“We now have very specific guidance that takes into account primarily a joint review of immunohistochemistry and in situ hybridization,” says Dr. Wolff, which “will help pathologists best resolve those difficult cases.”
It comes at a compelling juncture. He and his clinical colleagues are starting to see that “in the treatment of HER2-positive disease, outcomes are improving in a major way.”
Dramatic evidence of this appears in the APT study (Tolaney SM, et al. N Engl J Med. 2015; 372:134–141), which looked at treatment for patients with anatomic low-stage, HER2-positive disease, a group that had been ineligible for the pivotal trials of adjuvant trastuzumab. Patients received weekly paclitaxel and trastuzumab treatments for 12 weeks, followed by nine months of trastuzumab monotherapy. (Endocrine therapy was added in ER-positive cases.) The strategy of deescalating chemotherapy plus trastuzumab from two to three cytotoxic drugs to just one worked, Dr. Wolff says. The study has since been updated—seven-year data is available but not yet published, he says. “The survival in that initial paper [median follow-up: four years] was excellent, and we are now able to offer the potential of excellent survival outcome to patients treated with HER2-targeted therapies while avoiding excessive chemotherapy toxicity,” says Dr. Wolff, a coauthor of the study.
But for deescalation to work, “we need to be cautious,” he says. “We need to have as much certainty about the accuracy of the HER2 testing as possible.” If a candidate patient actually has triple-negative disease, rather than HER2-positive/estrogen-receptor-negative disease, chemotherapy regimens with two or three cytotoxic drugs would be the recommended adjuvant regimen, without any anti-HER2 targeting drugs like trastuzumab.
It’s possible, says Dr. Wolff, looking even further ahead, that deescalation might benefit patients with higher anatomic stage cancer. Patients who have meaningful response to perioperative therapy, who at the time of surgery have evidence of a pathologic complete response, might benefit from an approach similar to that used in the APT study. “In the next generation of HER2-target trials, we plan to integrate pathologic response to neoadjuvant therapy as a functional prognostic biomarker of outcome along with HER2 testing as a predictive biomarker of response to targeted therapy, and design studies that better enrich patients for therapy deescalation or escalation strategies, and ultimately be able to offer just the right treatment for the right patient.”
“So we really need to make the diagnosis as accurate as possible,” Dr. Wolff reiterates. He sends an approbative look toward the laboratory. “I think we are there.”Overall, IHC maintains its pole position as an excellent test for initial screens, assuming the test is well validated, says Dr. Allison.
That’s not an assumption the guidelines have ever taken lightly, the authors say. And as Dr. Allison notes, “All our same rules apply for test validation and proficiency testing, including fixation and preanalytical variable controls. Those haven’t changed. All those recommendations from the 2013 update still stand.”
With the new guideline, “We actually bring IHC testing into more prominence now that the quality control has gone up. Protein expression is a very important aspect of testing,” she says. “It’s really the phenotype you’re treating, which has a very tight association with HER2 gene amplification.”
While in situ hybridization testing is used by some laboratories as an initial test, most use it as a second-line test when IHC results are equivocal, says Dr. Allison. “And more and more labs are also doing dual testing—IHC and FISH testing on all cases.
“But that’s not a requirement in any way,” she continues. “Most labs can still follow the algorithm of IHC first.” If the result is equivocal (IHC 2+), subsequent ISH testing should follow. Results will unfold in several directions.
One possibility: getting clearly amplified cases (group-one results) that have elevated HER2 signals per cell (≥4.0), and a HER2/chromosome enumeration probe 17 ratio greater than or equal to 2.0. These are obvious ISH positives that correlate well with higher levels of protein expression by IHC (2–3+). In addition, cases with <4.0 HER2 signals per cell and ratios <2.0 are also obvious negatives (group-five results), and these correlate well with the absence of protein overexpression.
And then there are three groups that make up the gray zone. The 2013 guideline acknowledged their existence and proposed result categories for them, but also acknowledged the very limited to nonexistent evidence of their frequencies and clinical-pathologic features and behavior and leaving group-four results in the “no man’s land,” Dr. Allison says, of an equivocal or unresolved result.