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As Molecular Understanding of HER2-Positive Breast Cancer Advances, New Treatment Strategies Emerge

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Originally published Dec. 12.

SAN ANTONIO, TEX. – Fifteen years after it came on the market, Herceptin is still the poster child for personalized medicine, and when combined with chemotherapy it's still the standard of care for HER2-positive breast cancer.

However, with growing knowledge of the molecular underpinnings of cancer, HER2-positive breast cancer is no longer the monolithic disease grouping it once was. Researchers at the San Antonio Breast Cancer Symposium presented data showing that HER2-overexpressers can be further stratified into smaller molecular subgroups that experience varying benefits from different treatment strategies involving Herceptin.

Martine Piccart-Gebhart, chair of the Breast International Group in Brussels, presented four-year median follow-up data from the NeoALTTO trial, which looked at whether blocking the HER2 receptor with two tyrosine kinase inhibitors, Roche/Genentech's Herceptin and GlaxoSmithKline's Tykerb (lapatinib), in the neo-adjuvant setting (before surgery) improves patient response compared to using one HER2-targeted drug, either Herceptin or Tykerb. Piccart-Gebhart and her colleagues found that not only did breast cancer patients benefit more from dual HER2 blockade rather than a single agent, but that this effect was particularly pronounced in women with hormone receptor-negative disease.

Based on the results of the study, Piccart-Gebhart said that she "would not definitely change the standard of care" – Herceptin plus chemotherapy – at this point in time. However, she noted that if a larger study, called ALTTO, finds that dual HER2-blockade in the adjuvant setting significantly improves long-term outcomes in certain subsets of HER2-positive breast cancer patients, then that could be important for clinical practice. ALTTO is slated to be presented at the American Society of Clinical Oncology's annual meeting next year.

Importantly, to Piccart-Gebhar, the NeoALTTO study adds to a growing body of evidence that suggests that HER2-positive, hormone receptor-positive breast cancer is a different disease than HER2-positive, hormone receptor-negative breast cancer. Approximately 20 percent of women with breast cancer have HER2-positive disease. Within this group, 50 percent are hormone receptor-positive and the other half are hormone receptor-negative.

In line with this view, another study led by Sibylle Loibll of the German Breast Group used PIK3CA mutations to home in on new treatment insights for HER2-positive breast cancer patients by hormone receptor status. In this prospective trial, researchers found that hormone receptor-positive patients with PIK3CA mutations had very low pathologic complete response rates on dual anti-HER2 treatment and chemotherapy compared to wild-type patients. Meanwhile, for hormone receptor-negative patients, pathologic complete response rates didn't differ much based on PIK3CA mutation status.

Also at the SABCS, Sherene Loi, head of the Translational Breast Cancer Genomics Lab at the Peter MacCallum Cancer Center in Melbourne, Australia, delved deeper into why tumors with infiltrating lymphocytes – immune cells – tend to benefit more from Herceptin treatment than those without these lymphocytes. Loi and her team have hypothesized that given the better prognosis seen in breast cancer patients with tumor infiltrating lymphocytes (TILs), a T-cell checkpoint inhibitor in combination with Herceptin treatment might bolster outcomes in patients with HER2-positive disease.

Meanwhile, in the BETH trial, investigators looked at whether adding Roche/Genentech's anti-angiogenic drug Avastin (bevacizumab) to Herceptin and chemo (docetaxel and carboplatin) in the adjuvant setting imparted a greater benefit for patients compared to just Herceptin plus chemo. Researchers led by Dennis Slamon, director of clinical/translational research at the University of California, Los Angeles, found that adding Avastin didn't make a difference in patients' treatment outcomes. But because patients in the study did so well on Herceptin plus docetaxel/carboplatin, Slamon and colleagues believe that this chemo regimen may be better for HER2-positive breast cancer patients than anthracycline-based treatment.

At a press conference at SABCS, Jennifer Litton of MD Anderson Cancer Center noted that ongoing stratification of the HER2-positive breast cancer patient group by molecular subtype is poised to drastically change treatment paradigms in the future. She agreed with Piccart-Gebhart that HER2-positive breast cancer without hormone receptor involvement (ie., estrogen receptor-negative and progesterone-receptor-negative disease) is a drastically different disease than when hormone receptors are implicated.

"We're going to continue to find specific strategies and not [use] a one-therapy-fits-all [approach]," Litton said. "We're learning more and more about the molecular subsets of cancer. How we've broken them up into triple receptors is really going to go by the way side."

NeoALTTO

In NeoALTTO, 455 breast cancer patients with HER2-positive tumors larger than 2 cm were randomized to three arms: Herceptin, Tykerb, or both. First, patients received the targeted agents alone for six weeks. Then, paclitaxel chemotherapy was added to the regimen for 12 weeks, followed by surgery. After surgery, the patients went back to receiving their original targeted treatment and also received adjuvant chemotherapy for 52 weeks.

Piccart-Gebhart and colleagues have previously reported that 51.3 percent of patients receiving the dual-HER2 regimen experienced pathologic complete response, while only 24.7 percent in the Tykerb arm and 29.5 percent in the Herceptin arm experienced such a benefit. The new finding is that women with hormone receptor-negative disease had a particularly robust pathologic completed response on the Hercpetin/Tykerb combo (61.3 percent), compared to around 35 percent for those on the single agents.

The researchers will conduct another follow-up analysis in NeoALTTO in two-and-a-half years and will follow patients for a total of 10 years. Piccart-Gebhart noted the possibility that with longer follow-up, researchers may see an even greater benefit in the hormone receptor-negative subpopulation.

Although the trial was not powered to detect differences in event-free survival and overall survival between the treatments, the data suggested that HER2-positive, hormone receptor-negative women would also have better outcomes with dual HER2-blockage. Researchers expect a more definitive answer with regard to how Tykerb and Herceptin impact disease-free survival and overall survival in the 8,300-patient ALTTO study. This trial will investigate in the adjuvant setting Tykerb and Herceptin, given as single agents, in succession, and concomitantly.

In the NeoALTTO trial, irrespective of treatment, patients who achieved a pathologic complete response had significantly better event-free survival and overall survival compared to those who didn't have a pathologic complete response. However, the fact that hormone receptor-negative patients seemed to derive the most benefit from dual HER2-blockade suggested to Piccart-Gebhart that in this subset of patients, new targeted agents may be more efficiently brought to market by studying them in the neo-adjuvant setting using complete pathologic response as a surrogate endpoint for survival.

"Adjuvant trials tend to take forever. [They are] very time and money consuming, requiring thousands of patients," she noted. Piccart-Gebhart suggested possibly using pathologic complete response as a surrogate endpoint particularly in studies involving HER2-positive, hormone receptor-negative women, noting that this is a more homogenous population than the hormone receptor-positive subset. "Events tend to appear at the beginning of the disease for the hormone receptor-positive patients … and then endocrine therapy comes into the picture after surgery," she explained.

The US Food and Drug Administration in September approved the first neoadjuvant treatment for breast cancer, Roche/Genentech's HER2-targeted agent Perjeta (pertuzumab). Ahead of that approval, the agency issued a draft guidance last year advising drug developers on how to use pathologic complete response – when patients have no signs of invasive cancer in their breast and lymph nodes at surgery – as an endpoint to garner accelerated approval for a neoadjuvant treatment for high-risk, early-stage breast cancer. Roche gained accelerated approval for Perjeta using a study with pathologic complete response as an endpoint.

Piccart-Gebhart noted that the rationale for using pathologic complete response as an endpoint in neoadjuvant breast cancer treatment trials will be bolstered if the ALTTO study shows that dual HER2 blockade improves disease-free survival.

Still, based on the NeoALTTO trial, MD Anderson's Litton said that pathologic complete response "continues to be a very valid surrogate endpoint," in HER2 breast cancer and provides a path for "how you can develop new drugs and get them to patients quicker with a smaller number of patients and less cost."

Importance of PIK3CA

At SABCS, Gordon Mills, chairman of the department of systems biology at MD Anderson Cancer Center, noted during a presentation that the PI3 kinase may be "the most important target [in breast cancer], if we can figure out how to go after it.

"There are more mutations in this pathway and more molecules that activate cellular events and are targets to therapy than all other targets available," said Mills, who at the meeting was awarded the Brinker Award for Scientific Distinction in Basic Science. He noted that there is a volume of data suggesting that mutations in the PI3 kinase confer a much worse outcome for breast cancer patients treated with Herceptin.

In this light, in the GeparSixto (G6) trial, Loibll and her team assessed whether the presence of PIK3CA mutations impacted HER2-positive and triple-negative breast cancer patients' ability to have a pathologic complete response following neoadjuvant treatment. All patients received doxorubicin and paclitaxel, and were randomized to receive carboplatin or no additional chemotherapy. HER2-positive breast cancer patients also received Herceptin and Tykerb, while triple-negative patients received Avastin.

Researchers prospectively determined PIK3CA mutations in 512 patients, of which 240 had HER2-positive tumors and 272 had triple-negative breast cancer. Of these, 19 percent of HER2-positive and close to 8 percent of triple-negative patients had at least one PIK3CA mutation. HER2-positive, hormone receptor-positive patients had more PIK3CA mutations than the hormone receptor-negative subset (22 percent vs. 15 percent).

Significantly more women who had normal PIK3CA genes in the study had a pathologic complete response than those with PIK3CA mutations, 44 percent vs. 23 percent. But when looking at this effect by HER2-positive and triple-negative subgroups, only the HER2-positive breast cancer patients had a statistically significant result.

When researchers considered pathologic complete responses in HER2-positive patients by hormone receptor-positive status, those with PIK3CA mutations fared much worse (6 percent) than the wild-type cohort (30 percent). In the hormone receptor-negative subgroup, however, there was no meaningful difference between those with PIK3CA mutations and those with a normal form of the gene.

Patients with PIK3CA mutations "have a significantly lower" pathologic complete response rate, "especially low in those with hormone receptor-positive status," Loibll said at the meeting. "I think we need new treatment options for those patients and one of those might be a PIK3CA targeting agent."

She suggested as a possibility Novartis' PI3K inhibitor BKM120 (buparlisib), which in the NeoPHOEBE trial is being evaluated in combination with Herceptin and paclitaxel in HER2-positive primary breast cancer in the neoadjuvant setting.

Immune profiles and Herceptin

One major research focus this year at SABCS was the relationship between tumor infiltrating lymphocytes (TILs) – white blood cells of the immune system that have migrated from the bloodstream into the tumor – and Herceptin response. A key study presented at the conference by Loi and colleagues evaluated tumor samples from 156 patients with HER2-positive breast cancer, who received Herceptin plus chemotherapy before surgery, making them more likely to experience a complete pathologic response.

In these samples, researchers found that every time there was a 10 percent increase in the levels of TILs the number of patients who experienced a pathologic complete response also went up by 16 percent. This suggested to researchers that a breast cancer patient's immune system affects her ability to respond to Herceptin.

To delve deeper into the underlying mechanisms at play, Loi and colleagues analyzed samples from an earlier study, called FinHER, which compared Herceptin plus chemotherapy against just chemotherapy in HER2-positive primary breast cancers in the adjuvant setting. This revealed that patients who experienced a higher benefit from Herceptin had high expression of immunosuppressive genes, particularly CTLA-4 and PD-1. Those with low expression of these genes had less benefit from the drug.

"This needs further validation," Loi said, adding, "I'm not advocating you go out and measure lymphocytic infiltration." She noted, however, that this data suggests that somehow Herceptin is modulating the immune microenvironment and as such the drug may be even helping patients develop an anti-tumor immunity. The investigators hypothesized that an anti-PD1 agent in combination with Herceptin may boost the benefit to HER2-positive breast cancer patients.

Breast cancers tumors aren't typically associated with immune-related factors in the way melanoma or kidney cancer are. However, there is much interest among experts to try to untangle the complex interaction between certain breast tumors and immune cells. Loi and her team don't know why some breast tumors have TILs at diagnosis and others don't, but they're looking into it.

Other than the study by Loi and colleagues, there were a number of other trials at the meeting looking at the prognostic and predictive value of TILs in various cancer types, including triple-negative breast cancer and HER2-positive disease. Edith Perez, deputy director at large at the Mayo Clinic Cancer Center and a pioneer in HER2-targeted drug development, described early findings from unpublished research in which her research team used whole-genome sequencing to identify 87 genes that "appear to be in the category of immune enrichment, [and] which appear to correlate with patient outcomes to chemotherapy or to chemotherapy in combination with [Herceptin] in the adjuvant setting."

In this study, patients who were treated with Herceptin plus chemo and who had an immune enrichment profile had better outcomes than those who received Herceptin plus chemo or just chemo and didn't have the immune enrichment genomic profile. Perez, who at the SABCS received the Brinker Award for Scientific Distinction in Clinical Research for her contributions to the field of breast cancer treatment, said her research team will try to replicate this finding in another cohort.

Herceptin plus Avastin

In the 3,500-patient BETH trial, Slamon and colleagues aimed to look at whether adding Avastin to Herceptin plus chemotherapy in the adjuvant setting improved disease-free survival in HER2-positive breast cancer patients compared to the standard of care. In Cohort 1, more than 3,200 patients were randomized to receive either Taxotere/Carboplatin/Herceptin (TCH) or TCH with Avastin. Cohort 2 involved more than 270 patients randomized by physicians to either the anthracycline epirubicin plus Herceptin or epirubicin/Herceptin with Avastin.

At median follow up of 38 months, disease-free survival was 92 percent in both arms of Cohort 1. Meanwhile, in Cohort 2, disease-free survival was 92 percent in the Avastin plus Hercpetin/epirubicin arm compared to 89 percent in the Herceptin/epirubicin arm.

While the primary finding of BETH is that Avastin doesn't increase treatment benefit in HER2-positive breast cancer patients when added to Herceptin and chemo, Slamon believes that the study also signals that healthcare providers can forgo anthracycline-based therapy for this patient group. Anthracyclines, such as doxorubicin and epirubicin, have shown to improve outcomes in patients with certain molecular subtypes of HER2 positive disease, but they also can cause congestive heart failure and leukemia in patients.

However, given the findings from BETH, "it really is not necessary to include an anthracycline as part of the treatment regimen to obtain really ideal results for patients with HER2-positive breast cancer, even if they have a large tumor or have node-positive disease," Slamon said in a statement.

According to Litton, BETH definitively answered the question in the HER2-positive setting that Avastin "adds significant toxicity and really no benefit." The efficacy of anti-angiogenic drugs has been a controversial topic in oncology for some time. The FDA revoked the accelerated approval for Avastin in 2011 after a review of available data failed to convince the agency that the drug was safe and effective as a treatment for metastatic, HER2-negative breast cancer. Genentech tried to sway the FDA to keep the drug on the market for breast cancer patients who were responding while the firm conducted a biomarker-driven clinical trial to identify so called "super-responders." But the agency didn't budge.

Slamon noted that in studies anti-angiogenic drugs have repeatedly failed to extend breast cancer patients' lives. "So all these anti-angiogenic strategies, they've not really impacted survival in breast cancer," he said. "There still may be something there. We were never really able to find the right markers. … Unless there is a new strategy with a defined subgroup, I think this is not going anywhere."

However, Litton said she falls on the opposite side of the anthracycline debate from Slamon. "I do use TCH in several instances for patients," Litton said. "But I don't think we should throw away anthracyclines."

She asserted that the BETH trial was not designed to assess whether healthcare providers should rule out anthracyclines for HER2-positive breast cancer patients. She further noted that there may be selection bias in the study between TCH versus anthracyclines in early-stage breast cancer patients.

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