January 2023

This Phase 3 trail among HIV patients found to have anal high-grade squamous intraepithelial lesions on a screening high resolution ansoscopy found that the risk of progression to anal squamous cell carcinoma was lower with treatment for the precursor lesion than with active monitoring alone.

Summary: 
Similar to cervical cancer, anal squamous cell cancer (SCC) is caused by the human papilloma virus, and development of anal cancer is preceded by development of a precancerous lesion known as high-grade squamous intraepithelial lesions (HSIL). The risk for development of anal cancer varies by patient population, but the highest risk groups are those of immunocompromised patients, specifically those with HIV. Although formal screening practices and recommendations for treatment of HSIL exist for cervical cancer, similar guidelines for anal cancer are based on expert-opinion, and evidence-based guidelines for the management of anal HSIL are lacking. While some studies have supported screening and treatment of HSIL in HIV positive populations to prevent progression to cancer, others have found no clinically significant difference with treatment as compared to active surveillance of HSIL, and the data remain controversial. The purpose of the Anal Cancer–HSIL Outcomes Research (ANCHOR) trial was to determine whether treating anal HSIL is effective and safe in reducing progression to anal cancer among persons living with HIV as compared with active monitoring of HSIL without treatment.

The study consisted of HIV-positive patients 35 years or older with a pathologic diagnosis of HSIL. Patients were randomized into two groups: a treatment group or active surveillance group. The treatment group underwent immediate high-resolution anoscopy (HRA) and treatment of their HSIL. They then underwent surveillance with HRA every 6 months, with biopsy and treatment of any additional lesions found during surveillance. Treatment methods were chosen at the discretion of the provider. The active surveillance group underwent HRA every 6 months after randomization. Visible lesions were biopsied annually to confirm ongoing HSIL and the absence of cancer. The primary outcome was progression to anal cancer using a time-to-event analysis. A total of 2,227 patients and 2,219 patients were enrolled in the treatment and active surveillance group, respectively. The two populations were well balanced, including controlling for baseline CD4 counts and HSIL lesion size. Electrocautery ablation was employed for the vast majority of patients in the treatment group. A total of 9 participants in the treatment group received a diagnosis of invasive anal cancer, as did 21 participants in the active-monitoring group. The cumulative incidence of progression to anal cancer at 48 months was 0.9% in the treatment group and 1.8% in the active-monitoring groups, amounting to a relative risk reduction for progression to anal cancer of 57% (95% CI, 6 to 80; P=0.03 by log-rank test) with treatment.

While it is known that HSIL is a precursor lesion for development of anal SCC, the fundamental question of whether treating HSIL actually prevents progression to anal SCC has remained unanswered. The ANCHOR trial is an important study that helps answer this question, demonstrating that in HIV-positive patients, treatment of HSIL does prevent progression. However, a few points should be considered when interpreting the results of this trial. First, it’s important to note that the anal SCC in general is rare, and although the incidence is higher in the HIV population, it remains uncommon, as evidenced by the very low rate of development of cancer in either group. Although the relative risk of progression to cancer was reduced by >50% with treatment, the absolute risk for cancer development decreased from 1.8% to 0.9%, so even without treatment, the risk of development of anal SCC in even the highest risk populations remains low. Second, all patients in the trial underwent HRA, a procedure that is not practiced by even all colon & rectal surgeons, let alone by any other surgeons or medical practitioners. Use of such a specific method practiced by a select few raises the question of how to translate this study into clinical practice. Third, the two groups were on the opposite ends of the spectrum in regard to management: either aggressively treat any HSIL lesion identified, or don’t treat any at all, and just biopsy and watch. In reality, most surgeons probably lie somewhere in the middle, removing any visible condyloma lesions they see either with or without HRA, and if these turn out to be HSIL, then they’ve removed the lesion. Finally, the question of how to implement screening practices remains unanswered. Who should be screened, what screening practices should be employed, and how often patients should undergo screening evaluation, all are still unknown. 

Synopsis: This multicenter, phase 2 prospective trial was the first of its kind to show that in well-selected patients with a complete pathologic response to neoadjuvant systemic therapy for HER-2 positive or triple-negative breast cancer, breast surgery can be safely eliminated.

Summary: 
Patients with HER-2 positive or triple-negative breast cancer who undergo neoadjuvant systemic therapy (NST) have been shown to have a pathological complete response (PCR) rate as high as 60-80%, calling into question the need for subsequent breast and nodal surgery. This prospective, non-randomized trial enrolled 50 total women with clinical T1 or T2, N0 or N1 breast cancer (triple-negative or HER-2 positive), all of whom had first undergone standard NST. Exclusion criteria included distant disease, history of previous cancer in the ipsilateral breast, evidence of disease progression on NST, and post-NST imaging showing a residual suspicious area of more than 2 cm. Among the 50 patients, 29 had HER-2 positive tumors and 21 had triple-negative disease. Upon enrollment, patients underwent image-guided biopsy of the tumor bed with a minimum of 12 core biopsy samples obtained from each patient.

After NST, 31 of 50 patients had a PCR and did not undergo subsequent breast surgery. The remaining 19 had residual disease on biopsy and underwent standard breast and nodal surgery. All 50 patients underwent external beam whole breast radiation. Nine of the 50 patients had biopsy-proven nodal disease at the time of enrollment and underwent targeted axillary dissection after NST. Of these patients, 1 did not show a PCR on breast biopsy and therefore underwent standard breast and nodal surgery. The remaining 8 had both a breast PCR and complete nodal response on targeted axillary dissection, and therefore did not undergo additional surgical resection. Of note, although 31 total patients had a PCR on core needle biopsy, only 17 total patients had a complete radiologic response (of whom 3 did not have a PCR). No difference in rate of PCR was seen between triple-negative and HER-2 positive patients.

This paper reported a primary endpoint of tumor recurrence in patients who did not undergo breast surgery at 2 years follow-up, with 5 total years of follow-up planned.  Follow-up consisted of semi-annual history, physical examination, and mammography, with additional imaging and biopsy of suspicious findings completed as appropriate. Of the 31 patients who had a PCR after NST and did not undergo subsequent breast surgery, there were no breast cancer recurrences or deaths. Nine of these 31 patients did require biopsy on follow-up for radiographic changes, but in each instance the biopsy results were benign and concordant with imaging findings.

In the discussion, the authors note that while follow-up time is so far limited, patients with triple-negative or HER-2 positive tumors who do recur are likely to do so early. Still, radiotherapy, which was universally applied, may have only delayed future ipisilateral breast tumor recurrence. Protocols surrounding the timing of surveillance and indications for biopsy for patients in whom surgery is omitted after NST have yet to be developed.  The study also highlights the fact that even modern breast imaging techniques cannot reliability predict PCR, and any future trials of breast surgery omission will necessarily rely upon tissue sampling. Furthermore, vacuum assisted core needle biopsy, while low risk, may not be truly preferable to all patients compared to partial mastectomy. Still, this study suggests that for carefully selected patients, omitting surgery in the management of their breast cancer may be safe and feasible. This may represent the beginning of a major paradigm shift in the treatment of this highly prevalent disease. 

Synopsis: BMP signaling is altered in mice and humans with cancer-induced cachexia and pharmacologically restoring this pathway in mice prevents muscle wasting – providing a potential target for improving outcomes associated with cachexia in cancer, critical illness, and beyond. 

Summary:
Cachexia worsens morbidity and mortality across disciplines from critical illness to cancer. Defined as loss of skeletal mass despite adequate nutritional support, this clinical entity is particularly devastating in malignancy, reducing efficacy of treatment and hastening death in advanced cancer. The mechanisms driving cachexia are ill-defined and there are currently no effective treatment options. Preclinical animal work has found that preventing atrophy and restoring muscle mass has been associated with improved survival in animal models of cachexia, driving interest in developing ways to prevent and treat cachexia in cancer.

This paper examined the role of bone morphogenetic protein (BMP) in cachexia. The BMP pathway had been known to control the transcriptional regulation of protein breakdown and maintenance of the neuromuscular junction maintenance in fasting and denervation. The authors explored this pathway in various mouse models of cachexia including those with CD26+ tumors, gonadal tumors, and colon cancer. The authors fastidiously explored various facets of the BMP signaling pathway in muscle wasting and neuromuscular junction plasticity and found that not only was the BMP signaling pathway downregulated in mice with cancer-induced muscle atrophy and muscle denervation but restoring the BMP signaling pathway attenuated muscle-wasting. They then tested the pharmacological applicability of this pathway by using Tilorone, a compound known to activate BMP signaling in mouse models of pulmonary fibrosis. The authors found that tilorone administration again attenuated muscle wasting and prolonged survival in tumor mice without causing an increase in tumor size – suggesting a potential future paradigm for treating cachexia in cancer and other illnesses.

Most notably, the authors explored the clinical significance of their findings in patients with and without cancer-induced cachexia. Groups included healthy patients without cancer undergoing elective abdominal surgery, patients with cancer but not yet cachexia, and patients with cancer-induced cachexia. Gene expression analysis in muscle biopsies from these patients exhibited similar impairment from BMP signaling and neuromuscular junction remodeling in patients with cachexia as those exhibited in the preclinical animal models of cachexia. Future work will focus on combining these findings with those in the preclinical models to develop new targets to treat cachexia and improve outcomes in humans.