checkpoint inhibitor pembrolizumab (Keytruda) was well tolerated and demonstrated results in patients with PD-L1–positive, advanced esophageal tumors in the Merck-sponsored phase IB KEYNOTE-028 trial.

As shown in the study, published online in the Journal of Clinical Oncologythere were partial responses in seven of 23 heavily pretreated patients, for an overall response rate (ORR) of 30%.

 This included five of 18 patients (28%) with squamous histology and two of five patients (40%) with adenocarcinoma, reported Toshihiko Doi, MD, PhD, of the National Cancer Center Hospital East in Japan, and colleagues..

The median duration of response was 15 months, and 12 patients (53%) showed a decrease in target lesion burden. Nine patients had treatment-related adverse effects — most commonly reduced appetite, decreased lymphocyte count, and rash.

“There is a high unmet need for effective and well-tolerated treatments for patients with advanced esophageal carcinoma,” the researchers wrote. “Pembrolizumab demonstrated manageable toxicity and durable antitumor activity in patients with heavily pretreated, PD-L1–positive advanced esophageal carcinoma.”

KEYNOTE-028 is an international trial of pembrolizumab in patients with 20 different types of PD-L1–positive advanced solid tumors. Patients in the esophageal carcinoma cohort were enrolled at nine sites in France, Japan, the Republic of Korea, Taiwan, the United Kingdom, and the United States.

Patients could participate if they were age 18 or older, had measurable disease at baseline, had an Eastern Cooperative Oncology Group performance status of 0 or 1, demonstrated adequate organ function, and had PD-L1–positive, squamous cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction for which standard therapy did not exist or was ineffective.

Participants received 10 mg/kg of pembrolizumab intravenously once every 2 weeks for up to 2 years or until progression was confirmed, toxicity became intolerable, or the patient or investigator decided to stop. Patients had computed tomography (CT) or magnetic resonance imaging (MRI) scans every 8 weeks for the first 6 months and every 12 weeks thereafter. The researchers also profiled the gene expression of each patient’s tumor tissue.

Primary endpoints of the study were safety and overall response rate (ORR). Secondary endpoints were progression-free survival, overall survival, and duration of response.

Of the 23 patients enrolled in the study, 83% were men and 78% had squamous cell carcinoma histology; median age was 65. All but one patient had received previous therapy for advanced/metastatic disease; 87% had received at least two previous therapies for advanced/metastatic disease, and most (61%) had received previous radiation therapy.

The ORR was 30% (95% CI 13-53); all seven responses were confirmed partial responses. Of these seven patients, three (43%) had received prior radiation therapy. There was no discernible pattern in the previous chemotherapy regimen among these patients. For patients with squamous cell carcinoma, ORR was 28% (five of 18 patients); for those with adenocarcinoma, ORR was 40% (two of five patients).

Twelve patients (52%) experienced a decrease from baseline in target lesion burden; tumors shrank a median of -44.7% (range, -77.7 to -2.7).

Median progression-free survival was 1.8 months (95% CI 1.7-2.9); 6- and 12-month progression-free survival rates were 30% and 22%, respectively. Median overall survival was 7 months (95% CI 4.3-17.7); the overall survival rate was 60% at 6 months and 40% at 12 months.

All-grade treatment-related adverse events occurred in nine patients. Rash in three patients (13%), and reduced appetite and decreased lymphocyte count in two patients (9%) each, were most common.

Four patients had grade 3 treatment-related adverse events — two patients had decreased lymphocyte count, and one patient each had decreased appetite, liver disorder, and generalized rash. None had grade 4 adverse events.

Three patients had treatment-related serious adverse events: grade 2 pemphigoid, grade 3 decreased appetite, and grade 3 liver disorder in one patient each. No patients died because of a treatment-related adverse event.

The overall safety profile in the study was similar to that previously reported for pembrolizumab in patients with other advanced malignancies, the authors noted. Similar to the results from other studies of immune checkpoint inhibition in cancer, only a subset of patients with PDL1–positive esophageal cancer showed a clinical benefit from PD-1 blockade, suggesting that additional biomarkers could help predict clinical response.

Gene analysis showed delayed progression and increased response among pembrolizumab-treated patients with higher interferon-γ composite scores, consistent with findings in head and neck and gastric cancer, the researchers reported. However, they cautioned, there are limitations to this analysis, including the small sample size, variability in tissue biopsy storing, and potential sampling bias.

“These preliminary results regarding the potential predictive value of gene expression signature for pembrolizumab activity in esophageal carcinoma will therefore require additional exploration in a larger patient population.”

In addition, the team added, because all patients enrolled in KEYNOTE-028 had tumors with some degree of PD-L1 expression, the study cannot provide information about pembrolizumab in patients with advanced esophageal carcinoma and PD-L1–negative tumors.

Thyroid Cancer Epidemic of Overdiagnosis

Thyroid Cancer Epidemic of Overdiagnosis

Thyroid Cancer Epidemic of Overdiagnosis

The last 40 years have shown triple the incidence of thyroid cancer in women, yet the mortality rate has remained the same.  Why are physicians so quick to diagnose women with thyroid cancer?

American Idol Alum Jax Cole

The American Idol finalist Alum Jax Cole announced that she underwent thyroid surgery in April after discovering a “lump in her neck”.  She is now receiving radiation treatments, presumably radioactive iodine (I-131), after the finding of thyroid cancer at surgery.(1-3)

Alum Jax Cole Thyroid Cancer Epidemic of Overdiagnosis

An Epidemic of Overdiagnosis of Thyroid Cancer  In Women

According to Dr Gilbert Welch in 2014 Otolaryngology, there is an epidemic of overdiagnosis of thyroid cancer in young women.(4)

Since 1975, the incidence of thyroid cancer in women has more than tripled from  6.5 to 21.4 per 100,000 women, mostly from papillary cancer.

However, the “mortality rate from thyroid cancer was stable between 1975 and 2009 (approximately 0.5 deaths per 100 000).”  

In other words, mortality from thyroid cancer did not increase, even though the incidence tripled.  If this was real cancer, one would expect increase in mortality numbers.  There was none.

Dr Welch concludes:

“There is an ongoing epidemic of thyroid cancer in the United States. The epidemiology of the increased incidence, however, suggests that it is not an epidemic of disease but rather an epidemic of diagnosis. The problem is particularly acute for women, who have lower autopsy prevalence of thyroid cancer than men but higher cancer detection rates by a 3:1 ratio.”

Alum Jax Cole Thyroid Cancer Epidemic of Overdiagnosis

Above Chart shows thyroid cancer rising incidence females (GREEN Arrow), while thyroid cancer mortality is unchanged (flat line RED Arrow). Chart courtesy of Davies, Louise, and H. Gilbert Welch. (4) “Current thyroid cancer trends in the United States.” JAMA Otolaryngology–Head & Neck Surgery 140.4 (2014): 317-322.

Dr Robert Udelsman reported in Thyroid 2014, on”The Epidemic of Thyroid Cancer in the United States”. (16)   He says:

“The increased detection of thyroid cancer results in surgery and radioactive thyroid treatment that may be of limited benefit.”

“The autopsy prevalence rate of occult thyroid cancer in the Finnish population is 35.6%, suggesting that thyroid cancer is both common and clinically insignificant for the vast majority of individuals”

“It is likely that the majority of diagnosed thyroid cancer patients will not benefit from surgical and/or adjuvant interventions. “

Pathologists:  Many Thyroid Cancers Should be Reclassified

Dr Nikiforov writes in JAMA Oncology 2016 that many thyroid cancers are really not cancer and should be reclassified.(6)  An example is the encapsulated follicular variant of papillary thyroid carcinoma.  These cases are treated as having conventional thyroid cancer, yet they are not really cancer,  Dr Nikiforov says this type of pathology does not require radioactive iodine after surgery.

In 2016, Dr Lester Thompson reviews 94 cases of thyroid cancer with the pathology diagnosis of “Encapsulated follicular papillary thyroid carcinoma”. (17)  Because of the indolent nature, they recommended changing the pathology classification to Noninvasive Follicular Thyroid Neoplasm”  Dr Lester  Thompson went on to say: These are “exceedingly indolent tumors, best managed conservatively by lobectomy or thyroidectomy alone, without radioablative iodine or suppression therapy.”(17)

Thyroid Cancer: What are the Drivers of Overdiagnosis:

1)  Advent of High Resolution Ultrasound imaging and thyroid screening programs which detect ever smaller “abnormalities”.

2) Commercial and professional vested interests. Hospitals make more money if they do more thyroid biopsies, thyroidectomies, and radioactive iodine treatments.  Thyroidectomy creates a patient on thyroid medicine for life.

3) Conflicted panels such as the American Thyroid Association, and the Endocrine Society write guidelines that expand disease definitions and encourage overdiagnosis.

4) Malpractice Litigation punishes underdiagnosis but not overdiagnosis.

5) Health system incentives encourage more testing and more treatment.

6) Cultural beliefs that more is better; faith in early detection unmodified by its risks. (12)  Paraphrased from Ray Moynihan. “Preventing overdiagnosis how to stop harming the healthy .” Bmj (2012).

Medical Iatrogenesis in Women

Dr. Adriane Fugh-Berman states very clearly,  “there is a tradition in U.S. medicine of excessive medical and surgical interventions on women”.(14)

Over-Diagnosis of “Hysteria” in Women.

Perhaps one of the early examples of medical iatrogenesis in women occurred in the 1800’s in Paris with the over-diagnosis of “Hysteria” by Dr Charcot   Dr. Martin Charcot of the Paris hospital La Salpetriere diagnosed, ten “Hysterical” women each day,  The number of women diagnosed as “Hysteria” increased 17-fold from  from 1% in 1841 to 17% in 1883.(13,14)

DES  Diethyl-Stilbestrol

A more recent historical example of medical iatrogenesis in women is the 1938 story of DES (Diethylstilbestrol) the first synthetic hormone replacement drug.  This carcinogenic monster hormone was approved by the FDA and given to millions of women from 1940 until it was banned in 1975 because it was shown carcinogenic.  The first report of cervical cancer in the daughters of DES treated women was published in April 1971 in the New England Journal of Medicine.(15)


Our next example of medical iatrogenesis in women is Premarin, a horse estrogen isolated from the urine of pregnant horses.   Available since FDA approval in 1942, Premarin has caused an estimated 15,000 cases of endometrial cancer, representing the largest epidemic of serious iatrogenic disease ever reported.(15)    One might think this would be the end of any drug.   However Premarin was promptly rehabilitated with the addition of another synthetic hormone, a progestin, to prevent endometrial cancer.  Thus, in 1995, Prempro was born, a synthetic hormone pill containing both Premarin (the horse estrogen) and Provera (the progestin).  Again, this was FDA approved,  thought safe and handed out freely to millions of women.


Our next example of medical iatrogenesis in women is Prempro , the combination of Premarin with Provera (medroxyprogersterone) found to cause breast cancer and heart disease.  Four large scale studies showed increased breast cancer and heart disease from this estrogen-progestin combination pill.  The  Breast Cancer Detection Demonstration Project, published in 2000, showed an eight fold increase in breast cancer for estrogen-progestin users.(15)  The Swedish Record Review, published in 1996, had a fourfold increase in breast cancer with progestin use.(15)  The Million Woman study, published in Lancet in 2003, had a fourfold increase in breast cancer for estrogen-progestin combination users compared to estrogen alone users.(15)  Finally in 2002, JAMA published the Women’s Health Initiative (WHI), an NIH funded study terminated early because of increased breast cancer and heart disease in the estrogen-progestin users.(15)  Incredibly, the medical system is still dispensing this discredited drug to women.

SSRI Antidepressants Shown to be No More Effective Than Placebo

The next example medial iatrogeneiss in women is SSRI antidepressant drugs that were shown to have little benefit for patients with mild to moderate depression.  The benefits of SSRI drugs are equivalent to placebo pills.(15).  Adverse side effects include sexual dysfunction, movement disorders, increased suicidality, mania and violence and withdrawal effects.  In spite of this, the discredited SSRI drugs are still being dispensed freely to millions of women.

Mistreatment of Women by the Medical System – Excessive Hysterectomies  

The National Women’s Health Network has written extensively on the overuse of hysterectomies.  Ernst Bartsich, M.D., a  surgeon at Cornell in New York. says ” Of the 617,000 hysterectomies performed annually, “from 76 to 85 percent” may be unnecessary. “(CNN)  Thus representing another example of mistreatment of women by the medical system.(15)

More Discredited Treatments Used on Women: 

Radical MastectomyA disfiguring operation which provided no benefit compared to lesser procedures such as lumpectomy.

Bone Marrow Transplantation for Breast CancerWhich was abandoned when studies showed it offered no benefit.(Welch BMJ 2002)

Kyphoplasty for Osteoporotic FractureWas discredited when studies found no benefit compared to a sham procedure

Arthroscopy for OsteoarthritisWas abandoned after studies found no benefit compared to conservative treatment.

Screening mammogramsFor under 50 age women offers more harm than benefit.


Drs Welch, Udelsman, Nikiforov and Moynihan have come forward to alert the public to the “Epidemic of Overdiagnosis of Thyroid Cancer”,  a form of medical iatrogenesis in young women.   Since Alum Jax Cole’s pathology report was not made public, we don’t know if her particular case was overdiagnosis.

Based on the epidemiology data alone, many young women with thyroid cancer are overdiagnosed.  How many?  For every 43 women diagnosed with thyroid cancer, one (2.3%) will die from metastatic thyroid cancer, and the other 42 (97.7%) will eventually die from other causes.  About 1,070 women die from thyroid cancer annually. This number has not changed over 30 years in spite of aggressive detection and treatment.  For comparison, about 41,000 women die from breast cancer annually.

Update August 2016:  Autopsy studies do not mirror the increasing incidence of thyroid cancer, again indicating a problem with overdiagnosis (23):

“the observed increasing incidence (of thyroid cancer) is not mirrored by prevalence within autopsy studies and, therefore, is unlikely to reflect a true population-level increase in tumorigenesis. This strongly suggests that the current increasing incidence of iDTC most likely reflects diagnostic detection increasing over time. ” (23) by  L. Furuya-Kanamori,  Prevalence of Differentiated Thyroid Cancer in Autopsy Studies Over Six Decades: A Meta-Analysis. Journal of Clinical Oncology, 2016.

MSC Infusions Promising for GVHD After Haploidentical Transplant

Still, many problems remain to be solved to optimize the procedure.

Infusions of mesenchymal stromal cells (MSCs) helped prevent chronic graft-versus-host disease (GVHD) in patients with blood malignancies who underwent HLA-haploidentical hematopoietic stem-cell transplantation (HSCT), according to the results of a randomized, controlled trial.

The 2-year cumulative incidence of chronic GVHD in the treatment group was 27.4% (95% CI 16.2%-38.6%) compared with 49% in the control group (95% CI 36.5%-61.5%), Xi Zhang, MD, PhD, of Xinqiao Hospital in Chongqing China, and colleagues reported in the Journal of Clinical Oncology.

 “We demonstrate for the first time, to our knowledge, that reduplicative infusion of MSCs after HLA-haplo HSCT can reduce the incidence of chronic GVHD, accompanied by changes in the number of Treg cells, memory B lymphocytes, and natural killer cells, as well as the Th1:Th2 cell ratio. Future studies to adjust the MSC infusion program and understand the underlying mechanism will enable us to elucidate the in vivo effects of MSCs and help facilitate their broad application.”

In an accompanying editorial, Hillard Lazarus, MD, of Case Western Reserve University in Cleveland, Ohio, and Steven Pavletic, MD, of the Experimental Transplantation and Immunology Branch, Graft-versus-Host and Autoimmunity Section, of the National Institutes of Health in Bethesda, Md., said that on the basis of the study, future investigations of chronic GVHD prophylaxis using MSCs should be explored.

“The permutations and combinations for using different cell sources for deriving the MSCs, and in the context of different neoplastic disease, type and stage, conditioning regimen intensity, GVHD prophylaxis, graft and donor source, among other variables, are daunting,” they said. “Nonetheless, the results of the [Zhang et al] trial encourage us to further explore this approach.”

The phase II, randomized, double-blind, controlled trial included 124 patients with hematologic malignancies who underwent HLA-haploidentical hematopoietic stem-cell transplantation at five transplantation centers. Eligible patients met the following criteria: acute GVHD did not occur or was controlled for more than 100 days after transplantation; lack of chronic GVHD at 100 days after transplantation; and the absence of uncontrolled infections and severe liver, renal, lung, and heart diseases.

Patients were randomized 1:1 to receive either monthly infusions of umbilical cord-derived MSCs or saline. The infusions began 4 months after the transplant and continued for up to 4 months. Patients were enrolled from 2009 to 2013 and were followed until 2015.

 The primary endpoint was the development of chronic GVHD. Secondary endpoints included overall survival, disease-free survival, relapse, and changes in immune system cells.

Chronic GVD developed in 17 patients in the treatment group versus 30 in the control group. Seven patients in the control group developed severe lung GVHD, versus none in the treatment group.

The number of natural killer cells tended to be lower in the treatment group, but there were no significant changes in the proportions of T or B lymphocytes in the treatment versus the control group. However, an analysis of T lymphocyte subsets found that the numbers of CD4+, CD25+, and CD127- regulatory T-cells were significantly higher in the treatment group.

The investigators also found that the numbers of CD27+ B lymphocytes were significantly increased in the treatment group after the MSC infusions compared with pretreatment values.

Zhang and colleagues also reported that the ratio of type 1 to type 2 T-helper cells increased almost two-fold after four MSC infusions, from 1.37 to 2.86. “This result indicates that the Th0 cells developed a differentiation imbalance and tended to become Th2 cells before the treatment with MSCs. After four MSC infusions, the proportion of Th1 cells gradually increased, and the proportion of Th2 cells gradually decreased,” the investigators said.

 “Specifically, these results indicate that infusion with MSCs plays a role in downregulating excessive Th0-to-Th2 differentiation and increasing the proportion of Th1 cells, thereby reversing the Th1:Th2 cell imbalance in patients after HSCT. However, the increasing trend in the Th1:Th2 cell ratio disappeared after day 28.”

Two-year overall survival rates were not significantly different in the treatment versus the control group (66% versus 61%), and neither were the 2-year disease-free survival rates (65% versus 60%).

The rates of relapse were not significantly different between the treatment and control groups (31% versus 32%).

The infusions were well tolerated, with no acute infusional toxicity and no adverse events associated with them, Zhang and colleagues said.

Limitations of the study included that the investigators did not provide specific details of the MSC preparative steps, did not indicate if all centers received cells from the same batch of MSCs, and did not provide the protocol for cell infusion, Lazarus and Pavletic said in their editorial.

“In addition, the authors do not discuss blinding of subjects or observers, which, obviously, is critical in any GVHD study.”

New guideline takes on tough HER2 cases.

In HER2 testing for breast cancer, the term “equivocal” verges on being afour-letter word. If the patient has a clearly positive test result, therapies targeting HER2 become a treatment option, and a highly successful one at that. If the result is clearly negative, HER2-targeting drugs are off the table; the patient isn’t expected to benefit from the drugs, which are expensive and can be cardiotoxic.

But if the result isn’t clear? David Hicks, MD, can still remember the first time he reported a HER2 breast cancer result as “equivocal.”

Dr. Antonio Wolff says that over the years, many physicians have asked about the so-called best, most accurate test for HER2. In the new guideline, “We have taken the tack that it’s not an issue of which test is right, among those linked with clinical outcome, but whether the test selected is done right.”

Dr. Antonio Wolff says that over the years, many physicians have asked about the so-called best, most accurate test for HER2. In the new guideline, “We have taken the tack that it’s not an issue of which test is right, among those linked with clinical outcome, but whether the test selected is done right.”

“The medical oncologist called me and said, ‘I liked it much more when it was positive or negative,’” recalls Dr. Hicks, professor of pathology and laboratory medicine and director of surgical pathology, University of Rochester (NY) Medical Center.

Dr. Hicks is also a practicing breast pathologist and thus no stranger to the difficult HER2 cases that bedevil his physician colleagues and patients. Equivocal results aren’t the only challenges. What’s the best way to handle tumor heterogeneity? What about HER2 genotypic abnormalities, like aneusomy of chromosome 17; colocalization of HER2 and CEP17 signals that affect HER2/CEP17 ratio in dual-signal in situ hybridization assays; and genomic heterogeneity?

Such “rogue” cases, as Dr. Hicks calls them, should become easier for both pathologists and medical oncologists to manage with the arrival of a newly updated HER2 testing guideline issued by the American Society of Clinical Oncology and the CAP. The guideline, published online Oct. 7 in Archives of Pathology & Laboratory Medicine ( and Journal of Clinical Oncology (, updates the previous guideline, which appeared in 2007.

“We provide clear instructions and clear recommendations on how to handle difficult cases and how to reduce areas of uncertainty,’’ says Antonio Wolff, MD, who was the principal oncologist author of both guidelines.

The guideline also simplifies fixation time for HER2 specimens, bringing requirements in line with those for ER/PgR assays. This is a change that Dr. Hicks—another of the guideline’s authors—predicts will be “helpful and welcome news” for pathologists. And it defines bright-field ISH as a valid test platform for assessing HER2 amplification.

Dr. Hicks

Dr. Hicks

All these highly specific recommendations bring a new level of harmoniousness to HER2 testing—one that took considerable effort to achieve. HER2 testing puts in sharp relief two of medicine’s rival geometries. Medical oncologists, naturally, prefer to travel in a straight line, from test result to treatment. Pathologists, just as naturally, find it difficult to stick to that unswerving path. As Elizabeth Hammond, MD, the principal pathologist author of both the new guideline and the earlier one, says, “Unfortunately, cancer biology doesn’t work in a straightforward manner.” But with their latest guideline, the authors hope the odds that both parties will arrive together at agreeable answers have just gone up.

Above all, the guideline emphasizes the need for action. HER2 testing acts as a traffic light for HER2-targeted therapy, and idling at a yellow light indefinitely is not an option.

Yet pathologists are understandably leery of expressing a higher level of certainty than they feel, says Dr. Hammond, professor of pathology, University of Utah School of Medicine, and consultant pathologist, Intermountain Healthcare, Salt Lake City. For them, an “equivocal” result, for example, may well be not only an accurate answer but also the responsible one. But on its own, it doesn’t help the oncologist much. “The result you give needs to be something that helps the clinician make treatment decisions for the patient.”

In that sense, the guideline underscores the notion that test results can be seen as the start of a treatment, not the end of an assay, and that the role of the pathologist in patient care is an active one. Or, as Dr. Hicks puts it, “We’re not just someone who generates a result and throws it over the fence.”

As the guideline’s authors began their discussions in early 2012, they had plenty to talk about.

There has been, for example, no shortage of concern or confusion about how in situ hybridization tests were being counted, says Dr. Hammond. As a result, she says, “We spent a lot of time as a panel dealing with this.”

The guideline’s writers had a tough challenge. According to Dr. Hicks, their first thought was to set HER2 positive at 10 percent of cells with strong staining. But the definition for FISH was an average number over 40 or 60 nuclei. The two methods—cell-by-cell evaluation versus counting multiple nuclei—aren’t necessarily simpatico, however. Because of heterogeneity, a FISH result will depend on which nuclei are being counted. If 10 percent are amplified and 90 percent are not, but nuclei in the nonamplified area are counted, the result will be a 10 percent IHC positive with a HER2-negative FISH result.

The current authors recognized that earlier guidance was not specific enough in cases where tumor heterogeneity was an issue. “The method that we were advocating before was not the right method for finding small populations of tumor cells that might be amplified,” Dr. Hammond says, given that those small populations might have important implications.


Dr. Hammond

Dr. Hammond

In the past, pathologists were mostly doing a random counting of the tumor population, she says. Now, per the new guideline, the pathologist needs to scan the entire ISH slide prior to counting at least 20 cells; areas of potential amplification must be included; and those areas of amplification must be separately counted and reported. “This gives a much better chance that a patient will have an opportunity to get a positive result if there are any amplified or heterogeneous elements in their tumor by this FISH or ISH test method,” Dr. Hammond says.
Dr. Hicks, who has been using the new approach, says it should eliminate discordant cases due to intratumoral heterogeneity. “I think we got that right. Time will tell.” Panel members wanted the guideline to be as evidence-based as possible. “But sometimes, even when there are limitations in our knowledge, guidance needs to be provided. You have to start someplace. As Liz finally said, ‘Well, I think this is the best we can do,’” until more data become available.

Tumor heterogeneity appears to occur more frequently than previously thought, and there’s been concern and plenty of questions about how physicians can be certain the tumor block selected for testing is representative of the patient’s tumor. Dr. Hammond says, “We can never know that. So you have to make a rational decision about how much of a tumor you need to examine to get the right answer.”

The new guideline also takes on the equivocal category. Most notably, it aligns the ASCO/CAP equivocal category with that recommended by the FDA.

When the first guideline was written, says Dr. Hammond, “Our principal concern with HER2 testing was false-positives.” That concern led to one of the more vexing issues in HER2 testing. In the clinical trials for Herceptin, patients were considered positive for HER2 if their tumors contained more than 10 percent cells staining 3+ for HER2. The 2007 guideline writers chose a higher cutoff—more than 30 percent of cells because the panelists unanimously felt that almost all truly positive cases would have higher percentages of staining cells. Says Dr. Hammond: “We felt that tightening the threshold and being more specific about what constituted a positive would help limit the numbers of false-positives.”

Even as they did so, they knew the differing cutoffs might be confusing for practitioners, says Dr. Wolff, professor of oncology, Johns Hopkins University, Baltimore. But they had reasons for doing so.

Dr. Hammond calls setting the threshold at 30 percent “highly conservative. I still believe that’s the case.” In fact, she says, if proper specimen handling procedures are followed, the group of patients who fell into the previous equivocal category (that is, between 10 and 30 percent staining as 3+ positive) would be quite low. One retrospective paper (Perez EA, et al. J Natl Cancer Inst. 2012;104:159–162) considered patient eligibility for one of the trastuzumab adjuvant trials using both cutoffs and found that 3.7 percent of patients who met the FDA cutoff would have been declared ineligible by the ASCO/CAP criterion. “This high percentage would happen, though, only if recommendations from the 2007 guideline were ignored and reflex testing wasn’t done,” she says.

Therefore, Dr. Wolff says, physicians can set those concerns to rest. In a letter published in JNCI last year (Wolff AC, et al. 2012;104:957–958), he says, “We reanalyzed those data, and the actual number of patients affected would be about 0.2 percent of all patients newly diagnosed with breast cancer”—less, he adds, than the observed variability of various commercial assays in clinical use.

Dr. Hammond points out that the study population in the Perez paper consisted of patients who were put on clinical trials in the early 2000s before any specimen handling requirements were implemented. Wide acceptance of those requirements has lowered the false-positive rate since publication of the guideline in 2007. “We don’t believe this [the new guideline] is going to make any significant increase in the number of false-positives,” she says. It may even help curb them further, she adds.

Likewise, laboratories have shown a “meaningful increase” in participating in HER2 proficiency testing, Dr. Wolff says, adding that efforts to improve HER2 testing have gone beyond pathologists and oncologists, with health systems at large increasingly comprehending the need to provide the resources to implement accurate, standardized, and reproducible predictive biomarker testing, including proper handling of tissue specimens before they reach the pathology lab.

Might such improvements alone have led to a drop in equivocal cases, even without changing the threshold?

“That’s a great question, and I wish I knew the answer to it,” Dr. Hammond says. “Data from some large centers suggest so, and in my own laboratory, that is in fact the case.” Implementing careful specimen handling has had a dramatic effect on producing better pathology results at Intermountain, both by IHC and FISH, she says. In the past, perhaps up to 10 percent of cases would need a repeat FISH test. Her lab also has a “very, very small” number of patients who fell into the equivocal categories under the old guideline either by FISH or IHC, she says.
Nevertheless, she agrees using consistent criteria will help create standardized behavior. And, she adds, “We don’t want to create confusion.”

Concerns were raised about the 2007 guideline’s equivocal category for FISH, Dr. Hammond says. In the FDA guideline and in the clinical trials, a threshold of 2.0 was set to qualify patients for treatment. In the ASCO/CAP guideline, however, the authors said that, based on package inserts provided by assay manufacturers, a HER2/CEP17 ratio of 1.8 to 2.2 would be better considered equivocal rather than positive or negative, since they were within two standard deviations of the standard error of that measurement, says Dr. Hammond.

Now, the result is considered equivocal when the dual-probe HER2/CEP17 ratio is < 2.0 with an average HER2 copy number  4.0 and < 6.0 signals/cell.
As an example, Dr. Wolff says confusion occurs in cases in which there is evidence of coamplification in the region recognized by the CEP17 probe. “If that happens,” he says, “you could end up in

a situation where you have, say, an average HER2 signal copy number of six or seven, but also an increase of the average number of CEP17 copies detected to, say, four.” The result will be a ratio of less than two. Relying solely on that ratio, the pathologist runs the risk of calling the tumor nonamplified. “When in reality, we now recognized the occasional coamplification of the CEP17 region identified by the centromere probe. The new guideline mandates that such cases will have another HER2 test performed.

“The biggest message,” Dr. Wolff continues, “is that we ask physicians not only to look at the ratio alone, but actually to look at the individual average number of HER2 copies, which is provided in the numerator, because this can help with difficult cases.”

Again, the 2007 authors had their reasons for choosing the cutoffs they did. The equivocal category was created not to exclude patients from treatment, but to trigger additional testing. Unfortunately, it also led to confusion and controversy.

“Because it was within the error of the measurement,” says Dr. Hammond, “we felt it was useful for oncologists and pathologists to understand that the accuracy of a FISH estimate in that range might be affected by variability. But many of our colleagues later expressed concerns and preferred that we follow that same threshold provided in the clinical trial.”
Their desire is simple to understand, she says. “They want so much to find patients who are going to be HER2 positive.”

Medical oncologists might have been happier if the authors had just bid adieu to the equivocal category with this latest guideline. “We actually tried to get rid of it,” Dr. Hammond says. “But we could not do so. There always is an equivocal category, but we think we narrowed it considerably.”

That might have a bright side. The problem might not be with an equivocal result per se, but with viewing it as a final answer or the end of the discussion. As the authors of the new guideline emphasize, some difficult cases (including those with an equivocal result) will continue to exist and should start conversations.
Indeed, that’s what happened when they began to revise the guidelines and tried to answer the tough questions they face routinely in their own practices. “Most of us are practicing oncologists and practicing pathologists” as well as researchers, Dr. Wolff says.

Dr. Hammond calls the discussions “lively” but says they led to a strong document. It wasn’t unusual, she says, for her and Dr. Wolff to disagree about a subject initially or to reflect the differing opinions between medical oncologists and pathologists. “But when we talked it through, we were very much aligned, because both of us just wanted an accurate test result for the patient.” Yes, these conversations take time, and yes, they can be—temporarily—disconcerting. “But it’s worthwhile,” says Dr. Hammond. “It’s better than talking to yourself.”

Fortunately, not every case requires donnish oversight. “The cases we struggle with are very rare—one, two, three percent of the breast cancer population,” says Dr. Hicks. But little wonder the discussions were animated—there are few data on how to help this small subset of patients with unusual tumors.

Dr. Hicks would like to see those discussions continue in clinical practice. “It would be wonderful if after the guidelines are out, at every tumor board across the country, a pathologist sat up there and presented the changes and led a discussion about how this is going to affect the management of breast cancer in that institution going forward.”

As physicians familiarize themselves with the new guideline, they’ll be able to ask better questions about what test results mean. Dr. Hicks draws attention to the language in the guideline that asks medical oncologists and pathologists to confer on difficult cases, including thinking about HER2 results in the context of the patient’s histology. It’s a new spin on personalized medicine, distilled to answering a basic question: Does this make sense for this particular patient?

That may sound like an obvious question to ask, but in practice it wasn’t happening enough. “We describe the importance of ensuring that the assay results are concordant with the other histopathologic features,” Dr. Wolff says. Take a tubular breast cancer that is low grade and ER/PgR positive, for example. If the HER2 result for the tumor is positive, “those data don’t match in principle,” he says. In situations with such apparent histopathologic discordance, “We ask the pathologist and the oncologist to look back and examine the case as a whole” and consider additional testing if appropriate.

How have discordant results been handled up to now? “It really varied,” Dr. Wolff says. More experienced practitioners would catch the discrepancy, he says, and realize “something wasn’t quite right.” By formalizing this as a recommendation, even those who don’t specialize in breast pathology or breast oncology will know what to do.

Conversation is critical, says Dr. Wolff, but it “doesn’t happen as easily as we would like it to happen. By putting it in the document, we want to make that the norm.”

Similarly, the guideline gives specific recommendations listing the individual steps that pathologists and oncologists need to take as HER2 testing unfolds. “You can’t duck responsibility,” says Dr. Hammond.

It also provides specific guidance for patient and clinician conversations about HER2 testing. “Words matter,” says Dr. Wolff. “We spent a lot of time going over the meaning of everything we wrote.” Nothing, it seems, was left to chance.

That being said, tough cases, like the equivocal category, aren’t disappearing anytime soon. And just as this guideline reflects better knowledge and growing experience, so, too, will future changes create more challenges.

“We tried to do our best, but we’re very honest in saying we may not have covered everything,” Dr. Wolff says, “and we may not have gotten everything right. We did our best with the information available.” It’s inevitable that new classes of HER2 test results not covered in the guideline will become apparent once more data are available. Hence the need to keep the conversation going.

Some of those conversations will be sparked by new technologies, another topic that’s taken up in the new guideline.

While there’s plenty of interest in HER2 serum testing and RT-PCR, the only new platform endorsed in the guideline is FDA-approved bright-field in situ hybridization. The evidence for other methods was insufficient to warrant a recommendation right now. Conversely, the guideline notes, bright-field ISH measures gene amplification, which has clear clinical utility—it was the biological criterion used in prospective clinical trials. It shows high concordance levels with other ISH methods using FISH, and it appears to be reproducible across laboratories.
Bright-field offers another option for labs that currently offer only IHC testing. “That might be a much more interesting way for pathologists to operate,” Dr. Hammond says. While it brings challenges, it will also allow such labs to thoroughly examine the tumor in a way they likely didn’t before, she says.

Labs will also have more flexibility in specimen handling, thanks to other changes in the guideline.

Recognizing the need to further standardize preanalytical variables, the authors have extended the fixation time for HER2 specimens. Now, the fixation time is six to 72 hours, bringing it in line with the times used for ER/PgR testing. In the 2007 guideline, the time was six to 48 hours.

Another change addresses sample procurement. While the 2007 guideline implied that a tumor excisional sample was preferable because it provided more cells for study, says Dr. Hicks, HER2 testing on needle core biopsies has increased in recent years. The new guideline says the needle core biopsies are acceptable, though with clearly defined caveats.
“I think what’s been happening is people are doing the HER2 on the needles—if they’re negative, they’re calling them HER2 negative, and they’re not repeating the test,” says Dr. Hicks. “That may be fine 90, 95 percent of the time. But for that small number of patients who really are HER2 positive, and the needle didn’t get to that part of the tumor, they’re missing an opportunity to have a potentially life-prolonging or life-saving treatment.”

As with other difficult cases, the authors spent plenty of time grappling with this issue. Ultimately, they called for repeat testing in cases where the tumor is high grade; if there’s a limited amount of tissue on the needle core biopsy; if the needle core result falls into the equivocal range; or if the excisional sample contains a different component from that found on the core. The guideline also specifies the type of case when repeat testing is not warranted: if the test is negative and the tumor is grade one and strongly ER/PgR positive.

Even as the new guideline aims for clarity, no one expects it to be the final word on HER2 testing.

If anything, pressure to improve testing will only grow down the road. New studies are exploring the possibility of treating patients with HER2-targeted antibodies without chemotherapy, Dr. Wolff says. “In that situation we have to be incredibly clear and certain that the tumor is HER2 positive or not. Because we could be in a situation where a patient might only receive HER2-targeted treatments in the future.”

When it comes time for another update, the authors will have a good model to follow, says Dr. Hicks: this most recent panel. “More than anything, we are grateful for all the hard work by the guideline panel members and staff from CAP and ASCO.”

No one expects guidelines to be chiseled in stone like commandments. Even if nothing changed— and when was the last time that happened in medicine?—“At some point people start saying, ‘This is an old guideline. It can’t be valid anymore,’” says Dr. Wolff. With the 2007 guideline, “We knew all along that at some point we would need to update the document. And we’ve been more or less waiting for that moment. Now was the time.”


Source:  CAP TODAY 

Salvage surgery for recurrent oropharyngeal cancer after chemoradiotherapy.



The current study aimed to assess the role of salvage surgery for failure cases of oropharyngeal cancer (OPC) undergoing initial chemoradiotherapy (CRT).


The data for 523 patients with previously untreated OPC were gathered from 12 institutions belonging to the Head and Neck Cancer Study Group in Japan Clinical Oncology Group (JCOG).


Of the 170 patients who received CRT, 35 patients (21 %) had local recurrence or residual disease. Only 11 patients underwent further salvage surgery, and 24 patients received nonsurgical treatment. There were statistically significant differences between the two groups in terms of patient age and the presence of a simultaneous regional recurrence. The 5-year overall survival rates for the patients who underwent salvage surgery were 49.1 %, whereas those for the patients who received nonsurgical treatment were 16.3 %.


The initial treatment method for OPC should be decided carefully and the limitations of salvage surgery should be fully considered.

Source: International Journal of Clinical Oncology

Metformin May Lower Risk of Prostate Cancer Death.

Metformin, a widely used diabetes drug, may reduce the risk of dying from prostate cancer, according to new research.

A study of nearly 4,000 diabetic men found that those taking metformin when diagnosed with prostate cancer were less likely to die of the cancer or other causes compared to men using other diabetes drugs.

“We demonstrated that metformin is associated with improved survival among diabetic patients with prostate cancer,” said Dr. David Margel, a uro-oncologist at Rabin Medical Center in Petah Tikva, Israel, who conducted the research while at the University of Toronto.

“It’s associated in a dose-response manner,” he said. “The longer you were on metformin, the less likely you were to die of prostate cancer and of all causes.”

But whether metformin can prevent prostate cancer progression in people without diabetes remains to be seen, experts say.

Diabetes and prostate cancer are common in the United States. This year, about 239,000 new cases of prostate cancer will be diagnosed, and more than 29,000 men will die from it, according to the American Cancer Society.

Type 2 diabetes is rampant, and metformin is the drug most commonly prescribed to treat it. More than 61 million metformin prescriptions were filled in the United States last year. Brand names includeGlucophage and Glumetza. The drug, in its generic forms and certain brand names, is relatively inexpensive.

Previous research has focused on whether metformin might reduce the risk of getting prostate cancer, but most studies were negative. Some experts believe the drug instead works to improve survival once the cancer occurs.

In the new study, published online Aug. 5 in the Journal of Clinical Oncology, Margel looked at more than 3,800 diabetic men aged 67 or older who lived in Ontario. About one-third were taking metformin at the study’s start. Others were using different diabetes drugs.

The men took the metformin for a median of 19 months (half longer than that, half shorter) before the cancer was diagnosed and nearly nine months after.

During roughly four years of follow-up, Margel found those who took metformin had a 24 percent reduction in risk from prostate cancer death for every additional six months of use after their cancer diagnosis. The risk reduction of death from other causes was initially the same but declined over time.

In both instances, although an association was found between metformin and survival, a direct cause-and-effect relationship was not established.

No reduction in death risk was seen for patients taking any other diabetes drug.

Although other diabetes drugs work by increasing the body’s insulin production, metformin is an “insulin sensitizer” that works by making the body more sensitive to the insulin already produced. Insulin is needed to move glucose into cells for energy.

Some research suggests that high insulin levels can influence cancer growth. Metformin, by not increasing the body’s insulin production, may decrease cancer cells’ growth, some experts say.

Typical side effects of the drug are mild diarrhea and stomach problems, Margel said. “Usually they subside after one or two weeks,” he said.

In their next study, the researchers plan to test metformin in patients with prostate cancer but not diabetes. “Metformin is very safe to use among nondiabetic patients,” Margel said.

The findings point to a need for a large study in which men with early stage prostate cancer are assigned to a metformin group or placebo group, one expert said. Writing in an accompanying journal editorial, Kathryn Penney, an instructor in medicine at Brigham and Women’s Hospital in Boston, said at least nine ongoing trials are looking at metformin in men with recurrent or advanced prostate cancer.

But these current trials might be starting too late, she said. Instead, a trial should look at metformin’s effect at the time of diagnosis, when the disease is typically in early stages.

“If this trial showed a benefit, then yes, men without diabetes could be put on metformin at the time of prostate cancer diagnosis,” she said.


We Are What We Eat, Or Are We?

Not a clinic day goes by without multiple patients asking me what they should eat, both while on treatment for their cancer and during the survivorship period. If you Google diet and cancer, you are informed that there are 207 million results.1 Such an association seems logical; we all grew up hearing the phase “you are what you eat,” a phrase attributed to French politician and gastronome Jean Anthelme Brillat-Savarin, who wrote in 1826, “Dis-moi ce que tu manges, je te dirai ce que tu es [Tell me what you eat and I will tell you what you are].”2 Despite the persistent belief for the past nearly two centuries, there remain limited, consistent data on most dietary factors and many disease, including cancers.

Studies of red meat and processed meat have been a rare example of fairly consistent results showing an association between increased intake and risk of developing colorectal cancer.3,4 In 2007, The World Cancer Fund and American Institute of Cancer Research‘s expert panel reported that there was convincing evidence that red meat and processed meat increased the risk of developing colorectal cancer.5 Their meta-analyses found that consumption of red meat led to a 1.43 (95% CI, 1.05 to 1.94) increased risk of colorectal cancer per times per week consumed and 1.29 (95% CI, 1.04 to 1.60) per 100 g/d. Similarly, consumption of processed meat was associated with a 1.21 (95% CI, 1.04 to 1.42) increased risk per 50 g/d.4 Given these consistent findings, it seems reasonable to test whether consumption of red or processed meat affected patients who already have a diagnosis of colorectal cancer.

In this issue of Journal of Clinical Oncology, McCullough et al6 report on a cohort of 2,315 subjects who developed colorectal cancer while participating in the Cancer Prevention Study-II Nutrition Cohort. They report that the quantity of red and processed red meat consumed before the diagnosis of colorectal cancer was associated with all-cause but not colorectal cancer–associated mortality. Though not statistically significant, the data suggest that this increase was due to cardiovascular-associated mortality. However, the consumption of red and processed meat after diagnosis was not associated with either end point. Curiously, those with the highest consumption of red and processed meat consistently before and after diagnosis did have an increased risk of colorectal cancer–associated mortality. This seemingly highest risk group (high intake before and after diagnosis) did not have a statistically higher risk of overall or cardiovascular-associated mortality.

Several issues are worthy of consideration in interpreting the McCullough study.6 First, why did an exposure that convincingly increases the risk of developing colorectal cancer not affect the natural history of the disease once it developed?7,8 Although the exact mechanism of action for red and processed meat increasing colorectal cancer development is not known, several plausible biologic mechanisms have been proposed. Red and processed meats cooked at high temperatures contain heterocyclic amines, which are carcinogenic. A second mechanism involves endogenous formation in the gastrointestinal tract of N-nitroso compounds from the heme in red meat, many of which are carcinogenic. In addition, nitrites or nitrates added to meat for preservation could increase exogenous exposure to nitrosamines, N-nitroso compounds, and their precursors. All these proposed mechanisms lead to carcinogenic effects on the mucosa of the bowel, leading to mutational effects on those cells and potential for abnormal growth and cancer formation. The risk of recurrence for patients with nonmetastatic colorectal cancer is related to the growth of micrometastatic disease, already spread before detection and treatment of the primary lesion. Thus, local carcinogenic effects will be less significant to colorectal cancer survivors’ outside risk of forming new primary tumors. In contrast, recent studies on diet and colorectal cancer survivorship have demonstrated association with cancer recurrence, specifically as a result of high intakes of Western-pattern diet and glycemic load.9,10 Both exposures are proposed to be associated with disease recurrence by increasing insulin and insulin-like growth factors, which affect cell growth, proliferation, and metastatic potential, thereby influencing the growth of micrometastatic disease in colorectal cancer survivors.11

Another consideration in survivorship studies is what recommendations can be made to the patient at hand. When a patient is diagnosed with cancer, they want recommendations on what they can do now to help their chances of cure and/or survival. If an exposure before diagnosis is associated with an outcome, but not the exposure after diagnosis, there is not necessarily a recommendation that can be made to a patient. However, such data may suggest a factor that influenced the biology of the tumor that developed. Another question is whether more favorable or less favorable biology influenced by the exposure can be affected by what the patient does after diagnosis. One consideration could be whether a worse prognosis tumor as a result of dietary exposure should influence treatment given to the patient (ie, the factor having prognostic and predictive value). Certainly, studies of diet and lifestyle to date are far from being able to lead to such conclusions. However, it is possible such a mechanism might explain the curious finding that colorectal cancer–associated mortality was influenced by high consumption of red and processed meat both before and after diagnosis, but not in either time frame only. Specifically, patients with high consumption of red and processed meat before diagnosis should try to decrease intake after diagnosis because those who maintained high levels had a higher risk of recurrence. Such a conclusion is purely speculative on the basis of the data in this article and would need other cohorts to further clarify.

Finally, the study by McCullough et al suggests that some risk factors for colorectal cancer also increase risk for other diseases, and thus colorectal cancer patients will often have comorbidities that influence survival. Thus, the current study does remind clinicians that, although one cannot influence exposures before diagnosis, management of comorbidities is important in the care of colorectal cancer survivors to improve survival.

In conclusion, studies of host factors and cancer survival require us to consider whether the results can be of utility to our patients. First, if the exposure after diagnosis influences outcomes, one should consider whether the strength of the evidence justifies making recommendations to alter diet or lifestyle, for instance. Although a randomized controlled trial would be ideal to address this question, changing diet and lifestyle behaviors in the number of patients needed to have statistical powers remains a challenge. Because studies of diet and lifestyle in colorectal cancer survivors are all observational to date, one needs to consider potential biases and confounding. Second, it is important to understand whether an exposure affects cancer recurrence, survival, or both. Although both end points are important in survivorship care, they may have different management implications. Finally, although a message that prediagnosis diet influences outcomes may seem to have limited utility for a patient when they develop cancer, it furthers the strength of the recommendation for people to maintain a healthy diet and lifestyle throughout their life to maximize the health benefits.

Source: JCO