by Dario Trapani, Giuseppe Curigliano
The Breast:
Published: December 13, 2021
Triple-negative breast cancer (TNBC) is the most aggressive
subtype of breast tumors, associated with dismal prognosis. Innovative
treatments have expanded the therapeutic options for selected patients with
advanced disease (mTNBC). Inter alia, the new class of molecules of
antibody-drug conjugates (ADCs) has rapidly positioned in the setting of mTNBC,
providing significant benefits in pretreated patients. With the advent of ADCs,
progresses have been marked in targeting TNBC. Tackling this ‘un-targetable’
tumor type has been the real enterprise of the last years, overcoming the
original sin of classification of TNBC in a default ‘non-positive’ category,
ultimately grouping together a spectrum of heterogeneous diseases. As such,
ADCs have opened an ‘identity crisis’ for TNBC treatments. These molecules are
composed of a backbone of monoclonal antibody (MAb), exploiting the best role
they are engineered for: recognize antigens. But ADCs are linked to cytotoxic
payloads, resulting in tailored delivery of highly active agents, with the
intent to spare non-targeted tissues. At the end, they interpret essentially a
new pharmacological delivery model to treat tumors
The implementation of ADCs has first modernized the view on
MAb clinical utilization: not really only to switch-off hyperactive tumorigenic
signaling; ADCs can exert anti-neoplastic activities in disregard of the
biologic functions of their pharmacological receptors: antigens are linked,
payloads are released, cancer cells are killed via internalized chemotherapies.
Such a change in perspective implies that: (i) ADCs can exploit activity across
multiple tumor types – delivering agnostically, based on antigen
expressions; (ii) ADCs offer an attractive perspective for treatment personalization,
based on the multiple targetable antigens that can be identified in a single
patient - a possible declination of the theranostic paradigm. Agnosticity and theranosticity,
however, will be reached only with an optimal trade-off between antibody specificity
– to avoid off-target effects and non-specific activity related to the release
of the payload in the bloodstream – and patient tolerance of the cumulative
toxicities. Pursuing precision in this context will require understanding
better how these new ADCs tailor the targets; perhaps, most importantly, there
must be better knowledge on what is the minimal amount of membrane antigen to
be expressed, to determine ADCs efficacy, and if traditional techniques like
immuno-histochemistry are sensitive enough for this purpose.
