Think about a collection of switches on a wall.
When a affected person is recognized with most cancers, physicians typically determine which remedy to provide primarily based on the tumor’s distinctive profile of which switches are “on” and which switches are “off.” Breast most cancers is probably the best-known instance of this decision-making; as one of many first tumor sorts to be subclassified primarily based on the presence or absence of molecular markers, the positions of those switches have guided remedy for many years.
If a affected person’s tumor expresses hormone receptors, such because the estrogen and/or progesterone receptor, they could be eligible for endocrine remedy—remedies that block the exercise of the estrogen receptor or the manufacturing of estrogen within the physique. If a affected person’s tumor has overexpression of the expansion issue receptor HER2, they could be eligible for medicine that stop HER2 activation. If neither the hormone receptor swap nor the HER2 swap is “on,” sufferers typically obtain chemotherapy.
However what if HER2 isn’t a swap—what if it’s a dimmer?
Whereas researchers know that HER2 expression varies on a steady scale from very low to very excessive, remedies concentrating on HER2 have traditionally solely labored in sufferers with the best ranges of expression; everybody else has been ineligible whether or not their tumors have low ranges of HER2 or none in any respect. This paradigm shifted in August 2022, when trastuzumab deruxtecan (Enhertu, T-DXd) turned the primary remedy permitted to deal with breast tumors with HER2 expression higher than zero however lower than the brink of eligibility for different medicine.
The brand new approval has left researchers with a number of questions: Do HER2-low tumors characterize a brand new subtype of breast most cancers? How ought to physicians measure HER2 in these tumors to find out who will profit most from T-DXd?
On the 2022 San Antonio Breast Most cancers Symposium, held in a hybrid format December 6-10, researchers mentioned the nuances underlying these questions. Within the particular session “HER2-low: A Separate Entity?” specialists debated whether or not HER2-low must be thought of a biomarker, a separate subtype, or one thing else completely.
HER2 Detection and Remedy
HER2 standing is routinely assessed in breast most cancers utilizing immunohistochemistry (IHC), which stains HER2 molecules in human tissue. Pathologists then rating the pattern based on staining energy—IHC-0 if the tissue has no seen HER2 expression, and 1+, 2+, or 3+ as HER2 expression will increase.
Prior to now, most sufferers have been eligible for HER2-targeted remedy provided that their tumors had a HER2 staining rating of IHC-2+ with confirmed genetic amplification or IHC-3+. Such sufferers traditionally obtained monoclonal antibodies concentrating on HER2, equivalent to trastuzumab (Herceptin) and pertuzumab (Perjeta).
Sadly, some tumors don’t reply to those therapies, or they develop resistance, necessitating new remedy choices. A brand new class of medication referred to as antibody-drug conjugates (ADCs)—two-part molecules consisting of an antibody linked to a toxin—supplied some hope. The antibody portion of those molecules acknowledges a protein on the floor of most cancers cells—on this case, HER2. When the ADC binds to HER2, it’s internalized into the cell, the place it releases its poisonous payload.
Two HER2-targeting ADCs—T-DXd and trastuzumab emtansine (Kadcyla, T-DM1) have been permitted to deal with tumors with excessive expression of HER2. Nonetheless, as a result of even low HER2 expression is enough to draw ADCs to the most cancers cells, researchers puzzled whether or not T-DXd may successfully deal with tumors with out HER2 overexpression.
Moreover, research have proven that after a most cancers cell dies following publicity to T-DXd, it releases its poisonous payload into the tumor microenvironment, the place it will possibly kill most cancers cells that don’t categorical HER2—a phenomenon generally known as the bystander impact.
Within the DESTINY-Breast04 scientific trial, sufferers with HER2-low illness randomly assigned to obtain T-DXd had a considerably longer median total survival and median progression-free survival than sufferers handled with a doctor’s selection of remedy—typically endocrine remedy for sufferers with hormone receptor-positive illness and chemotherapy for sufferers with hormone receptor-negative illness. These outcomes led to the U.S. Meals and Drug Administration (FDA) approval of T-DXd for the remedy of sufferers with HER2-low breast most cancers.
An Impartial Subtype?
With a singular remedy possibility accessible, researchers started trying extra intently on the molecular and scientific traits of tumors with IHC-1+ and IHC-2+ staining. Do these traits distinguish HER2-low breast most cancers sufficient from different subtypes to think about it a separate entity?
Giuseppe Curigliano, MD, PhD, an affiliate professor of medical oncology on the College of Milano and the pinnacle of the division of Early Drug Growth on the European Institute of Oncology in Italy, argued in favor of a reclassification.
Curigliano defined that HER2-low breast most cancers wants to meet three standards to represent an unbiased entity: a prognosis distinct from different subtypes, a singular remedy plan, and defining organic traits with correct assays to determine them.
When it comes to a definite prognosis, researchers have observed that HER2-low tumors are much less ceaselessly grade 3 and generally have a decrease proliferation index than triple-negative tumors. Different research have instructed that sufferers with HER2-low breast most cancers have an extended disease-free survival and decrease threat of recurrence than sufferers with HER2-negative or HER2-high tumors.
As for a singular remedy plan, Curigliano summarized this level in a single sentence: “We’ve got a drug permitted for the remedy of the illness.”
Curigliano elaborated by explaining that T-DXd could serve sufferers with HER2-low tumors higher than remedies they’d have in any other case obtained. In a retrospective research introduced as a poster throughout the assembly, during which the outcomes of sufferers with hormone receptor (HR)-positive breast most cancers have been evaluated by HER2 standing, these with HR-positive, HER2-low tumors skilled fewer pathological full responses, a shorter median total survival, and a shorter median progression-free survival than these with HR-positive, HER2-negative tumors when handled with endocrine remedy plus a CDK4/6 inhibitor.
These findings complement the DESTINY-Breast04 trial, which positioned T-DXd as superior to endocrine remedy and chemotherapy for sufferers with HER2-low illness.
Along with HER2 expression, a brand new subtype of breast most cancers would require a definite set of organic traits. Curigliano supplied a number of examples of genetic and transcriptomic variations between HER2-low and HER2-negative tumors, together with variations in driver mutation prevalence (particularly TP53 and PIK3CA), signaling pathway activation (equivalent to androgen receptor signaling and fatty acid metabolism), and total gene expression profiles.
Curigliano argued that extra sturdy assays to distinguish HER2-low from HER2-negative illness are additionally essential. In a research introduced at SABCS 2021, 30 p.c of sufferers with IHC-0 breast tumors responded to T-DXd. To evaluate whether or not these responses could also be pushed by tumors with “ultralow” HER2-expression—expression that’s undetectable by IHC however doubtlessly detected by sequencing or mass spectrometry—researchers are together with sufferers with HER2-ultralow tumors within the ongoing DESTINY-Breast06 trial.
“We’ve got an obligation for our sufferers to make these useful, clinically annotated specimens accessible for secondary research with assays which might be analytically and clinically validated and that would assist us higher outline which sufferers are almost definitely to learn from these thrilling new therapies,” Curigliano mentioned.
A Biomarker of T-DXd Efficacy?
Sara Tolaney, MD, MPH, chief of the Division of Breast Oncology and affiliate director of the Susan F. Smith Heart for Girls’s Cancers at Dana-Farber Most cancers Heart and an affiliate professor of medication at Harvard Medical Faculty, argued that HER2-low breast most cancers falls wanting a brand new subtype.
MD, MPH
Tolaney largely agreed with the subtype standards outlined by Curigliano, however with one caveat: Distinct most cancers subtypes will need to have distinct molecular drivers. Tolaney careworn that HER2-low tumors should not pushed by HER2, as evidenced by the truth that different HER2-targeted therapies don’t enhance the survival of sufferers with HER2-low illness. The efficacy of T-DXd is subsequently extra seemingly dependent upon the cytotoxic payload than the blockade of HER2 exercise.
“This implies that HER2-low just isn’t a brand new subtype characterised by an oncogenic driver however is somewhat a biomarker for the good thing about antibody-drug conjugates that potently goal HER2,” Tolaney mentioned.
In keeping with Tolaney, the distinct prognosis and lots of the distinctive biomarkers of HER2-low breast most cancers additionally seemingly outcome from different oncogenic drivers, particularly the estrogen receptor (ER); as ER expression will increase, the probability of HER2-low tumors additionally will increase, suggesting a hyperlink between the 2 components. Additional, when researchers regulate for HR standing, variations in survival charges between sufferers with HER2-low and HER2-negative tumors typically disappear.
The prevalence of HR-positivity can also clarify some organic options of HER2-low illness, equivalent to earlier stage at prognosis and decrease proliferation index, each of that are additionally widespread amongst ER-positive tumors. In a single research of breast most cancers transcriptomes, Tolaney additional confirmed that samples clustered based totally on HR expression, and that HER2-low and HER2-negative samples with the identical HR standing have been just about indistinguishable.
Tolaney additionally argued that HER2 expression itself just isn’t constant sufficient to outline an unbiased entity of breast most cancers. Utilizing information from a number of research, she demonstrated that HER2 expression can fluctuate extensively amongst totally different areas of a tumor, totally different metastatic websites, and/or totally different time factors throughout a affected person’s remedy.
“In actual life, we want to consider the affected person who sits earlier than us, who has a number of totally different tissue biopsies with totally different outcomes,” Tolaney mentioned. “Which one will we use to decide about choice for trastuzumab deruxtecan?”
Sensible Concerns
Whether or not HER2-low breast most cancers represents an unbiased subtype or not, the survival profit imparted by T-DXd makes correct HER2 detection and evaluation an pressing precedence. The session organizers introduced in David Rimm, MD, PhD, director of the Yale Most cancers Heart Tissue Microarray Facility and Yale Pathology Tissue Companies, and a professor of pathology and medication at Yale Faculty of Drugs, to offer some context round how researchers are working towards higher assays.
Rimm defined that the present exams are designed to determine samples with the best ranges of HER2 expression. The staining depth is calibrated such that the distinction between IHC–3+ and IHC-2+ is evident, however that may trigger ambiguity within the IHC-0 to IHC-1+ vary.
Pathologists additionally should not as adept at differentiating IHC-0 from IHC-1. In a single research, a gaggle of 18 pathologists agreed on whether or not a set of 170 samples was IHC-3+ or not IHC-3+ 89 p.c of the time, however they solely agreed on whether or not the identical samples have been IHC-0 or not IHC-0 59 p.c of the time. Rimm careworn that pathologists should regulate to the significance of differentiating zero from nonzero scores.
Rimm instructed that one other resolution could contain redesigning the assay to make it extra quantitative—measuring the exact focus of HER2 protein—and extra delicate to variations amongst decrease HER2 expression ranges. In such an assay, researchers might use HER2-expressing cell traces (during which the focus of HER2 protein is well decided) to create a regular curve that computationally correlates IHC staining depth with an empirical HER2 focus.
This, Rimm mentioned, would permit researchers to know precisely what vary of HER2 expression signifies a probable response to T-DXd. “I might argue that the majority oncologists wouldn’t settle for an ordinal worth for sodium or magnesium or potassium or glucose,” Rimm mentioned. “Neither do you have to settle for an ordinal worth for HER2.”
The session additionally featured Patricia Spears, a affected person advocate and analysis supervisor of the Affected person Advocates for Analysis Council on the College of North Carolina Lineberger Complete Most cancers Heart, who knowledgeable the dialogue from a affected person perspective. Spears agreed with Rimm that precision is essential when figuring out eligibility for T-DXd, as a result of getting it mistaken might have important penalties.
On one hand, Spears defined, T-DXd gives a brand new remedy for some sufferers beforehand categorized as triple-negative, for whom therapeutic choices are restricted. Turning into eligible for T-DXd might change the course of those sufferers’ remedy; nonetheless, ADCs additionally pose unwanted effects that warrant warning when it comes to overprescribing. Spears warned in opposition to giving T-DXd to sufferers unlikely to learn from it, particularly to sufferers with nonaggressive or early-stage illness.
“It’s actually essential to get this proper,” Spears mentioned. “We depend on the pathologists for our remedies 110 p.c, and we belief that their info is correct. No matter check comes out for this, I actually need it to be equitable and accessible to everybody.”
