Rapid regression of HER2 breast cancer

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Anti-HER2 Combo Shrunk Breast Tumors in Under 2 Weeks

“This has groundbreaking potential because it allows us to identify a group of patients who, within 11 days, have had their tumors disappear with anti-HER2 therapy alone and who potentially may not require subsequent chemotherapy,” said researcher Nigel Bundred, MD, professor of surgical oncology at the University of Manchester in the United Kingdom, in a statement. “This offers the opportunity to tailor treatment for each individual woman.”

Following initial news reports of the EPHOS-B trial, the authors earlier today issued a statement urging caution in interpreting the results: “While we do not wish to downplay the significance of the findings,” they wrote, “we wish to emphasize that our research has shown this treatment to be suitable for a group of women with a particular type of breast cancer. We have no evidence that it would be effective for anything other than patients with newly diagnosed, HER2-positive breast tumors.”

The trial was split into two parts and included 257 newly diagnosed, operable, HER2-positive breast cancer patients.

In the first part of the trial, 130 patients were randomized to a control group that received no pre-operative treatment, or to one of three treatment arms that received therapy for 11 days prior to surgery: trastuzumab alone, lapatinib alone, or the combination of trastuzumab and lapatinib. All patients were treated with standard of care after surgery.

In the second part of the trial, 127 patients were randomized to receive trastuzumab alone (n = 32), the combination of trastuzumab and lapatinib (n = 66), or a control group that received no pre-operative treatment (n = 29). Results from this part of the trial showed that in patients who received the combination treatment, 11% had a pathologic complete response (pCR) and 17% had minimal residual disease (MRD). In patients who received trastuzumab alone, none had a pCR and only 3% had MRD. No patient in the control group had either a pCR or MRD. Patients in the combination treatment arm also had a reduction in Ki67, a marker of apoptosis.

Median age of patients in the trial was 52 years, 48% of women had tumors greater than 2 cm, and 51% were grade 3 as assessed by biopsy.

“These results show that we can get an early indication of pathologic response within 11 days, in the absence of chemotherapy, in these patients on combination treatment. Most previous trials have only looked at the pathologic response after several months of treatment,” said Judith Bliss, MD, of the Institute of Cancer Research in London and Vice-Chair of the UK Breast Intergroup, who took part in the clinical trial, at a press conference.

The study researchers emphasized that these results need to be confirmed in larger trials.

“This study proposes a simple way to identify those patients very early on, which could help spare them unnecessary chemotherapy. What is now indispensable is to confirm if these early responses translate into better or equal long-term survival,” said Fatima Cardoso, MD, chair of EBCC-10 and director of the breast unit at the Champalimaud Clinical Centre in Lisbon, in a statement.

The EPHOS-B trial was funded by Cancer Research UK and GlaxoSmithKline.

Breast Cancer Drug Combination Could Shrink Tumors in Days

Seth Augenstein, Digital Reporter    http://www.biosciencetechnology.com/news/2016/03/breast-cancer-drug-combination-could-shrink-tumors-days

A combination of breast cancer drugs administered before surgery could drastically shrink particular tumors within days – and potentially eliminate the need for chemotherapy in some patients, according to British researchers.

Herceptin (trastuzumab) in concert with lapatinib on tumors that are HER-2 positive can shrink or even destroy tumors within just 11 days before surgery, according to The Institute of Cancer Research in London.

Some 20 percent of all breast cancers are HER-2 positive, according to analysis by the Mayo Clinic.

The theory was the two drugs would work as a one-two punch: the Herceptin would block the HER-2 proteins on which the tumors rely, and then the lapatinib would inhibit other enzymes that may potentially remain unaffected by the other drug.

The study observed the tumor size in 257 women in the days-long window between diagnosis and removal of the tumors.

The participants were initially split up into three groups – one each getting one of the drugs, and a third getting no treatment for the 11 days before the surgery, according to the scientists.

However, other trials had indicated the drug combination could have a dramatic effect, so additional women were put in the lapatinib group and also given the Herceptin.

Roughly a quarter of the 66 women who got both drugs had tumors that were too small for the second measurement before surgery, they found.

“Our trial set out to try to use the window between diagnosis and surgery to find clues that combined treatment with (Herceptin) and lapatinib was having a biological effect on HER-2 positive tumors,” said Judith Bliss, director of the Cancer Research Clinical Trials and Statistics Unit at the Institute of Cancer Research. “So it was unexpected to see quite such dramatic responses to the (Herceptin) and lapatinib within 11 days.”

The results were presented at the European Breast Cancer Conference on Thursday.

“These results are very promising if they stand up in the long run and could be the starting step of finding a new way to treat HER-2 positive breast cancers,” said Arnie Purushotham, senior clinical adviser at Cancer Research UK.

Breast cancer cells stained for DNA (red), NFkB (green), and a reactive oxygen species probe (blue) (photo: Julia Sero/the ICR)

A drug combination – of lapatinib and trastuzumab (Herceptin) – before surgery shrinks and may even destroy tumours in women with HER2 positive disease within 11 days, according to new research.

The EPHOS B trial, led by researchers at The Institute of Cancer Research, London, the University of Manchester and University Hospital of South Manchester NHS Foundation Trust, studied 257 women with HER2 positive breast cancer in the short gap between initial diagnosis and surgery to remove their tumours.

The research may lead to fewer women needing chemotherapy.

The results, from a Cancer Research UK-funded trial, are being presented at the 10th European Breast Cancer Conference (EBCC10) today (Thursday).

In the trial, women were split into three groups and treated for 11 days before their surgery. Initially, women were randomised to receive either trastuzamab, or lapatinib or no treatment – but halfway through the trial, after evidence emerged from other trials of the effectiveness of the combination, the design was altered so that additional women allocated to the lapatinib group were also prescribed trastuzumab.

Drug combination shrinks HER2-positive breast cancers within 11 days

A drug combination – of lapatinib and trastuzumab (Herceptin) – before surgery shrinks and may even destroy tumours in women with HER2 positive disease within 11 days, according to new research.

The EPHOS B trial, led by researchers at The Institute of Cancer Research, London, the University of Manchester and University Hospital of South Manchester NHS Foundation Trust, studied 257 women with HER2 positive breast cancer in the short gap between initial diagnosis and surgery to remove their tumours.

The research may lead to fewer women needing chemotherapy.

The results, from a Cancer Research UK-funded trial, are being presented at the 10th European Breast Cancer Conference (EBCC10) today (Thursday).

In the trial, women were split into three groups and treated for 11 days before their surgery. Initially, women were randomised to receive either trastuzamab, or lapatinib or no treatment – but halfway through the trial, after evidence emerged from other trials of the effectiveness of the combination, the design was altered so that additional women allocated to the lapatinib group were also prescribed trastuzumab.

The trial set out to study the biological effects of the drug combination by measuring biological markers of cellular proliferation after 11 days of therapy. But when trying to measure this, the researchers discovered that in roughly a quarter of the 66 women who received both drugs, the remaining tumour was too small for the second measurement of cell proliferation.

Seventeen per cent of the women receiving both drugs had only minimal residual disease – defined as an invasive tumour smaller than 5mm in size – and 11% had a pathological complete response, meaning no biological sign of invasive tumour could be found in the breast.

‘Very promising’

Three per cent of the women treated with trastuzumab only had residual disease or complete response.

HER2-positive breast cancer is more likely to come back after treatment than some other types of breast cancer. It is generally treated with surgery, chemotherapy, endocrine therapy and targeted anti-HER2 drugs.

Around 53,400 women are diagnosed with invasive breast cancer – with about 10-15% of these characterised as HER2 positive breast cancer – and around 11,600 women die from the disease in the UK every year.

Current treatments are effective and complete response is common after three to four months, but the researchers say observing a disease response after 11 days was very surprising.

Trial Co-leader Professor Judith Bliss, Director of the Cancer Research UK-funded Clinical Trials and Statistics Unit at the ICR, said: “Our trial set out to try to use the window between diagnosis and surgery to find clues that combined treatment with trastuzumab and lapatinib was having a biological effect on HER2 positive tumours. So it was unexpected to see quite such dramatic responses to the trastuzumab and lapatinib within 11 days.

“Our results are a strong foundation on which to build further trials of combination anti-HER2 therapies prior to surgery – which could reduce the number of women who require subsequent chemotherapy, which is also very effective but can lead to long-term side-effects.”

Clinical Chief Investigator and Trial Co-leader Professor Nigel Bundred, Professor of Surgical Oncology at The University of Manchester and Clinical Consultant at University Hospital of South Manchester NHS Foundation Trust, said: “These early and significant tumour regressions seen on dual anti-HER2 therapy suggest that we will be able to personalise treatment for these cancers on the basis of early response, allowing us to identify patients who in the future may avoid treatment morbidity or avoid chemotherapy”.

Professor Arnie Purushotham, Senior Clinical Adviser at Cancer Research UK, said: “These results are very promising if they stand up in the long run and could be the starting step of finding a new way to treat HER2-positive breast cancers. This could mean some women can avoid chemotherapy after their surgery – sparing them the side-effects and giving them a better quality of life.”

Breast Cancer Vaccines and Checkpoint-Inhibitor Immunotherapy

Q&A | March 15, 2016 | MBCC 2016, Breast Cancer
By Elizabeth A. Mittendorf, MD, PhD

Elizabeth A. Mittendorf, MD, PhD
As part of our coverage of the 33rd Annual Miami Breast Cancer Conference, held March 10-13 in Miami Beach, Florida, we spoke with Elizabeth A. Mittendorf, MD, PhD, associate professor at the department of breast surgical oncology at the University of Texas MD Anderson Cancer Center in Houston, Texas, who presented at the meeting on cancer vaccines and checkpoint inhibitors.
Cancer Network: How has being both a surgeon and immunologist, shaped your views of the potential clinical roles of cancer vaccines?

Dr. Mittendorf: As a surgeon, I see and treat patients with early-stage breast cancer that is potentially curable. Unfortunately, despite our best treatment—surgery, chemotherapy when indicated, radiation if required—we still see recurrences in up to 20% of these patients. I think it is not unreasonable to hypothesize that this recurrence is in part attributable to a failure of the immune response against the cancer—hence my enthusiasm for vaccines that could potentially augment that antitumor immunity, thereby decreasing the risk of recurrence.

Cancer Network: In what settings do breast cancer vaccines show the most promise?

Dr. Mittendorf: Secondary prevention. There is currently one vaccine that is being investigated in a phase III trial—NeuVax—which is made up of an immunogenic peptide combined with an immunoadjuvant. The trial is vaccinating patients in the adjuvant setting with the goal being to determine if vaccination can decrease the risk of recurrence.

Cancer Network: Is there reason for optimism that cancer vaccines might prove useful against advanced breast cancers?

Dr. Mittendorf: In my opinion, vaccines as monotherapy are not likely to be successful in advanced breast cancer. With that said, it is possible that vaccines could be administered as part of a combination strategy with other drugs that could augment the immune response such as certain chemotherapy regimens, trastuzumab, or other immunomodulatory drugs such as the checkpoint blockade agents.

Cancer Network: What insights do epidemiologic studies, such as those regarding childhood infections and cancer risk, offer for cancer immunotherapy?

Dr. Mittendorf: There is epidemiologic data to suggest that individuals who have had childhood infections (ie, chicken pox, pertussis, and other febrile illnesses) have a decreased risk of developing cancer. It is likely that these individuals develop adaptive immune responses against epithelial antigens. These responses could be augmented in the setting of a premalignant condition (ie, a colonic adenoma, or ductal carcinoma in situ), thereby tipping the scales back in favor of the immune response, leading to elimination of the threat of malignancy.

Cancer Network: Are the KEYNOTE trial reports to date reason for optimism about immune checkpoint blockade’s potential against breast cancer?

Dr. Mittendorf: Absolutely. These trials have confirmed that pembrolizumab (anti-PD-1 antibody) is fairly well tolerated by breast cancer patients and suggest some clinical activity. Through the portfolio of KEYNOTE trials, which have enrolled the different subtypes of breast cancer, we’re likely to learn more about which subtypes of breast cancer are most likely to respond to pembrolizumab as monotherapy, which in turn would suggest which subtypes might need additional immune stimulation (ie, a combination strategy) in order for the checkpoint blockade agent to be effective.

Cancer Network: What is the significance of PD-L1 expression in tumor cells vs the tumor microenvironment?

Dr. Mittendorf: Whether PD-L1 expression on the tumor cells is required for response to anti-PD-1 or anti-PD-L1 therapy remains a subject of much discussion. Data from the JAVELIN trial presented at the San Antonio Breast Cancer Symposium in December suggested that PD-L1 expression on the tumor was less important than PD-L1 expression on immune cells in the microenvironment—what they referred to as “immune hotspots.”

Cancer Network: Do you anticipate clinical roles for checkpoint blockade in secondary prevention? Breast cancer treatment in combination with other agents, like trastuzumab? (Are there other promising combinations? Do you anticipate immunotherapy combinations that exploit different immune system pathways?)

Dr. Mittendorf: I see a potential role for checkpoint blockade in the adjuvant setting (effectively secondary prevention) in high-risk patients in whom the risk/benefit ratio favors using these agents, which do have some toxicity associated with them. As an example, the SWOG cooperative group is developing a trial that will evaluate pembrolizumab in patients with triple-negative breast cancer who have at least 1 cm of tumor or positive lymph nodes after neoadjuvant chemotherapy. With respect to using in combination with other agents—yes; in fact the PANACEA trial currently accruing in Europe is combining pembrolizumab with trastuzumab in patients with HER2-positive metastatic breast cancer.

http://www.cancernetwork.com/mbcc-2016/breast-cancer-vaccines-and-checkpoint-inhibitor-immunotherapy#sthash.UenTvjsF.dpuf

Prognostic DCIS Score: ‘Ready for Prime Time’

News | March 14, 2016 | MBCC 2016, Breast Cancer
By Bryant Furlow
Not all ductal carcinoma in situ (DCIS) is dangerous, and the prognostic genomic Oncotype DX DCIS Score allows for routine risk stratification of patients to avoid unnecessary treatment, reported Patrick I. Borgen, MD, chair of the department of surgery at Maimonides Medical Center in Brooklyn, New York. Dr. Borgen spoke at the 33rd Annual Miami Breast Cancer Conference, held March 10–13 in Miami Beach, Florida.
Recent jumps in DCIS diagnoses have been driven by overdetection. “There’s a reservoir of DCIS in the female breast that was never going to become invasive—or would do so, so slowly that it was never going to threaten our patient,” Dr. Borgen noted.

Graphing the utilization of mammography over time, one sees that it “completely parallels the increase in DCIS diagnoses,” Dr. Borgen said. “There’s a similar slope of percent-change over time for DCIS and mammography screening. That either means the mammograms are causing DCIS, or, much more likely, that some of this [DCIS] was not going to become clinically relevant.”

When more sensitive digital mammography became more widely used, DCIS rates jumped again, he added. “Better imaging, more DCIS.”

The prevalence of occult DCIS in autopsy studies is “about an order of magnitude higher” than what we see in screening studies, Dr. Borgen noted, as further evidence for subclinical DCIS.

Thanks to landmark prospective randomized studies like the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-17 study, the standard of care for DCIS is lumpectomy and radiation. Those studies did not identify subsets of patients who failed to benefit from radiation, but they did find that 80% of patients would do well with surgery alone. “We focus on the 10% who do better with radiotherapy, but 10% recur despite radiotherapy. The challenge is, how do we find the 80% of patients who, much later—15, 20, 25 years later—are going to be well?”

Nomograms “leave significant room for improvement,” he noted. “It is possible that clinical parameters alone are insufficient to predict outcome. We have moved away from morphology—from looking down a microscope to determine whether it’s a bad lesion.”

Instead, the field has turned to prognostic analyses of DCIS genomics.

“The Oncotype DX DCIS Score isn’t a mathematical model and doesn’t require bootstrapping,” he said. “It looks at DCIS genomics in the patient in front of you—a subset of the 21-gene assay that we use routinely.”

It has been validated in the Eastern Cooperative Oncology Group (ECOG) E5194 and Ontario DCIS Cohort studies for recurrence prognostication and risk stratification of women with DCIS who underwent breast-conserving surgery and had negative margins.

“I would argue that it’s ready for prime time” in routine clinical use, Dr. Borgen told attendees.

The DCIS Score divides patients into low, intermediate, and high-risk DCIS categories, with 65% of patients falling into the low-risk group, meaning that at 10 years, they face a 4% chance of developing invasive breast cancer.

Dr. Borgen noted that the addition of radiation doesn’t diminish the DCIS Score’s predictability. “The DCIS Score is associated with the risk of local recurrence in a population of patients with pure DCIS treated with breast-conserving surgery, with or without radiation. It’s almost certain there’s a very high-risk cohort of the disease, as well, and those patients may benefit from an entirely different treatment.”

http://www.cancernetwork.com/mbcc-2016/prognostic-dcis-score-ready-prime-time