Fertility and Toxicity Considerations Factor into TNBC Management

Nerea Lopetegui-Lia, MD

As the efficacy of triple-negative breast cancer (TNBC) treatments improves, increased attention must be paid to aspects of therapy that influence patients’ quality of life, including family planning and treatment-related toxicities, according to Nerea Lopetegui-Lia, MD.

In an interview with OncLive®, Lopetegui-Lia, a breast medical oncologist and assistant professor at The Ohio State University Comprehensive Cancer Center—James in Columbus, discussed common pretreatment fertility preservation options for patients with TNBC; considerations for managing treatment-related toxicities; and what the future may hold regarding ways to address disease recurrence, treatment resistance, and novel therapy sequencing.

She highlighted the developing role of antibody-drug conjugates (ADCs) in metastatic TNBC management in another article.

OncLive: What fertility preservation options are available for younger patients diagnosed with TNBC?

Lopetegui-Lia: TNBC affects younger women. There are some special considerations we should keep in mind when treating younger patients with any type of breast cancer, one of them being family planning and fertility preservation. Many treatments—not only chemotherapy, but sometimes radiation therapy and surgery—can affect fertility, leading to infertility or premature menopause; some of these [treatments] have long-term morbidities. Addressing fertility in young patients as early as possible is critical, ideally before we initiate cancer-directed therapy.

For fertility preservation in men, we typically use sperm cryopreservation. It's the most effective method in post-pubertal males. There is some concern around genetic damage to sperm that's collected after initiation of therapy, so we try to put all our efforts into cryopreserving sperm prior to starting treatment. If patients are unable to provide semen samples, testicular sperm extraction is an option. Testicular tissue extraction and cryopreservation in pre-pubertal males is experimental and should only be used in the setting of clinical trials. There's no role for hormonal suppression in males, although that is the case in females.

For fertility preservation in women, oocyte cryopreservation and/or embryo cryopreservation are typically the most used techniques for fertility preservation. Those are performed via controlled ovarian stimulation and oocyte retrieval. The only established [fertility preservation] method for pre-pubertal females is ovarian tissue cryopreservation, but there are other techniques that are less commonly used, such as ovarian transposition or conservative gynecologic surgeries. There are also some emerging therapies like in vitro maturation or investigational methods that include uterine transposition. However, typically, we refer these patients to our colleagues in [the Reproductive Endocrinology and Infertility specialty].

Gonadotropin-releasing hormone [GnRH] agonist treatment should not be used in place of established fertility preservation methods, although it can be offered as an adjunct for females with breast cancer. We use it a lot during systemic cancer-directed treatment because it [results in] a modest increase in pregnancies, and it decreases the risks of ovarian insufficiency in survivors of breast cancer. Therefore, in some patients, unfortunately, if we don't have the luxury of time, and if there's an oncologic emergency requiring urgent oncologic therapy, GnRH agonists may be offered for menstrual suppression.

What adverse effects (AEs) are important to be aware of when treating patients with TNBC?

[We are] always considering toxicities and immune-related AEs [irAEs]. This remains an issue. The use of immune checkpoint inhibitors [ICIs] can lead to irAEs, which can be severe, sometimes permanent, and, in some cases, even fatal. Despite research efforts, there's no single biomarker or even a combination of biomarkers proven to be sufficiently accurate to predict irAE development in clinical practice. However, we watch for these carefully.

In the phase 3 KEYNOTE-522 trial [(NCT03036488), among patients who received] pembrolizumab [Keytruda], irAEs occurred in [35.0%] vs [13.1%] of patients in the placebo [plus] chemotherapy group.1 We typically focus a lot on grade 3 or higher irAEs, and those occurred in [13.0%] of patients in the pembrolizumab arm vs [1.5%] of those in the chemotherapy/placebo arm. The most common grade 3 irAEs in the pembrolizumab arm included severe skin reactions, hypophysitis, adrenal insufficiency, pneumonitis, and thyroiditis.

Grade 3 toxicities usually require stopping ICIs. We also typically treat patients with high-dose corticosteroids, which we usually taper over the course of 4 to 6 weeks based on clinical improvement. In patients who develop grade 4 toxicities, we permanently discontinue ICIs [except in the event of] endocrinopathy, in which case we usually just provide hormone replacement.

ADCs [are a] newer class of drugs we've been using in TNBC and in other cancer subtypes. With sacituzumab govitecan-hziy [Trodelvy], we typically think of neutropenia, including febrile neutropenia and diarrhea. However, I encourage everyone to review the phase 2 PRIMED trial [NCT05520723] data. [This trial investigated] prophylactic granulocyte colony–stimulating factor and loperamide [in patients with locally advanced or metastatic TNBC who received sacituzumab govitecan].2 Using those prophylactic [agents] led to reductions in AEs.

Fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu] is the other ADC [used in patients with TNBC]. We oftentimes think about interstitial lung disease/pneumonitis. [and] regular monitoring for this serious AE is recommended. The other major AE [associated with T-DXd] is left ventricular dysfunction, therefore close monitoring and keeping that in mind is important.

Additionally, although datopotamab deruxtecan-dlnk [Datroway] hasn't been approved in [TNBC] yet, it may be approved in the near future. Two of the main toxicities to watch out for [with this drug] are ocular toxicities and stomatitis. In those cases, we typically treat patients with supportive care using lubricant eye drops or steroid mouthwash.

What questions remain regarding the future of TNBC management?

Despite initial response rates, a significant proportion of patients with TNBC experience disease recurrence and metastases, which highlights the need for novel therapeutic strategies. Those could be combination therapies, which we’re seeing more of, as well as biomarker-guided treatment and identification of novel targets; there are a lot of research efforts being placed in those settings. Treatment resistance also remains a significant challenge in the treatment of patients with TNBC; therefore, investigating strategies to overcome this resistance is going to be key.

Another question we oftentimes get asked—especially now with all these new ADCs—is whether we can we use ADCs in sequence. There is an ongoing [study] called the phase 2 TRADE DXd trial [NCT06533826]—a prospective, randomized clinical trial—addressing sequential ADC administration with a switch in targets, which will be interesting to see the results of.

References

1. Schmid P, Cortes J, Dent R, et al. Overall survival with pembrolizumab in early-stage triple-negative breast cancer. N Engl J Med. 2024;391(21):1981-1991. doi:10.1056/NEJMoa2409932
2. Preventive stRategy for IMMU132-relatED AEs in TNBC - PRIMED (PRIMED). ClinicalTrials.gov. Updated May 6, 2024. Accessed April 25, 2025. https://www.clinicaltrials.gov/study/NCT05520723