New Cellular Target May Put the Brakes On Cancer’s Ability to Spread

A team led by Johns Hopkins researchers has discovered a biochemical signaling process that causes densely packed cancer cells to break away from a tumor and spread the disease elsewhere in the body. In their study, published online May 26 in Nature Communications, the team also reported that the combined use of two existing drugs disrupts this process and appears to significantly slow cancer’s tendency to travel, a behavior called metastasis.

The new findings are important, the researchers said, because 90 percent of cancer deaths are caused by metastasis, and anything that derails this activity could improve the prognosis for patients. The crucial new signaling process turned up when the team took a closer look at cellular events that promote metastasis.

“We found that it was not the overall size of a primary tumor that caused cancer cells to spread, but how tightly those cells are jammed together when they break away from the tumor,” said lead author Hasini Jayatilaka, a postdoctoral fellow at Johns Hopkins’ Physical Sciences-Oncology Center. “At a fundamental level, we found that cell density is very important in triggering metastasis. It’s like waiting for a table in a severely overcrowded restaurant and then getting a message that says you need to take your appetite elsewhere.”

Jayatilaka and her colleagues found a medication mix that kept this microscopic message from being delivered. The team members cautioned that this treatment was tested in animal models, but not yet on human cancer patients. Nevertheless, they said the discovery contributes to a promising new focus for cancer research: disrupting the biochemical activity that prods cancer cells to spread through the body.

One of the study’s senior authors, Denis Wirtz, who is Johns Hopkins University’s vice provost for research and director of its Physical Sciences-Oncology Center, said no commercial drugs are now being produced specifically to inhibit metastasis because drug companies believe the best way to stop cancer from spreading is to destroy the primary tumor from which it originates.

“The pharmaceutical companies view metastasis as a by-product of tumor growth,” said Wirtz, who also holds Johns Hopkins faculty appointments in chemical and biomolecular engineering, in pathology and at the Johns Hopkins Kimmel Cancer Center. “Our study looked more closely at the steps that actually initiate metastasis. By doing this, we were able to develop a unique therapeutic that directly targets metastasis, not the growth of the primary tumor. This treatment has the potential to inhibit metastasis and thus improve cancer patient outcomes.”

The two key drivers of metastasis, Wirtz said, are cancer cells’ tendency to reproduce at a rapid rate and their ability to move through surrounding tissue until they reach the bloodstream, where they can then hitch a ride to spread the disease to other parts of the body.

By studying tumor cells in a three-dimensional environment that resembles human tissue, the researchers were able to determine how these activities begin. The team discovered that as two types of cancer cells reproduced and created more crowded conditions in the test site, these cells secreted certain proteins that encouraged migration. The researchers identified these proteins as Interleukin 6 (IL-6) and Interleukin 8 (IL-8).

“IL-6 and IL-8 seem to deliver a message to cancer cells, telling them to move away from the densely populated primary tumor,” said lead author Jayatilaka, who recently earned her doctorate in chemical and biomolecular engineering as a member of Wirtz’s lab team and earlier received her undergraduate degree from Johns Hopkins’ Whiting School of Engineering.

In the team’s animal studies, the researchers found that applying two existing drugs — Tocilizumab and Reparaxin — blocked the receptors that enable cancer cells to get their relocation orders. Tocilizumab is an approved medication for rheumatoid arthritis and is in trials for use in ovarian cancer cases. Reparaxin is being evaluated as a possible treatment for breast cancer.

“In our eight-week experiment, when we used these two drugs together, the growth of the primary tumor itself was not stopped, but the spread of the cancer cells was significantly decreased,” Jayatilaka said. “We discovered a new signaling pathway that, when blocked, could potentially curb cancer’s ability to metastasize.”

To read this full article on ScienceDaily, please click here.

In Landmark Move, FDA Approves Cancer Drug for a Biomarker Not a Tissue

Colon, pancreatic, stomach, or ovarian cancer; it increasingly shouldn’t matter. In an era of precision medicine, the treatment approach should reflect the genetic makeup of the person’s tumor and the presence or absence of key biomarkers.

That ethos was set in stone on Tuesday, with the landmark FDA approval of Merck’s checkpoint inhibitor, Keytruda (pembrolizumab), for patients with solid tumors that express so-called mismatched repair genes.

In a statement, FDA noted the historic nature of its decision. “This is the first time the agency has approved a cancer treatment based on a common biomarker rather than the location in the body where the tumor originated.”

It has been a long time in the making. Scientists’ understanding of cancer has shifted dramatically in the 21st Century, helped along by initiatives such as the human genome project and the advent of next-generation sequencing.

One of the biggest revelations has been the degree of heterogeneity between cancers that arise from a single tissue: A breast cancer might be more akin to a melanoma than another breast cancer. As a result, it often makes sense to classify cancers based on their genetics, not their origin, when selecting oncology treatments.

Following today’s approval, one the defining features of certain solid tumors will be whether they are microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). Both are abnormalities that affect the proper repair of DNA inside the cell (aka mismatch repair genes).

According to FDA, colorectal, endometrial and gastrointestinal cancers have the highest rates of these mutations. MSI-H and dMMR also appear, albeit less commonly, in cancers arising in the breast, prostate, bladder, thyroid gland and other places. Approximately 5 percent of patients with metastatic colorectal cancer have MSI-H or dMMR tumors.

Scientists at the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins Medicine were the first to hypothesize that tumors with these mismatch repair genes would be particularly susceptible to immunotherapies, such as Keytruda. The idea was advanced into clinical trials and ultimately given the green light via FDA’s accelerated approval route.

“I think that this is a really positive development for a couple of reasons,” said Joydeep Goswami, president, clinical NGS and oncology at Thermo Fisher Scientific, in online correspondence. “First, it reinforces the idea of cancer treatment being stratified by the molecular signature of the tumor. Second, it clarifies that the molecular signature of a tumor is more significant than the organ of origin. Both these emphasize the molecular nature of cancer and confirm the need to tie therapy selection to the precise molecular signature in order to ensure the best patient outcomes.”

Keytruda is already approved for the treatment of certain patients with metastatic melanoma, metastatic non-small cell lung cancer, recurrent or metastatic head and neck cancer, refractory classical Hodgkin lymphoma, and urothelial carcinoma.

Other checkpoint inhibitors, such as Bristol-Myers Squibb’s Opdivo, are hot on Merck’s heels chasing market share.

Is Medicine Ready?

It’s one thing to get an FDA approval, it’s another to implement this form of medicine nationwide. As many observers noted on Twitter, oncologists often specialize based on the tissue of origin. They’re colon cancer or breast cancer experts.

Perhaps more importantly, the bulk of cancer patients in the U.S. still aren’t having their tumors sequenced. The next-generation sequencing diagnostics can cost thousands of dollars and insurers have argued that the clinical utility isn’t there. Medicare and Medicaid have taken the same stance.

Today’s approval could help the industry move forward. Indeed, it has been noted that the lack of routine sequencing holds back recruitment for clinical trials, which in turn limits the approval of drugs that would validate the sequencing.

Scott Tomlins, co-founder and laboratory director of Strata Oncology, stressed via email that there is much more work to be done to break this treatment stalemate. Strata deals with it firsthand through its work matching eligible patients with precision medicine trials.

“Results like this confirm that we should be assessing the critical and targetable molecular alterations driving every individual’s cancer,” Tomlins said. “However, it is critical to recognize that with presently available drugs, only a small subset of patients with cancer are likely to benefit from this or most other targeted therapies. Thus, finding patients whose tumors have highly targetable alterations, and enrolling them onto the most appropriate clinical trials remain the critical barriers to accelerating approval of promising therapies and gaining widespread reimbursement for molecular profiling.”

There’s also value in ruling out patients that are unlikely to respond to personalized therapies. Keytruda launched in the U.S. with a list price of $12,500 per patient per month, or $150,000 per year. Many trials are underway studying checkpoint inhibitors as part of combination therapies, which would see the cost climb further.

The case is definitely building for genetic testing, as means to finding the right individuals and saving the expense and struggle of treating those who are unlikely to benefit.

To read this full article on MedCity News, please click here.

Unexpected Presence of Glucose Receptor in Ovarian Cancer Links Metabolism to Most Aggressive Cases

A new study of non-diabetic women with ovarian cancer reveals a potential correlation and area for further study regarding the expression of the GLUT1 glucose transporter receptor at the cancer tissue level. GLUT1 is a receptor protein involved in the absorption of glucose, or sugar, in the bloodstream and across membranes in the body. Physiologically, GLUT1 is not traceable in the ovaries. However, in patients diagnosed with ovarian cancer, use of immunohistochemical methods revealed the presence of this receptor, which tends to be intensely expressed in the most aggressive cases.

The study, titled, “GLUT1 receptor expression and circulating levels of fasting glucose in high grade serous ovarian cancer,” appeared recently in the journal entitled Journal of Cell Physiology, an international, peer reviewed journal focused on cancer-related issues. The authors belong to a multidisciplinary Italian-American team, which has long collaborated with Prof. Antonio Giordano, Director of the Sbarro Institute for Cancer Research and Molecular Medicine at Temple University in Philadelphia.

“Ovarian cancer is the leading cause of death among gynecological cancers. Despite remarkable achievements in terms of diagnoses and therapeutics, patient outcomes in terms of survival rates have remained largely unchanged. This is largely due to our limited understanding of the underlying mechanisms and pathways,” says Dr. Maddalena Barba, researcher at the IRCCS Regina Elena National Cancer Institute of Rome, Central Italy.

“This study revealed a higher expression of the glucose transporter 1 in cancer samples of patients with lower glucose levels in non-diabetic women. These findings provide evidence in support of our prior results from this same study population. Indeed, we have recently observed an association between cancer stage at diagnosis and circulating levels of fasting glucose,” explains Dr. Vici, clinical researcher at the division of Medical Oncology 2 of the IRCCS Regina Elena National Cancer Institute.

The study included 40 randomly selected patients from a larger cohort of 147 women diagnosed with high-grade, advanced stage ovarian cancer.

“The findings from the immunohistochemical assessment of this population are key to understanding a variety of factors and determinants related to glucose metabolism in ovarian cancer. In addition, our findings establish a link between fasting glucose, and the expression of the glucose transporter GLUT1. We thus provide support to the hypothesis stated in our prior work within this same pipeline and, at the same time, ascertain the existence of a relation between a systemic and a local tissue biomarker related to energy metabolism. If confirmed in future studies, this may translate into the identification and characterization of innovative drug targets in ovarian cancer patients,” concludes Prof. Antonio Giordano, a scientist with widely recognized expertise in cancer with a specific focus on translational research.

To read this full article on ScienceDaily.com, please click here.

New Guidance for Targeting Residual Ovarian Tumors

Most women diagnosed with ovarian cancer undergo surgery to remove as many of the tumors as possible. However, it is usually impossible to eliminate all of the cancer cells because they have spread throughout the abdomen. Surgery is therefore followed by 18 weeks of chemotherapy.

Delivering chemotherapy drugs directly to the abdomen through a catheter offers better results than other methods, but this regimen suffers from significant complications, and many patients are unable to complete it.

MIT researchers who are working on an implantable device that could make intraperitoneal chemotherapy more bearable have published a new study that offers insight into how to improve chemotherapy strategies for ovarian cancer, and how to determine which patients would be most likely to benefit from this device.

“As we entered into this project, our question was how do we get the same beneficial outcomes and reduce all the side effects?” says Michael Cima, the David H. Koch Professor of Engineering in the Department of Materials Science and Engineering, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the study.

The findings suggest that the outcome of initial surgery plays a key role in the effectiveness of subsequent intraperitoneal chemotherapy. Cisplatin, one of the most commonly used drugs, effectively treats very tiny tumor cell clusters when it is delivered continuously or as a single large dose. But the researchers found that for larger tumor cell clusters, continuous delivery of cisplatin, at higher doses than are tolerable with the current periodic chemotherapy method, was more effective. The device they are developing would make delivery of such higher, continuous doses possible.

Laura Tanenbaum, a recent MIT PhD recipient, is the lead author of the paper, which appears in the journal Gynecologic Oncology. Other authors are MIT graduate students Aikaterini Mantzavinou and Kriti Subramanyam, and Massachusetts General Hospital gynecologic oncologist Marcela del Carmen.

Targeting Residual Tumors

Ovarian cancer is usually not detected until the cancer has reached an advanced stage, with metastases covering organs throughout the peritoneal cavity, including the liver, bladder, and intestines. After surgery, known as “tumor debulking,” patients receive two types of chemotherapy to treat tumors left behind: intravenous delivery of paclitaxel and intravenous or intraperitoneal delivery of a platinum drug such as cisplatin.

Intraperitoneal chemotherapy is pumped directly into the abdomen through a catheter every three weeks for a total of six cycles. This allows cisplatin to come in direct contact with the residual tumors, which has been shown to be more effective than intravenous delivery but is not tolerable for many patients. “It’s painful and the catheter can be a site of local infections,” Cima says.

Several years ago, Cima and colleagues set out to develop an implantable device that could deliver cisplatin into the abdomen without all of the side effects produced by the catheter and the large, repeated cisplatin doses.

Their device is made of a drug-loaded polymer that could be inserted at the beginning of treatment and remain in place for the full treatment course, then removed with minimally invasive surgery. The researchers have tested proof-of-concept devices in mice and are now developing a version that could be tested in humans, though more animal studies are needed before human trials can begin.

In their new study, the researchers set out to investigate how the size of the residual tumors would affect their response to continuous, low-dose cisplatin delivery. They believed that size would play some role because once tumors reach a certain size, the drug may not be able to penetrate all the way into the inner core of the tumors.

To test this hypothesis, the researchers grew spherical ovarian cancer cell clusters 100 or 200 microns in diameter in a lab dish and exposed them to varying doses of cisplatin. Continuous, low-dose cisplatin delivery, similar to what tumors would receive from an implanted device, was as effective against 100-micron tumor spheroids as a single high dose, similar to that delivered by a catheter.

However, by increasing the continuous cisplatin dose, the researchers found that they could treat the larger 200-micron spheroids more effectively than they could with the single high dose. This increased dose could be delivered using an implantable device, but it would not be tolerable for patients if given through an abdominal catheter.

Better Treatment Strategies

Cima believes that the findings may also help to explain some of the preliminary results of a recent, large clinical trial in which doctors found that intraperitoneal cisplatin delivery was no more effective than intravenous chemotherapy alone. This contradicted previous findings from smaller studies, indicating that cisplatin delivery by catheter improved patient survival.

In the newer trial, conducted at about 500 treatment centers, surgeons admitted patients to the study based on size estimates of the tumors remaining after surgery. However, Cima says, this subjective evaluation may have resulted in patients entering the study whose tumors were too large to be helped by the current intraperitoneal therapy.

This points to the importance of both developing a good method for screening patients before future trials begin, to make sure they are likely to benefit from the treatment, and devising new strategies to help surgeons remove as many tumors as possible, Cima says.

To read this full article on ScienceDaily.com, please click here.

Study Reveals Disparities in End-of-Life Care Among Patients With Ovarian Cancer

Within the last 30 days of life, black and Latina women with ovarian cancer were less likely than white women to enroll in hospice care, according to results recently published in the Journal of Clinical Oncology.

Additionally, white women were less likely to undergo more intensive care in the last month of life, to be admitted to the intensive care unit (ICU), have more than one emergency room (ER) visit, undergo life-extending care and undergo invasive care.

“Our analysis confirmed that, irrespective of other sociodemographic factors, patients of black and Hispanic racial and ethnic backgrounds were less likely to meet end-of-life quality-care metrics,” lead researcher Jolyn S. Taylor, M.D., University of Texas MD Anderson Cancer Center and co-authors, wrote.

Previous research has suggested that avoiding aggressive end-of-life care may lead to improved quality of life and lower health care costs. Although hospice use has increased overall during the past decade, many patients still receive intensive and invasive care in the last month of life, particularly minorities and/or patients of lower socioeconomic status.

In an interview with CURE, Taylor said that the study was not designed to explore why these disparities exist, but said it is clear that black and Hispanic women are not receiving optimal end-of-life care.

“The existence of these disparities is likely multifactorial,” she said. “Additional education for patients and providers could be beneficial to start the conversation early regarding goals of care for the end of life.

An important initial step is starting the conversation early with all patients to discuss what patients understand about care near the end of life and what are their priorities and goals for care near the end of life.

To identify racial and ethnic disparities in end-of-life care among patients with ovarian cancer, the researchers used Texas Cancer Registry-Medicare data to assess end-of-life care for women with ovarian cancer who died from 2000 to 2012.

They evaluated a range of factors including: chemotherapy in the final 14 days of life, ICU admission in the final 30 days of life, more than one ER or hospital admission in the final 30 days of life, invasive or life-extending procedures in the final 30 days of life, enrollment in hospice, enrollment in hospice during the final 3 days of life and enrollment in hospice while not hospitalized.

A total of 3,666 patients were included, 77 percent white, 15 percent Latina, 7 percent black, and 1 percent other. All patients had at least 13 months of continuous Medicare coverage before death. Most patients (72 percent) enrolled in hospice before death, but only 64 percent died while enrolled. Nearly 10 percent of patients who enrolled in hospice did so within the last three days of life.

Black and Latina women were less likely than white women to enroll in hospice. Similarly, black and Latina women were less likely to die in hospice compared with white patients.

Among those who died after enrolling in hospice, patients of other or unknown race were more likely to enroll in hospice during the last three days of life.

No group was more likely than others to have multiple hospice enrollments before death. Researchers also found that demographics of patients who enrolled, but did not die, while in hospice were similar.

Latina women and patients of other/unknown were more likely to be admitted to the ICU in the final 30 days of life. In the final 30 days of life, black women were more likely to visit the ER more than once and to receive a life-extending procedure.

The likelihood of having more than one hospital admission in the final 30 days of life and undergoing chemotherapy in the final 14 days of life did not differ by race.

A sensitivity analysis confirmed that black women had increased odds for dying while not enrolled in hospice and for visiting the ER more than once and receiving a life-extending procedure in the final 30 days of life. Latina women were more likely to be admitted to the ICU during the final 30 days of life.

To read this entire article on CURE, please click here.

New Study Offers Insight Into How to Improve Chemotherapy Strategies for Ovarian Cancer

Most women diagnosed with ovarian cancer undergo surgery to remove as many of the tumors as possible. However, it is usually impossible to eliminate all of the cancer cells because they have spread throughout the abdomen. Surgery is therefore followed by 18 weeks of chemotherapy.

Delivering chemotherapy drugs directly to the abdomen through a catheter offers better results than other methods, but this regimen suffers from significant complications, and many patients are unable to complete it.

MIT researchers who are working on an implantable device that could make intraperitoneal chemotherapy more bearable have published a new study that offers insight into how to improve chemotherapy strategies for ovarian cancer, and how to determine which patients would be most likely to benefit from this device.

“As we entered into this project, our question was how do we get the same beneficial outcomes and reduce all the side effects?” says Michael Cima, the David H. Koch Professor of Engineering in the Department of Materials Science and Engineering, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the study.

The findings suggest that the outcome of initial surgery plays a key role in the effectiveness of subsequent intraperitoneal chemotherapy. Cisplatin, one of the most commonly used drugs, effectively treats very tiny tumor cell clusters when it is delivered continuously or as a single large dose. But the researchers found that for larger tumor cell clusters, continuous delivery of cisplatin, at higher doses than are tolerable with the current periodic chemotherapy method, was more effective. The device they are developing would make delivery of such higher, continuous doses possible.

Laura Tanenbaum, a recent MIT PhD recipient, is the lead author of the paper, which appears in the journal Gynecologic Oncology. Other authors are MIT graduate students Aikaterini Mantzavinou and Kriti Subramanyam, and Massachusetts General Hospital gynecologic oncologist Marcela del Carmen.

Targeting Residual Tumors

Ovarian cancer is usually not detected until the cancer has reached an advanced stage, with metastases covering organs throughout the peritoneal cavity, including the liver, bladder, and intestines. After surgery, known as “tumor debulking,” patients receive two types of chemotherapy to treat tumors left behind: intravenous delivery of paclitaxel and intravenous or intraperitoneal delivery of a platinum drug such as cisplatin.

Intraperitoneal chemotherapy is pumped directly into the abdomen through a catheter every three weeks for a total of six cycles. This allows cisplatin to come in direct contact with the residual tumors, which has been shown to be more effective than intravenous delivery but is not tolerable for many patients. “It’s painful and the catheter can be a site of local infections,” Cima says.

Several years ago, Cima and colleagues set out to develop an implantable device that could deliver cisplatin into the abdomen without all of the side effects produced by the catheter and the large, repeated cisplatin doses.

Their device is made of a drug-loaded polymer that could be inserted at the beginning of treatment and remain in place for the full treatment course, then removed with minimally invasive surgery. The researchers have tested proof-of-concept devices in mice and are now developing a version that could be tested in humans, though more animal studies are needed before human trials can begin.

In their new study, the researchers set out to investigate how the size of the residual tumors would affect their response to continuous, low-dose cisplatin delivery. They believed that size would play some role because once tumors reach a certain size, the drug may not be able to penetrate all the way into the inner core of the tumors.

To test this hypothesis, the researchers grew spherical ovarian cancer cell clusters 100 or 200 microns in diameter in a lab dish and exposed them to varying doses of cisplatin. Continuous, low-dose cisplatin delivery, similar to what tumors would receive from an implanted device, was as effective against 100-micron tumor spheroids as a single high dose, similar to that delivered by a catheter.

However, by increasing the continuous cisplatin dose, the researchers found that they could treat the larger 200-micron spheroids more effectively than they could with the single high dose. This increased dose could be delivered using an implantable device, but it would not be tolerable for patients if given through an abdominal catheter.

Better Treatment Strategies

Cima believes that the findings may also help to explain some of the preliminary results of a recent, large clinical trial in which doctors found that intraperitoneal cisplatin delivery was no more effective than intravenous chemotherapy alone. This contradicted previous findings from smaller studies, indicating that cisplatin delivery by catheter improved patient survival.

In the newer trial, conducted at about 500 treatment centers, surgeons admitted patients to the study based on size estimates of the tumors remaining after surgery. However, Cima says, this subjective evaluation may have resulted in patients entering the study whose tumors were too large to be helped by the current intraperitoneal therapy.

This points to the importance of both developing a good method for screening patients before future trials begin, to make sure they are likely to benefit from the treatment, and devising new strategies to help surgeons remove as many tumors as possible, Cima says.

To read this entire article on News-Medical.net, please click here.

Bringing Ovarian Cancer Research Into This Century

By: Marcella Lee, CBS 8 Anchor/Reporter

A local non-profit is working to improve ovarian cancer survival rates by guiding patients into a new frontier.

Ovarian cancer is known as a silent killer because symptoms are vague like: bloating, abdominal or back pain, frequent urination – and symptoms are often misdiagnosed until it is too late.

An emergency room physician for more than 30 years, doctor Tania Homochuk has helped save countless lives. Now, she is a patient in the fight of her own life and taking part in a clinical trial out of Boston

Doctor Homochuk is battling her third recurrence of stage three ovarian cancer – originally diagnosed in 2010.

Surprised and scared Dr. Homochuk’s life flashed before her eyes. Despite her extensive training in emergency medicine, she had little experience in oncology.

“I immediately went back to what I learned in the late 70s, early 80s which is that ovarian cancer is the kiss of death and I was going to die,” said Dr. Homochuk.

Hillary Theakston is executive director of the Clearity Foundation in San Diego. It’s the only non-profit of its kind in the nation, using precision medicine to help ovarian cancer patients get individualized care.

“About 22,000 women every year are diagnosed with ovarian cancer and we lose 14,000 women every year to the disease. We help women understand their tumor biology. We often identify some out of the box treatment options that their physicians might not have thought about,” said Theakston.

One challenge in treating ovarian cancer is that each tumor is unique. By studying the cells and learning how they are mutating, the Clearity Foundation helps each patient understand how best to tackle her tumor.

“Sometimes ovarian tumors behave more like a lung cancer tumor or colon cancer tumor or breast cancer tumor, so some of the drugs that have been developed specifically to target those genetic mutations, might also work in ovarian cancer,” said Theakston.

The startling reality is that many ovarian cancer patients are treated with drugs developed more than four decades ago.

Only one, out of every three women survive ten years after being diagnosed.

The Clearity Foundation helps patients, free of charge, find the best treatment options and clinical trials.

Visit the Clearity Foundation website to learn more about its work and symptoms of ovarian cancer.

Video of Foundation Medicine Lab provided by James Guardino/Bluedeeno.

To watch the full video interview, please click the link: CBS News 8 – San Diego, CA News Station – KFMB Channel 8

Avastin Benefit Varies By Ovarian Cancer Subtype

Superior progression-free survival (PFS) was seen for patients with proliferative or mesenchymal ovarian tumors who were treated with Avastin (bevacizumab), compared with patients with  immunoreactive or differentiated tumors. Further, Avastin was setting a trend toward improved overall survival (OS) for this group, according to results from a study published in Clinical Cancer Research.

In univariate analysis, adding Avastin to standard chemotherapy with carboplatin and paclitaxel was associated with a median PFS of 21.9 months versus 11.8 months for standard chemotherapy alone in patients with the proliferative subtype of ovarian tumors. That represents an improvement of 10.1 months.

Avastin was associated with a nonsignificant improvement in PFS of 8.2 months in patients with mesenchymal subtype tumors.

“We demonstrate that molecular subtypes with the poorest survival (proliferative and mesenchymal) derive a comparably greater benefit from treatment which includes bevacizumab,” the researchers wrote. “Taken together, these data indicate that stratifying patients by molecular subtype could be an effective therapeutic strategy for ovarian cancer.”

In the paper, Stefan Kommoss, M.D., with the department of women’s health at Tuebingen University Hospital in Tuebingen, Germany, and his colleagues noted that antiangiogenic treatment is crucial to treating in ovarian cancer, but there is no biomarker identifying which patients are most likely to benefit. They designed this study to determine whether there was a correlation between ovarian cancer molecular subtypes and outcomes after treatment with Avastin.

Researchers reviewed gene expression array data from patients enrolled in the AGO-OVAR11 trial, the German cohort from the ICON7 multicenter phase III trial. In that trial, women with peritoneal, tubal, or ovarian carcinoma were randomly assigned to carboplatin and paclitaxel with or without Avastin.

Of the 359 patients included in this analysis, 73 (20 percent) had differentiated tumors, 122 (34 percent) tumors were immunoreactive, 68 (19 percent) were mesenchymal, and 96 were proliferative (27 percent). Patients were separated into Avastin (189 patients) and standard chemotherapy alone (170 patients) cohorts.

For all patients, there was a 6.5-month improvement in median PFS for the Avastin arm compared with the standard arm (21.1 vs 14.6). When adjusted for high risk of progression, age, grade, and histology, Cox regression analysis showed that Avastin significantly improved. Improvement in OS was only borderline significant.

In univariate analysis of the immunoreactive and differentiated subtypes, Avastin produced nonsignificant PFS improvements of 3.8 months and 3.7 months, respectively. Improvements in PFS for the mesenchymal, immunoreactive, and differentiated groups remained nonsignificant in multivariate analysis. In preliminary OS results, only the proliferative subtype showed a statistically significant trend toward improved OS. Multivariate analysis showed that any improvements in OS in the mesenchymal, immunoreactive, and differentiated groups were nonsignificant.

“The present investigation is the first to examine the correlation of ovarian cancer molecular subtypes with outcome after treatment with bevacizumab in a randomized controlled phase III trial of primary ovarian cancer,” wrote Kommoss et al. “We show that the proliferative and mesenchymal molecular subtypes appear to benefit most, with a prolongation in PFS and a trend toward greater OS.”

Brian Slomovitz, M.D., director of the division of gynecologic oncology at the University of Miami Sylvester Comprehensive Cancer Center, reviewed the results. While he said the findings had “great promise,” it’s impossible to draw any conclusions until the results are validated in a prospective study.

“This study reflects great potential,” he said. “Why do we want to identify patients who respond to different therapies? One, so patients can be directed toward that therapy. But perhaps more importantly, to prevent a patient from receiving a noneffective therapy, one in which they’d only be receiving side effects without the potential benefit.

“It’s an interesting idea. It’s a great idea. In order for us to get better at treating patients with cancer, we need to do a better job identifying different subgroups of patients who will respond to different therapies.”

To read this entire article on CureToday.com, please click here.

Bevacizumab Benefit Varies Among Ovarian Cancer Subtypes

Patients with proliferative or mesenchymal ovarian tumors treated with bevacizumab (Avastin) had superior progression-free survival (PFS) and a trend toward improved overall survival (OS) compared with patients with immunoreactive or differentiated tumors, according to results published in Clinical Cancer Research.

In univariate analysis, adding bevacizumab to standard chemotherapy with carboplatin and paclitaxel was associated with a median PFS of 21.9 months versus 11.8 months for standard chemotherapy alone in patients with the proliferative subtype of ovarian tumors. That represents an improvement of 10.1 months (HR, 0.55; 95% CI, 0.34-0.90; P = .016).

Bevacizumab was associated with a nonsignificant improvement in PFS of 8.2 months (HR, 0.78; 95% CI, 0.44-1.40; P = .41) in patients with mesenchymal subtype tumors.

“We demonstrate that molecular subtypes with the poorest survival (proliferative and mesenchymal) derive a comparably greater benefit from treatment which includes bevacizumab,” the researchers wrote. “Taken together, these data indicate that stratifying patients by molecular subtype could be an effective therapeutic strategy for ovarian cancer.”

In the paper, Stefan Kommoss, MD, with the department of women’s health at Tuebingen University Hospital in Tuebingen, Germany, and his colleagues noted that antiangiogenic treatment is crucial to treating in ovarian cancer, but there is no biomarker identifying which patients are most likely to benefit. They designed this study to determine whether there was a correlation between ovarian cancer molecular subtypes and outcomes after treatment with bevacizumab.

Researchers reviewed gene expression array data from patients enrolled in the AGO-OVAR11 trial, the German cohort from the ICON7 multicenter phase III trial. In that trial, women with peritoneal, tubal, or ovarian carcinoma were randomly assigned to carboplatin and paclitaxel with or without bevacizumab.

Of the 359 patients included in this analysis, 73 (20%) had differentiated tumors, 122 (34%) tumors were immunoreactive, 68 (19%) were mesenchymal, and 96 were proliferative (27%). Patients were separated into bevacizumab (n = 189) and standard chemotherapy alone (n = 170) cohorts.

For all patients, there was a 6.5-month improvement in median PFS for the bevacizumab arm compared with the standard arm (21.1 vs 14.6; HR, 0.68; 95% CI, 0.53-0.89; P = .005). When adjusted for high risk of progression, age, grade, and histology, Cox regression analysis showed that bevacizumab significantly improved PFS (HR, 0.64; 95% CI, 0.49-0.83; P = .0008). Improvement in OS was only borderline significant (HR, 0.66; 95% CI, 0.44-1.00; P = .05).

In univariate analysis of the immunoreactive and differentiated subtypes, bevacizumab produced nonsignificant PFS improvements of 3.8 months (P = .08) and 3.7 months (P = .61), respectively. Improvements in PFS for the mesenchymal, immunoreactive, and differentiated groups remained nonsignificant in multivariate analysis.

In preliminary OS results, only the proliferative subtype showed a statistically significant trend toward improved OS (HR, 0.50; 95% CI, 0.24-1.03; P = .06). Multivariate analysis showed that any improvements in OS in the mesenchymal, immunoreactive, and differentiated groups were nonsignificant.

“The present investigation is the first to examine the correlation of ovarian cancer molecular subtypes with outcome after treatment with bevacizumab in a randomized controlled phase III trial of primary ovarian cancer,” wrote Kommoss et al. “We show that the proliferative and mesenchymal molecular subtypes appear to benefit most, with a prolongation in PFS and a trend toward greater OS.”

Brian Slomovitz, MD, director of the division of gynecologic oncology at the University of Miami Sylvester Comprehensive Cancer Center, reviewed the results for OncLive. While he said the findings had “great promise,” it’s impossible to draw any conclusions until the results are validated in a prospective study.

“This study reflects great potential,” he said. “Why do we want to identify patients who respond to different therapies? One, so patients can be directed toward that therapy. But perhaps more importantly, to prevent a patient from receiving a noneffective therapy, one in which they’d only be receiving side effects without the potential benefit.

“It’s an interesting idea. It’s a great idea. In order for us to get better at treating patients with cancer, we need to do a better job identifying different subgroups of patients who will respond to different therapies.”

To read this entire article on OncLive, please click here.

ImmunoGen Drug Moving Ahead In Single-Agent, Combination Trials

Latest results from a mid-stage trial of ImmunoGen Inc’s experimental antibody-drug conjugate show that it shrinks or stabilizes tumors in nearly half of advanced ovarian cancer patients with at least medium levels of a key biomarker whose disease has become resistant to standard chemotherapy.

Looking at all 113 patients so far evaluated in the trial, 30 percent responded to the drug and patients lived for a median of 4.3 months without their disease progressing.

For its pivotal trial, ImmunoGen is enrolling only patients with platinum-resistant disease and medium or high levels of a biomarker known as folate receptor alpha who have received up to three prior lines of therapy. Of the 36 trial earlier-stage trial patients meeting those criteria, 47 percent responded to the drug and median progression-free survival was 6.7 months, the company said on Wednesday. The full research will be presented next month at a meeting of the American Society of Clinical Oncology.

“We are looking to get on the market as quickly as possible in the single agent setting,” ImmunoGen Chief Executive Mark Enyedy told Reuters. The company expects to have final data from the pivotal trial in 2019.

About 22,400 American women are diagnosed with ovarian cancer each year and about 14,000 will die from the disease, according to the American Cancer Society.

Mirvetuximab soravtansine combines an antibody targeting a receptor, anti-folate alpha, associated with certain types of cancer cells with an anti-tumor agent to kill the targeted cells.

ImmunoGen is also studying the drug in combination with other treatments for earlier-stage ovarian cancer, and said it will move forward with more advanced combination trials involving Roche Holding AG’s Avastin and Merck & Co Inc’s Keytruda. It is also evaluating future studies with carboplatin chemotherapy combinations.

Early-stage trial results showed that for advanced ovarian cancer patients treated with Avastin and the ImmunoGen antibody-drug conjugate, 29 percent responded to the treatment with a median progression-free survival of 9.5 months.

Side effects in the Avastin group included excess protein in the urine for 36 percent of patients and hypertension in 21 percent of patients.

ImmunoGen said it was too early to assess results for the Keytruda arm of the trial.

To read this full article on Reuters.com, please click here.